Clin Pharmacokinet 2005; 44 (6): 571-590 0312-5963/05/0006-0571/$34.95/0

REVIEW ARTICLE

© 2005 Adis Data Information BV. All rights reserved.

Clinical Pharmacokinetics of Atomoxetine John-Michael Sauer,1 Barbara J. Ring2 and Jennifer W. Witcher2 1 2

Elan Pharmaceuticals, Inc., South San Francisco, California, USA Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 1. Overview of Pharmacological Agents Used for the Treatment of Attention-Deficit Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572 2. Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 3. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 3.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 3.2 Absorption and Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576 3.3 Distribution and Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577 3.4 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577 4. Overview of Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 4.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 4.2 In Vitro and In Vivo Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 4.3 Clinical Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 5. Pharmacokinetic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 5.1 Interactions with Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 5.2 Interactions with Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 5.3 Interactions with Desipramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 5.4 Interactions with Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 6. Implications of Pharmacokinetic Properties for Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 6.1 Dosages and Therapeutic Range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 6.2 Sex and Racial Differences in Atomoxetine Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 6.3 Influence of Age and Bodyweight on Atomoxetine Pharmacokinetics . . . . . . . . . . . . . . . . . . . . 585 6.4 Diseases and the Pharmacokinetics of Atomoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 6.4.1 Chronic Impairment of Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 6.4.2 Hepatic Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587

Abstract

Atomoxetine (Strattera®), a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation

572

Sauer et al.

and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine. The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1–2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype. Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.

1. Overview of Pharmacological Agents Used for the Treatment of Attention-Deficit Hyperactivity Disorder Attention-deficit hyperactivity disorder (ADHD) is the most common neurobehavioural disorder of childhood. The incidence of ADHD is 5–10% in children and the symptoms are known to persist into adulthood in 10–60% of cases.[1-5] Behavioural features of ADHD include inattention, hyperactivity and impulsivity, which may lead to academic underachievement, poor interpersonal relationships and low self esteem.[6] Additionally, comorbid medical conditions are often associated with ADHD, includ© 2005 Adis Data Information BV. All rights reserved.

ing oppositional defiant disorder, conduct disorder, depression, anxiety disorders and tic disorders.[7,8] The exact aetiology of ADHD is unknown, although neurotransmitter deficits, genetic traits and prenatal complications have been implicated.[9] Symptoms of ADHD respond to treatment with psychostimulants. These drugs have been demonstrated to increase the availability of extracellular dopamine by blocking dopamine transporters[10] and in some cases enhancing dopamine release.[11] Psychostimulants are the most common pharmacological intervention used in the treatment of ADHD.[12] A detrimental attribute associated with the drugs in this Clin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

class (pemoline, methylphenidate and amphetamines) is their potential for abuse.[13] These effects place the psychostimulant drugs as Schedule II or IV (pemoline), putting them under close monitoring by regulators. As these drugs were developed many years ago, contemporary clinical metabolism and drug interaction studies are lacking or have only recently received description. Markowitz and Patrick[14] provide an authoritative review on the pharmacokinetic and pharmacodynamic interactions of psychostimulants with other drugs. Among the psychostimulants, methylphenidate in a variety of formulations (Ritalin® 1, Ritalin LA®, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Concerta®, Alza Corporation, Mountain View, CA, USA) is the most widely prescribed medication for the treatment of ADHD. Methylphenidate, a dopamine transporter inhibitor, does not appear to be a substrate for transport into the neuron and it elicits little presynaptic dopamine release. Methylphenidate is a racemic mixture of threo-(R,R)-(+)- and threo-(S,S)-(–)-isomers, but some marketed forms only include a single enantiomer [threo-(R,R)-(+)-isomer]. Methylphenidate is rapidly cleared from the systemic circulation and has a half-life of 2.5 hours. Recently, several modified-release products (Concerta®, Ritalin LA®) have been introduced into the market to extend the apparent plasma half-life of methylphenidate by altering its absorption kinetics.[15,16] Dexamfetamine, the (S)-(+)-isomer of amfetamine, as well as mixed isomers (81% [–] and 19% [+]) of amfetamine salts have been demonstrated to be an effective treatment of ADHD. Amfetamine is cleared from the systemic circulation by oxidative metabolism and has a half-life of approximately 12 hours. Recently, a longer acting formulation, Adderall XR® (Shire Laboratories, Inc., Wayne, PA, USA), was introduced into the market. Adderall XR® alters the pharmacokinetics of the mixed amphetamine salts by prolonging the absorption kinetics.[17] Aromatic oxidation catalysed by cytochrome P450 (CYP) 2D6 is the primary means of systemic 1

573

clearance for the amphetamines.[18] Definitive clinical drug interaction studies with CYP2D6 inhibitors or substrates have not been reported for amfetamine. Likewise, the effect of the polymorphic expression of CYP2D6 on the metabolism of amfetamine has not been reported. Pemoline (Cylert®, Abbott Laboratories, Abbott Park, IL, USA), unlike the other psychostimulants, is not a phenethylamine derivative. The risk of hepatotoxicity has significantly limited the clinical usage of pemoline.[19] The half-life of pemoline is approximately 12 hours and it is typically administered once daily. The isoforms of CYP responsible for oxidative metabolism of pemoline are unknown. Additionally, there are no published reports on the interaction of pemoline with other drugs. Several other pharmacological interventions including tricyclic antidepressants and selective serotonin reuptake inhibitors have been used to treat ADHD.[20] However, until the recent introduction of atomoxetine (Strattera®; Eli Lilly and Company, Indianapolis, IN, USA), a potent and selective norepinephrine reuptake inhibitor,[21] no new medications have been developed for the treatment of this disease over the last 3 decades. Atomoxetine increases both dopamine and norepinephrine in the prefrontal cortex.[22] This is markedly different from the actions of psychostimulants like methylphenidate, which increases dopamine in the prefrontal cortex, as well as the striatum and nucleus accumbens.[22] Neurotransmitter changes in the striatum and nucleus accumbens are postulated to be responsible for the abuse potential associated with psychostimulants.[13] With a favourable safety profile and novel mechanism of action, atomoxetine represents an advance for the treatment of ADHD in children, adolescents and adults.[23-27] In 2003, atomoxetine was launched in the US and is currently marketed under the brand name Strattera®. Atomoxetine is the first nonstimulant treatment approved by the US FDA for ADHD and has the advantage of not being a scheduled drug.

The use of trade names is for product identification purposes only and does not imply endorsement.

© 2005 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2005; 44 (6)

574

Sauer et al.

2. Physicochemical Properties Atomoxetine hydrochloride is known chemically as (–)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, or (–)-N-methyl-γ-(2methylphenoxy) benzenepropanamine hydrochloride (figure 1). Atomoxetine is marketed as the R(–) isomer (apparent inhibition constant [Ki] = 1.9 nmol/L), which is approximately 9-fold more potent as an inhibitor of the norepinephrine transporter than the S(+) isomer (Ki = 16.8 nmol/L).[21] Compared to its effect on the norepinephrine transporter, atomoxetine (R(–) isomer) has very little affinity for the dopamine (Ki = 1800 nmol/L) or serotonin (Ki = 750 nmol/L) transporters.[21] Atomoxetine hydrochloride (C17H21NO • HCl) has a molecular weight of 291.8 and a free base molecular weight of 255.4. Atomoxetine hydrochloride is a white to practically white solid. Its solubility is 27.8 mg/mL in water and its dissociation constant (pKa) is 10.13. 3. Pharmacokinetics 3.1 Overview

Following oral administration, atomoxetine is well absorbed. It is primarily cleared from the body via oxidative metabolism and is subsequently eliminated into the urine as conjugated metabolites.[28] Similar to many compounds, the biotransformation of atomoxetine governs its overall disposition in humans. As a result of the central role of CYP2D6 in the metabolism of atomoxetine, the activity of this enzyme plays a significant role in its pharmacokinetics.[28-30] The enzymatic activity of CYP2D6 is determined by a genetic polymorphism resulting in two primary populations of individuals with either extensive or poor metabolic capabilities for substrates of this H3C

H N

O CH3 Fig. 1. Chemical structure of atomoxetine, a selective norepinephrine transporter inhibitor.

© 2005 Adis Data Information BV. All rights reserved.

enzyme (table I and figure 2).[31] The majority of people (>90%), who metabolise atomoxetine and other CYP2D6 substrates relatively rapidly, are designated as CYP2D6 extensive metabolisers. These individuals possess a range of activities considered to be normal CYP2D6 activity. Mutations or deletion of the CYP2D6 gene results in a minority of people (up to 7%) who are known as poor metabolisers of CYP2D6 substrates and metabolise atomoxetine relatively slowly. As the clearance of atomoxetine is influenced by its metabolism, it is not surprising that its clearance across patients results in a bimodal distribution indicative of a genetic polymorphism (figure 3). The extensive metaboliser population can be subdivided into three groups based on the number of available wild-type alleles, homozygous, heterozygous and ultra-rapid metabolisers. Ultra-rapid metabolisers of CYP2D6 substrates result from gene duplication of functional CYP2D6 alleles.[32] The ultra-rapid metabolisers genotype accounts for approximately 3–7% of the population.[33] The ultrarapid metaboliser population appears to be comparable to the upper end of the extensive metaboliser range, with a great deal of overlap of apparent plasma clearance (CL/F) values between ultra-rapid metaboliser and extensive metaboliser patients (figure 3). The extensive metaboliser subpopulations are not distinguishable from each other on an individual patient basis. Therefore, genotype is more useful for differentiating extensive and poor metabolisers, rather than predicting an individual’s precise clearance within the extensive metaboliser range of clearances. The plasma pharmacokinetic parameters of atomoxetine in extensive and poor metaboliser subjects have been reported in a number of publications (table II).[28-30,34-37] In extensive metaboliser individuals, the absorption is rapid and the maximum plasma concentration (Cmax) of atomoxetine is 533 ng/mL (coefficient of variance [CV] 32%) after a 1 mg/kg dose and occurs at a median time of 1–2 hours following oral administration.[36] The mean half-life is 5.2 hours (range 3.7–7.5 hours) with a mean CL/F of 0.35 L/h/kg (intersubject CV Clin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

575

Table I. Noncompartmental pharmacokinetic parameters for atomoxetine and its metabolites in cytochrome P450 (CYP) 2D6 extensive and poor metabolisers following oral administration of atomoxetine 20mg twice daily (≈0.5 mg/kg/day)[28] Parameter

Arithmetic mean (CV %) atomoxetine

4-hydroxyatomoxetine

N-desmethylatomoxetine

4-hydroxyatomoxetineO-glucuronide

CYP2D6 extensive metabolisers Cmax,ss (ng/mL)

159.70 (51.9)

Cmin,ss (ng/mL)

36.05 (115.8)

Cav,ss (ng/mL)

89.64 (64.3)

tmaxa (h)

2.00 (1.00–3.00)

t1/2b (h)

2.03 (17.5)

7.02 (71.5)

413.88 (35.5)

0.52 (115.6)

3.12 (113.6)

104.36 (19.3)

5.15 (86.4)

228.70 (13.6)

2.50 (2.00–4.00)

3.50 (2.00–6.00)

2.00 (2.00–4.00)

5.34 (3.67–9.09)

8.97 (2.11–21.9)

6.74 (5.90–8.30)

AUCτ (μg • h/mL)

1.08 (64.3)

0.0618 (86.4)

2.74 (13.6)

CLss/F (L/h/kg)

0.373 (75.1)

Vz/F (L/kg)

2.33 (51.0)

CYP2D6 poor metabolisers Cmax,ss (ng/mL)

914.72 (30.5)

259.22 (39.6)

88.00 (16.9)

Cmin,ss (ng/mL)

502.84 (29.2)

193.09 (40.6)

69.27 (16.4)

Cav,ss (ng/mL)

703.63 (26.9)

234.89 (41.2)

77.88 (17.0)

tmaxa (h) t1/2b (h)

2.00 (2.00–3.00) 20.0 (16.8–25.2)

AUCτ (μg • h/mL)

8.44 (26.9)

CLss/F (L/h/kg)

0.0357 (26.2)

Vz/F (L/kg)

1.06 (42.9)

a

Median (range).

b

Mean (range).

6.00 (3.00–6.00) 33.3 (27.7–42.7) 2.82 (41.2)

4.00 (2.00–6.00) 19.0 (15.2–22.8) 0.935 (17.0)

AUCτ = area under the plasma concentration-time curve during a dosage interval (τ) at steady state; CLss/F = apparent plasma clearance at steady-state; Cav,ss = average steady-state drug concentration in plasma; Cmax,ss = maximum (peak) steady-state drug concentration in the plasma; Cmin,ss = minimum (trough) steady-state drug concentration in the plasma; CV = coefficient of variance; t1/2 = half-life; tmax = time to maximum plasma concentration; Vz/F = apparent volume of distribution during terminal phase.

56%).[37] The volume of distribution is 0.85 L/kg (CV 16%) after an intravenous dose, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers.[37] With a short half-life and rapid clearance, accumulation after twice-daily administration is minimal (mean 9%, range 5–15%) with a mean plasma fluctuation of 273%.[36] The mean maximum steady-state plasma concentration (Cmax,ss) is 584 ng/mL (CV 46%) after 1 mg/kg twice-daily administration and, when compared with Cmax following a single dose, indicates minimal accumulation.[36] The poor metaboliser trait, inherited as an autosomal recessive characteristic, is an important source of intersubject variability in metabolism for a number of drugs metabolised through CYP2D6.[38,39] Although the inability to metabolise CYP2D6 substrates is principally mediated by the genetic poly© 2005 Adis Data Information BV. All rights reserved.

morphism associated with CYP2D6, the phenotypic manifestation of this condition can result from exposure to potent inhibitors of this metabolic pathway. In individuals lacking CYP2D6 activity, oxidative metabolism is still the primary route of atomoxetine clearance, albeit at a much slower rate than that observed in extensive metabolisers. In poor metabolisers, the mean Cmax after a single 1 mg/kg dose is approximately 2-fold higher than Cmax for extensive metabolisers. The mean half-life in poor metabolisers is considerably longer than in extensive metabolisers (21.6 hours, range 14.1–26.8 hours) and the CL/F (0.03 L/h/kg, intersubject CV 19%) is about one-tenth of the extensive metabolisers’ value.[37] The mean apparent volume of distribution (1.06 L/kg, CV 43%) is about half the extensive metabolisers’ value, likely due to differences in first pass metabolism.[28] The average steady-state plasClin Pharmacokinet 2005; 44 (6)

576

Sauer et al.

Atomoxetine N-desmethylatomoxetine 4-Hydroxyatomoxetine 4-Hydroxyatomoxetine-O-glucuronide a

b

1000 800 600

Plasma concentration (μg/L)

400 200 0

1000

100

10

1

0.1 −12

0

12

24

36

48

60

72

0

24 48 72 96 120 144 168 192 216

Time (h) Fig. 2. Mean plasma concentration-time profiles (cartesian [upper panel] and semi-log [lower panel]) for cytochrome P450 2D6 extensive metabolisers (a) and poor metabolisers (b). Multiple 20mg doses of atomoxetine were administered twice daily for 6 days.

ma concentration (Cav,ss) is about 10-fold higher than observed in extensive metabolisers and is readily predictable from half-life and dosing interval. Although Cav,ss is approximately 10-fold higher in poor metabolisers compared with extensive metabolisers, at the Cmax,ss the difference is only about 5-fold.[37] For example, following 6 days of 20mg twice-daily administration of atomoxetine (≈0.5 mg/kg/day) the mean Cav,ss was 90 ng/mL (CV 64%) in extensive metabolisers and 704 ng/mL (CV 27%) in poor metabolisers.[28] The mean Cmax,ss was 160 ng/mL (CV 52%) in extensive metabolisers and 915 ng/mL (CV 31%) in poor metabolisers.[28] The dissimilarities observed be© 2005 Adis Data Information BV. All rights reserved.

tween extensive and poor metabolisers are principally mediated by differences in first-pass metabolism and clearance rather than being driven by differences in absorption of atomoxetine. 3.2 Absorption and Bioavailability

As a result of its high water solubility, as well as its favourable dissolution and intestinal permeability characteristics, atomoxetine is rapidly absorbed following oral administration.[28] The absolute oral bioavailability of atomoxetine is 94% (90% CI 0.88, 0.99) in poor metabolisers and 63% (90% CI 0.59, 0.67) in extensive metabolisers, indicating nearly complete absorption with higher first-pass metaboClin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

3.3 Distribution and Protein Binding

The tissue and organ distribution of atomoxetine was evaluated in rats following an oral dose (50 mg/kg) of radiolabelled atomoxetine.[41] Peak concentrations of radiocarbon occurred at 1 hour after administration in nearly all tissues. By 8 hours after administration, radiocarbon associated with most tissues, including the brain, had declined to either low or background levels. In humans, regardless of CYP2D6 status, atomoxetine is well distributed and its volume of distribution is equivalent to total body water at 0.85 L/kg.[37] Atomoxetine and its metabolites undergo only limited partitioning into human red blood cells.[28] In plasma, atomoxetine is highly proteinbound (98.7% bound in plasma) primarily to albumin.[28] The plasma protein binding of N-desmethylatomoxetine (99.1% bound) is similar to atomoxetine, while the binding of 4-hydroxyatomoxetine to plasma protein (66.6% bound) is substantially less than atomoxetine.[28] In vitro drug-displacement studies demonstrated that atomoxetine did not affect the binding of warfarin, aspirin (acetylsalicylic acid), phenytoin and diazepam to human albumin.[37] Similarly, these compounds did not affect the binding of atomoxetine to human albumin. The ability of atomoxetine and its metabolites to cross the placenta was examined in gravid rats following an oral dose (50 mg/kg) of radiolabelled atomoxetine on gestational day 18.[42] Atomoxetine and/or its metabolites crossed the placenta. Nonetheless, fetal tissue exposure was substantially less than that observed in maternal tissues. The distribution of radioactivity in milk was investigated in lactating rats. Only a small amount of atomoxetine and/or its metabolites were present in rat milk (<1% of the dose). © 2005 Adis Data Information BV. All rights reserved.

3.4 Metabolism and Excretion

As with many compounds, the rate of metabolism of atomoxetine governs its overall pharmacokinetic profile in humans.[28] Atomoxetine is primarily cleared from the body by oxidative metabolism and nearly all of its metabolites are eliminated by excretion into urine. Three primary biotransformation reactions direct the overall metabolism of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. For most of the primary metabolites, secondary aromatic oxidation is also observed. Conjugation of hydroxylated metabolites by uridine diphosphate glucuronosyltransferase is the only conjugation (phase II) metabolic pathway to participate in the biotransformation of atomoxetine. Figure 4 illustrates the overall biotransformation of atomoxetine in humans. Aromatic ring-hydroxylation forms the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine. This metabolite is subsequently glucuronidated and excreted in urine.[28] Biotransformation of atomoxetine to 4-hydroxyatomoxetine is primarily mediated by CYP2D6.[43] Therefore, the overall pharmacokinetic parameters of atomoxetine are influenced by polymorphic expression of this enzyme. In individuals lacking CYP2D6 activity, 4hydroxyatomoxetine is still the major oxidative metabolite. This fact demonstrates that the metabolite can also be formed by several isoforms of CYP, albeit at a much lower efficiency than CYP2D6. The 80

No. of patients

lism in extensive metabolisers.[40] Food does not affect the extent of atomoxetine absorption but does decrease Cmax (37% with a standard high-fat breakfast and 9% with a more typical meal) and delays time to reach maximum plasma concentration (tmax) by 3 hours.[37,40]

577

PM EM UM

60

40

20

0 0

1

2

3

4

5

Ln (CL/F) [L/h/kg] Fig. 3. Frequency distribution of individual atomoxetine clearance values based on cytochrome P450 2D6 genotype. EM = extensive metaboliser; Ln (CL/F) = log transformed apparent plasma clearance; PM = poor metaboliser; UM = ultra-rapid metaboliser.

Clin Pharmacokinet 2005; 44 (6)

No. of subjects

Age group

20mg PO

Adult

Paediatric

© 2005 Adis Data Information BV. All rights reserved.

Adult

Adult

Paediatric

Adult

Adult

6

60mg PO, bid

Adult

Adult 4

2

1

1

1.7

1

2

1

2

tmax (h)

14

Adult

1.5

Child-Pugh B.

Child-Pugh C.

b

c

6

3 126

116

16

11

0.16

0.21

0.06

0.04

0.04

0.40

0.33

0.48

0.40

0.37

0.51

0.46

CL/F (L/h/kg)

2.7

3.3

0.8

34

34

30

35

28

35

1.8

1.1

35

36

30

35

34

36

Reference

1.5

2.3

2.2

2.3

2.7

2.0

Vz/F (L/kg)

contains compartmental analysis for atomoxetine in extensive and poor metabolisers, which is not shown in this table as different parameters

Adult

Adult

11

20

3.4

4.0

3.3

4.0

5.3

4.3

3.1

t1/2 (h)

bid = twice daily; CL/F = apparent plasma clearance; Cmax = maximum observed plasma concentration; Cmax,ss = maximum (peak) steady-state drug concentration in the plasma; CYP = cytochrome P450; PO = oral; t1/2 = half-life; tmax = time to reach Cmax; Vz/F = apparent volume of distribution during terminal phase.

The study by Farid et were calculated.

a

al.[29]

4

POc

20mg

6

20mg POb

CYP2D6 extensive metabolisers with hepatic impairment (single dose)

20mg PO, bid

690

2610

915

591

552

537

184

160

142

144

Cmax or Cmax,ss (ng/mL)

Healthy CYP2D6 extensive metabolisers (multiple dose) with CYP2D6 inhibitor

3

20mg PO, bid

Healthy CYP2D6 poor metabolisers (multiple dose)

15

60mg PO, bid

20–45mg PO, bid

6

16

20mg PO, bid

40mg PO, bid

4

21

20mg PO, bid

Healthy CYP2D6 extensive metabolisers (multiple dose)

7

10

10mg PO

Healthy CYP2D6 extensive metabolisers (single dose)

Dosage

Table II. Summary of atomoxetine pharmacokinetic parametersa

578 Sauer et al.

Clin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

579

and poor metabolisers.[28] Although the overall metabolism of atomoxetine is similar regardless of CYP2D6 status, quantitative amounts of metabolites formed and the rate of their formation are different between extensive and poor metabolisers. Radiolabelled atomoxetine has been given to extensive and poor metabolisers. The mean Cmax of radioactivity is essentially the same in both extensive and poor metabolisers, but the area under the plasma concentration-time curve from zero to infinity (AUC∞) was larger in poor metabolisers because of the slower metabolism and elimination. The mean half-life of atomoxetine-derived radioequivalents is

average Michaelis-Menten constant (Km) for 4hydroxyatomoxetine formation in human liver microsomes containing a full complement of CYP was 2.3 μmol/L, and in CYP2D6-deficient microsomes was 149 μmol/L. In addition, the estimated intrinsic clearance (CLint) for 4-hydroxyatomoxetine formation was 200-fold higher for the microsomes with a full complement of CYPs than that calculated for the CYP2D6-deficient microsomes (103 versus 0.2 μL/ min/mg, respectively).[43] Atomoxetine undergoes the same biotransformation regardless of CYP2D6 activity, with no phenotype-specific metabolites being formed in extensive H2N

H2N

OH

(CYP2D6)

CYP2C19

N-desmethylatomoxetine

HO O CH3

N-desmethyl-4-hydroxyatomoxetine

H3 C

CYP2D6

OH OH

O

CH3

CH3

H N

UGT

O

O

H3C

HO2C O

H2N

H N

N-desmethyl-4-hydroxyatomoxetine-O-glucuronide

H3C

UGT

OH

HO2C O

H N

OH OH

O HO

O

O

O

CH3

CH3

CH3

4-Hydroxyatomoxetine-O-glucuronide

4-Hydroxyatomoxetine

Atomoxetine

H3 C

H N

H3C

H N

UGT

HO2C O

O

O

C H2

CH2OH

2-Hydroxymethylatomoxetine

OH OH

O HO

2-Hydroxymethylatomoxetine-O-glucuronide

H3C

H N

H3C

H N

OH

H N

OH O

OH O

COOH

COOH

2-Carboxyatomoxetine

H N

H3C

O

O

H3C

UGT

Hydroxy-2-carboxyatomoxetine

UGT

HO

CH2OH

OH OH

COOH

Hydroxy-2-carboxyatomoxetine-O-glucuronide

H3C

H N

OH

HO2C O HO

O

Dihydroxyatomoxetine

HO2C O

OH OH

CH2OH

Dihydroxyatomoxetine-O-glucuronide

Fig. 4. Metabolic biotransformation of atomoxetine. For hydroxy-2-carboxyatomoxetine, dihydroxyatomoxetine and their respective glucuronide conjugates, multiple sites of aromatic hydroxylation were observed. Although only cytochrome P450 (CYP) 2D6 and CYP2C19 are shown for the formation of 4-hydroxyatomoxetine and N-desmethylatomoxetine, respectively, several other isoforms of CYP (with reduced affinity) can form these metabolites. UGT = uridine diphosphate glucuronosyltransferase.

© 2005 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2005; 44 (6)

580

18 hours in extensive metabolisers and 62 hours in poor metabolisers. In extensive metabolisers, the majority of the radioactive dose is excreted within the first 24 hours with >96% of the dose excreted in the urine.[28] Excretion rate is slower in poor metabolisers and the majority of the radioactive dose is excreted within 72 hours. Only 80% of total radioactivity is excreted in the urine of poor metabolisers and the remaining 20% is excreted in faeces. The difference between the amount of metabolites formed in the extensive and poor metaboliser patient populations is reflected by the relative formation of 4-hydroxyatomoxetine. The fraction of the dose excreted in the urine and faeces as 4-hydroxyatomoxetine and 4-hydroxyatomoxetine-O-glucuronide is greater in the extensive metabolisers (approximately 86%) than the poor metabolisers (approximately 40%). Although only 40% of the excreted dose is 4-hydroxyatomoxetine-O-glucuronide in poor metabolisers, this product represents the most abundant metabolite. In poor metabolisers, less prominent routes of biotransformation such as N-desmethylatomoxetine- and 2hydroxymethylatomoxetine-derived metabolites are increased. Regardless of CYP2D6 metabolic status, very little atomoxetine (<3%) was excreted into the urine unchanged, indicating a relatively minor role for direct renal elimination. Atomoxetine and 4-hydroxyatomoxetine-Oglucuronide are the principle circulating species in the plasma of extensive metabolisers, while atomoxetine and N-desmethylatomoxetine are the principle circulating species in poor metabolisers (figure 2).[28] Although N-desmethylatomoxetine is a major circulating metabolite in poor metabolisers, the contribution of the metabolic pathway to the overall metabolism of atomoxetine is relatively minor (approximately 6% of the total dose). Extensive metabolisers have relatively low plasma concentrations of N-desmethylatomoxetine; nonetheless, the formation amounts of this metabolite are only slightly smaller than the amount formed in poor metabolisers. Human microsomal studies provide an average apparent Km value of 83 μmol/L for the formation of N-desmethylatomoxetine regardless of © 2005 Adis Data Information BV. All rights reserved.

Sauer et al.

microsomal CYP2D6 content.[43] These studies indicated that CYP2C19 is the primary enzyme responsible for N-desmethylatomoxetine formation. However, because of its minor role in atomoxetine clearance it was predicted that perturbations in this route of metabolism would not influence the overall clearance of atomoxetine. Thus, the higher plasma concentrations of N-desmethylatomoxetine in poor metabolisers are not due to enhanced formation of N-desmethylatomoxetine, but rather due to a parallel decrease in the systemic clearance of this metabolite. Elimination of N-desmethylatomoxetine requires secondary oxidation (aromatic hydroxylation) that appears to be primarily mediated by CYP2D6. Because this enzyme is functionally absent in poor metabolisers, similar to atomoxetine, there is an accumulation of N-desmethylatomoxetine to higher steady-state concentrations. Thus, differences in atomoxetine concentrations between extensive and poor metabolisers are attributed to a decrease in the rate of formation of 4hydroxyatomoxetine, and subsequent 4-hydroxyatomoxetine-O-glucuronide. These differences result in a reduction in the overall rate of elimination of atomoxetine in poor metabolisers. In vitro enzyme studies of the potential for atomoxetine and its two primary oxidative metabolites, N-desmethylatomoxetine and 4-hydroxyatomoxetine, to inhibit CYP1A2, CYP2C9, CYP2D6 and CYP3A were conducted in human hepatic microsomes.[35] These compounds exhibit very little inhibition of CYP2C9 (diclofenac 4′hydroxylation) or CYP1A2 (phenacetin O-deethylation) enzymatic activity. Although apparent Ki values could not be determined for atomoxetine or 4hydroxyatomoxetine, the formation of 4′-hydroxy diclofenac was inhibited by approximately 37% by atomoxetine at concentrations of 800 μmol/L, and 34% by 4-hydroxyatomoxetine at concentrations of 500 μmol/L. The formation of paracetamol (acetaminophen) was inhibited by approximately 30% by atomoxetine at concentrations of 800 μmol/L and 10% by 4-hydroxyatomoxetine at concentrations of 500 μmol/L. For reference, the estimated maximum plasma concentrations of atomoxetine and its meClin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

tabolites following 1.0 mg/kg twice-daily doses (2.0 mg/kg/day) of atomoxetine hydrochloride are 12.9 μmol/L for atomoxetine, 6.3 μmol/L for Ndesmethylatomoxetine and 0.03 μmol/L for 4-hydroxyatomoxetine. N-desmethylatomoxetine inhibits CYP2C9 and CYP1A2 enzymatic activity at high concentrations with Ki values of 53 μmol/L and 271 μmol/L, respectively. Thus, the likelihood of in vivo inhibition of CYP2C9 and CYP1A2 is very low.

581

The ability of atomoxetine to induce catalytic activities associated with CYP1A2 and CYP3A was studied in primary cultures of human hepatocytes. Atomoxetine had no effect on the catalytic activities of 7-ethoxyresorufin O-deethylation (CYP1A2) or midazolam 1′-hydroxylation (CYP3A).[35] 4. Overview of Pharmacodynamic Properties 4.1 Mechanism of Action

Both atomoxetine and N-desmethylatomoxetine inhibit CYP3A (midazolam 1′-hydroxylation) enzyme activity and yield Ki values of 34 μmol/L and 16 μmol/L, respectively. In addition, atomoxetine, N-desmethylatomoxetine and 4-hydroxyatomoxetine significantly inhibit CYP2D6 (bufuralol 1′-hydroxylation) enzyme activity and yield Ki values of 3.6 μmol/L, 5.3 μmol/L and 17 μmol/L, respectively.

Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other monoamine transporters or receptors.[21,45-47] Furthermore, as a result of its novel mechanism of action, atomoxetine does not share the abuse potential associated with psychostimulant drugs.[48]

These in vitro data predict the possible effect of atomoxetine on the clearance of coadministered drugs. The relationship (I/[I + Ki]) • 100, where I is inhibitor concentration, can be used to calculate an estimate of expected percent inhibition.[44] Differences in accumulation and overall exposure profiles between extensive and poor metaboliser populations were considered in the interpretation of the in vitro findings. A conservative approach was used to estimate inhibitor concentration in these calculations, which assumes that all of the drug measured in the plasma is potentially an inhibitor. As such, the calculations did not take into account the high plasma protein binding of either atomoxetine or Ndesmethylatomoxetine. Significant enzyme inhibition was predicted for CYP3A (56% predicted inhibition in poor metaboliser patients) and CYP2D6 (60% predicted inhibition in extensive metaboliser patients) for typical therapeutic plasma concentrations. On the basis of these in vitro findings, drug interaction studies in healthy subjects were conducted using probe substrates for CYP2D6 (desipramine) in CYP2D6 extensive metaboliser subjects and CYP3A (midazolam) in CYP2D6 poor metaboliser subjects (see sections 5.3 and 5.4).

In vitro studies demonstrate that atomoxetine has potent nanomolar to subnanomolar affinity for the rat and human norepinephrine transporters and minimal affinity for serotonin and dopamine transporters, as well as other receptors and ion channels.[21] The human transporter affinities of the primary oxidative metabolites of atomoxetine, 4-hydroxyatomoxetine and N-desmethylatomoxetine have been assessed. 4-Hydroxyatomoxetine has similar affinity for the norepinephrine transporter (Ki = 12.5 μmol/L) to that of atomoxetine (Ki = 8.5 μmol/L), and little affinity for the dopamine transporter (Ki >1000 μmol/L). Unlike atomoxetine (Ki >1000 μmol/L), 4-hydroxyatomoxetine (Ki = 11.3 μmol/L) has relatively high affinity for the human serotonin transporter. N-desmethylatomoxetine, on the other hand, had less affinity for the monoamine transporter system compared with atomoxetine and 4-hydroxyatomoxetine. As with atomoxetine, these metabolites do not have affinity for other neuronal receptors or ion channels.[49] A number of preclinical in vivo studies defined the central and peripheral potency of atomoxetine as an inhibitor of norepinephrine reuptake sites.[45,46,50] In rats, orally administered atomoxetine inhibits

© 2005 Adis Data Information BV. All rights reserved.

4.2 In Vitro and In Vivo Activity

Clin Pharmacokinet 2005; 44 (6)

582

Sauer et al.

radioligand binding to the norepinephrine transporter with a dose that produces 50% response (ED50) of 2.4 mg/kg, while a small amount (30%) of inhibition of the serotonin transporter is observed at the higher doses of atomoxetine (60 mg/kg). Norepinephrine transporter inhibition was maximal 1 hour after administration and yet still significant for up to 6 hours after administration. Interestingly, the half-life of atomoxetine in rats is approximately 2 hours,[51] suggesting a difference between the pharmacodynamic and pharmacokinetic half-lives of atomoxetine. Microdialysis measurement of brain extracellular monoamines was utilised to evaluate the central effects of atomoxetine.[22] In these studies, atomoxetine increased extracellular norepinephrine in the prefrontal cortex 3-fold, but did not alter serotonin. Atomoxetine also increased dopamine concentrations in the prefrontal cortex 3-fold, but did not alter dopamine in striatum or nucleus accumbens. In contrast, methylphenidate increased norepinephrine and dopamine equally in prefrontal cortex, and also increased dopamine in the striatum and nucleus accumbens. The expression of the neuronal activity marker Fos was increased 3.7-fold in prefrontal cortex by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional increases of dopamine. Bymaster et al.[22] concluded that due to the promiscuous transport of dopamine via the norepinephrine transporter in the prefrontal cortex, atomoxetine selectively increases both dopamine and norepinephrine neurotransmission in a region of the brain involved in attention and memory. In contrast to methylphenidate, atomoxetine does not increase dopamine in striatum or nucleus accumbens, suggesting it would have less potential for motoric or drug abuse liabilities. This conclusion is supported by the finding that atomoxetine did not substitute appreciably for metamfetamine in drug discrimination studies in monkeys.[52] 4.3 Clinical Pharmacodynamics

The results of prospective, placebo-controlled and dose-finding studies demonstrate that atomoxe© 2005 Adis Data Information BV. All rights reserved.

tine is an effective and well tolerated treatment for paediatric, adolescent and adult patients with ADHD. In children and adolescents, atomoxetine in a single or divided daily dose of 1.2 mg/kg has been shown to be superior to placebo in randomised, placebo-controlled studies.[25,26] Efficacy was assessed by ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRSIV-Parent:Inv). Effectiveness of atomoxetine in improving ADHD symptoms is comparable to treatment with methylphenidate.[27] In adult patients with ADHD, atomoxetine efficacy was initially evaluated in a small, double-blind, placebo-controlled, crossover study.[23] Atomoxetine, at an average dose of 76 mg/day, was well tolerated. Improvement in ADHD symptomatology was significant overall and sufficiently robust to be detectable in a parallel-group comparison. Eleven of 21 patients showed improvement after receiving atomoxetine, while only 2 of 21 patients improved after receiving placebo. These results demonstrated that atomoxetine was effective in treating adult ADHD, resulting in clinically and statistically significant improvement in ADHD symptoms, and was well tolerated. A number of additional studies have been conducted demonstrating the effectiveness of atomoxetine treatment in adults with ADHD.[24] The safety, tolerability and efficacy of atomoxetine in children and adolescents with ADHD have been rigorously characterised in comparison to the other drugs used to treat this disease.[25,53] The most common drug-related adverse event reported was decreased appetite and an initial period of weight loss followed by an apparently normal rate of weight gain. There are no effects on the corrected QT interval, and CYP2D6 phenotype of patients does not affect the overall safety and tolerability of the drug. However, tachycardia, as well as increases in diastolic blood pressure (2–5mm Hg) and systolic blood pressure (3mm Hg) have been observed following treatment with atomoxetine.[54-56] No serious adverse events have been associated with atomoxetine administration, and there have been few discontinuations resulting from adverse events. The safety and tolerability associated with atomoxetine adminClin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

istration in children are similar to those previously reported for adults.[23,57,58] Since individuals lacking CYP2D6 activity have higher atomoxetine plasma concentrations after multiple doses, it was initially believed that poor metabolisers would not tolerate higher concentrations. Moreover, there was concern that poor metaboliser patients would need to be phenotypically or genotypically identified before the initiation of treatment with atomoxetine. In early clinical trials, patients were given doses in accordance with their genotype and poor metabolisers received lower doses than extensive metabolisers.[25,55] After demonstrating safety in initial safety and tolerability studies in poor metabolisers, atomoxetine was administered without regard for genotype in later clinical trials.[59] A comparison of 1290 extensive metabolisers with 67 poor metabolisers taking at least 1.2 mg/kg/day of atomoxetine, which is the initial target dose for efficacy, showed little difference in discontinuations or reporting rates of adverse events.[53,59] However, poor metabolisers did develop a slightly higher increase in heart rate (10.6 bpm versus 6.9 bpm) and lost slightly more weight (–1.2kg versus +0.8kg) than extensive metabolisers. Thus, with the apparently large therapeutic index, differential dosing based on genotype is not required. 5. Pharmacokinetic Interactions 5.1 Interactions with Food

Food does not affect the extent of atomoxetine absorption. However, ingestion of the atomoxetine dose with food decreases Cmax by 37% with a standard high-fat breakfast or by 9% with a more typical meal. Food also delays tmax by 3 hours.[37,40] The effect of food on atomoxetine pharmacokinetics is regarded as not clinically important given the small decrease in Cmax observed in clinical efficacy studies. The relative oral bioavailability of atomoxetine administered in the presence of either Maalox® (Novartis Consumer Health, Parsippany, NJ, USA) or omeprazole was approximately 100% and it ap© 2005 Adis Data Information BV. All rights reserved.

583

pears that an increase in gastric pH had no substantial effect on the absorption of atomoxetine.[40] 5.2 Interactions with Paroxetine

The role of CYP2D6 in the biotransformation of atomoxetine[28,29,43] and the potential for interaction with other drugs[30,35] make it important to assess the impact of concomitant drug treatment. Although the systemic clearance of atomoxetine is dependent upon the polymorphic expression of CYP2D6, chemical inhibitors of this enzymatic pathway also alter the pharmacokinetics of atomoxetine. In humans, coadministration of paroxetine, a potent inhibitor of CYP2D6-catalysed reactions,[60,61] with known CYP2D6 substrates (such as metoprolol, desipramine or perphenazine) result in significant pharmacokinetic interactions in extensive metabolisers.[62-65] Although paroxetine substantially inhibits CYP2D6, it does not seem to affect CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme activities in vivo at therapeutic dose.[66-71] Administration of paroxetine (20mg once daily) for 17 days results in steady-state plasma concentrations that are in the same range as its Ki for CYP2D6 (0.15 μmol/L). Consequently, concomitant administration of paroxetine and atomoxetine (20mg twice daily) led to an increase in the plasma concentrations of atomoxetine and its N-demethylated metabolite.[30] Paroxetine increased mean Cmax,ss and AUC during a dosage interval (τ) at steady state (AUCτ) values of atomoxetine by about 3.5- and 6.5-fold, respectively, which is in the same order of magnitude as the reported effects of paroxetine on other CYP2D6 substrates.[62-64] Correspondingly, the concentration of 4-hydroxyatomoxetine, the major CYP2D6 oxidative metabolite, was lower. After concomitant treatment with paroxetine, steady-state pharmacokinetic parameters of atomoxetine in extensive metabolisers are similar to the pharmacokinetic values obtained for poor metabolisers who were administered atomoxetine alone.[28,29] For example, the CL/F of atomoxetine averaged 0.0599 L/h/kg after coadministration with paroxetine, which is comparable to that observed in poor metabolisers (CL/F = 0.03 L/h/kg).[37] InClin Pharmacokinet 2005; 44 (6)

584

Sauer et al.

creases in N-desmethylatomoxetine concentrations after concomitant treatment with paroxetine are also consistent with the pharmacokinetics of atomoxetine in poor metabolisers. Thus, coadministration of paroxetine and atomoxetine results in an inhibition of CYP2D6-mediated conversion of atomoxetine to 4-hydroxyatomoxetine, and produces an atomoxetine pharmacokinetic profile similar to that found in poor metabolisers. 5.3 Interactions with Desipramine

In vitro inhibition studies designed to evaluate the 1′-hydroxylation of bufuralol suggest that atomoxetine has the potential to inhibit CYP2D6-mediated metabolism (see section 3.4).[35] The in vitro predictions indicate that atomoxetine (54% predicted inhibition) but not its metabolites (5% predicted inhibition) would be primarily responsible for inhibition. These in vitro findings led to an in vivo study in healthy CYP2D6 extensive metabolisers evaluating the coadministration of atomoxetine and desipramine.[35,72] Desipramine is a sensitive and selective probe drug for CYP2D6-dependent metabolism; its biotransformation to 2-hydroxydesipramine is almost exclusively mediated by CYP2D6 and is not affected by inhibitors of other isoforms of CYP.[73] Twice-daily 60mg doses of atomoxetine ranged from 1.2 to 2.3 mg/kg/day, with a median dose of 1.6 mg/kg/day. At these doses, Cmax,ss of atomoxetine ranged from 241 to 1046 ng/mL (0.9–4.1 μmol/L) and these values are in the range of and exceed the estimated Ki values of atomoxetine for CYP2D6 (Ki = 3.6 μmol/L [919 ng/ mL]).[35] However, because of the rapid elimination of atomoxetine, the Cav,ss are below the Ki value (Cav,ss range 105–569 ng/mL [0.4–2.2 μmol/L]). Upon the concomitant administration of a single 50mg oral dose of desipramine with atomoxetine, no change in desipramine pharmacokinetics was observed. Thus, in clinical practice, atomoxetine at maximum steady-state conditions is not likely to inhibit the metabolic clearance of drugs metabolised by CYP2D6. © 2005 Adis Data Information BV. All rights reserved.

Effects of atomoxetine on desipramine metabolism were not studied in poor metabolisers because of the lack of CYP2D6 activity in this population. 5.4 Interactions with Midazolam

In vitro enzyme inhibition studies suggest that atomoxetine may impact the pharmacokinetics of agents metabolised by CYP3A, but only when atomoxetine and N-desmethylatomoxetine plasma concentrations are relatively high (see section 3.4).[35] These are potential conditions for poor metaboliser patients. Therapeutic doses of atomoxetine in poor metabolisers may achieve concentrations that approach the Ki values for inhibition of CYP3A. The in vitro predictions indicate that both atomoxetine (28% predicted inhibition) and Ndesmethylatomoxetine (28% predicted inhibition) could participate in CYP3A inhibition. These findings led to a clinical study evaluating the coadministration of atomoxetine and midazolam in healthy CYP2D6 poor metabolisers.[35,74] Midazolam is a sensitive and selective probe drug for CYP3Adependent metabolism.[75] Twice-daily 60mg doses of atomoxetine ranged from 1.5 to 2.7 mg/kg/day, with a median dose of 1.7 mg/kg/day. At these doses, Cmax,ss of atomoxetine ranged from 1456 to 3319 ng/mL (5.6–12.9 μmol/L) and N-desmethylatomoxetine ranged from 755 to 2485 ng/mL (3.2–10.4 μmol/L), well below their respective predicted Ki values for CYP3A (34 μmol/L [8757 ng/ mL] and 16 μmol/L [3837 ng/mL], respectively).[35] Following a single 5mg oral dose of midazolam in healthy CYP2D6 poor metabolisers, the midazolam Cmax and AUC∞ were about 16% larger when midazolam was concomitantly administered with atomoxetine; however, the increase was not statistically significant or regarded as a change that would reflect a clinically important inhibition of CYP3A activity. Coadministration of the potent CYP3A inhibitor ketoconazole with midazolam results in a 15-fold increase in midazolam AUC and a 4-fold increase in Cmax.[76] Furthermore, midazolam half-life increases from 2.9 hours to 7.0 hours. Unlike the interaction observed with ketoconazole, atomoxetine did not Clin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

alter the half-life of midazolam or increase midazolam exposure statistically.[35] Yuan et al.,[77] demonstrated that moderate inhibitors of CYP3A, such as grapefruit juice, cause pharmacokinetic changes in midazolam (increased Cmax and AUC) that are substantially greater than those observed for atomoxetine. Because there are only minimal changes in midazolam pharmacokinetics observed, it is predicted that atomoxetine at maximum recommended clinical doses will not inhibit the metabolic clearance of drugs metabolised by CYP3A. 6. Implications of Pharmacokinetic Properties for Therapeutic Use 6.1 Dosages and Therapeutic Range

The relationship between exposure and efficacy of atomoxetine has been evaluated in a randomised, double-blind, placebo-controlled study conducted in children and adolescents with ADHD.[78] Patients were randomised to a target dose of atomoxetine (placebo, 0.5 mg/kg/day, 1.2 mg/kg/day, 1.8 mg/kg/ day). Using a population pharmacokinetic model, the modelled clearance values for each patient provided estimated AUCτ values as a measure of atomoxetine exposure. A nonlinear model (maximum effect [Emax] model) was fit to the observed AUC and change from baseline in ADHDRS-IVParent:Inv total scores data to explore the relationship between AUC and efficacy. The modelling was restricted to extensive metaboliser data, as there was only a sparse amount of poor metaboliser data available. The relationship between AUCτ and change from baseline in ADHDRS-IV-Parent:Inv total score suggests that the expected maximum improvement from baseline is –17.4 (compared with –6.2 for 8 weeks of placebo administration) in ADHDRSIV-Parent:Inv total score. The overall maximum benefit of atomoxetine treatment was –11.2 over that for placebo. At the median AUC values for atomoxetine doses of 0.5 mg/kg/day, 1.2 mg/kg/day or 1.8 mg/kg/day, there was a 62%, 78% and 85% maximum improvement over baseline, respectively. Therefore, a relationship between systemic exposure to atomoxetine and efficacy was apparent and these © 2005 Adis Data Information BV. All rights reserved.

585

improvements in efficacy are similar to those observed between atomoxetine dose and efficacy. 6.2 Sex and Racial Differences in Atomoxetine Pharmacokinetics

In general, the plasma pharmacokinetic parameters and biotransformation of atomoxetine are not affected by sex or race.[37] However, as described earlier, the disposition of atomoxetine is dependent upon CYP2D6 activity, a trait that differs among races. For example, the poor metaboliser trait, inherited as an autosomal recessive characteristic, is most prevalent in Caucasians; up to 7% of the Caucasian population can be genetically classified as poor metabolisers,[31] while this genetic trait is observed in <1% of the Asian population,[79,80] <2% in Arabian populations[81] and approximately 3% in African populations.[82] Likewise, mutations (allelic variations) observed in the extensive metaboliser population that have relatively minimal functional consequences for CYP2D6 are also distributed differently among Caucasian, Asian, Arabian and African populations.[83] 6.3 Influence of Age and Bodyweight on Atomoxetine Pharmacokinetics

Witcher et al.,[36] evaluated single-dose and steady-state pharmacokinetics of atomoxetine in children and adolescent patients across a wide range of doses. Identical to the pharmacokinetics in adults, the paediatric pharmacokinetic parameters of atomoxetine demonstrated a linear and predictable pharmacokinetic behaviour. As atomoxetine doses are increased, proportional increases in plasma exposure (AUC and Cmax) are observed. Furthermore, repeated administration of atomoxetine results in a predictable pharmacokinetic profile based on the single-dose data. Because of the rapid absorption and elimination of the drug, steady-state profiles are remarkably similar to single-dose profiles in paediatric extensive metaboliser patients. The ability of children and adolescents to metabolise atomoxetine rapidly and similarly to adults suggests CYP2D6 metabolic activity is mature and has reached adult competency by 7–14 years of age. Phenotype distriClin Pharmacokinet 2005; 44 (6)

586

Sauer et al.

a

b 26.3kg

400 Atomoxetine plasma concentration (μg/L)

29.6kg 35.3kg

300

26.3kg 29.6kg

43.6kg

35.3kg

200

70.0kg

43.6kg 70.0kg

100

0 0

3

6

9

12

15

18

21

24

0

3

6

9

12

15

18

21

24

Time from dose (h) Fig. 5. Predicted effect of bodyweight on atomoxetine plasma concentrations for (a) a 40mg dose and (b) a 1 mg/kg dose.

bution studies for CYP2D6 in children (mean age of 10.4 ± 3.7 years) and adolescents are a mirror of the distributions observed in adults.[84,85] The paediatric pharmacokinetic data reported by Witcher et al.[36] are similar to data described in adults after adjustment for bodyweight. This study provides evidence that it is appropriate to administer atomoxetine on a bodyweight-adjusted basis (mg/kg) in paediatric patients. Bodyweight has a significant impact on atomoxetine pharmacokinetics, which was demonstrated in a separate analysis using population pharmacokinetic modelling. As bodyweight increases, both the clearance and volume of distribution increase in an essentially proportional manner.[37] Figure 5 shows the predicted effect of bodyweight on atomoxetine plasma concentrations for a fixed 40mg dosing regimen in comparison to a weight-adjusted dose. The similarity between the profiles for the weight-based dose administration suggests this is a useful means to provide comparable exposures between patients of different bodyweights. This dosing method also maintains constant exposure to drug as a patient matures and bodyweight increases. 6.4 Diseases and the Pharmacokinetics of Atomoxetine 6.4.1 Chronic Impairment of Renal Function

Because atomoxetine is primarily cleared through oxidative metabolism, it is unlikely that the © 2005 Adis Data Information BV. All rights reserved.

systemic clearance of atomoxetine is influenced by renal disease. However, the metabolites of atomoxetine are primarily excreted in urine. Therefore, the pharmacokinetics of atomoxetine and its primary metabolites were evaluated in six adults with endstage renal disease and compared with age-matched healthy subjects.[37] Atomoxetine mean plasma concentrations with end-stage renal disease patients were higher than the mean for healthy subjects (about a 65% increase). However, after adjustment for bodyweight, the differences between these groups were minimal. As expected, the plasma concentrations of 4-hydroxyatomoxetine-O-glucuronide, a metabolite excreted in urine with no known pharmacological actions, were substantially higher in individuals with end-stage renal disease. Pharmacokinetics of atomoxetine and its metabolites in individuals with end-stage renal disease suggest that no dosage adjustments are necessary.[37] 6.4.2 Hepatic Insufficiency

Since atomoxetine is primarily cleared from the systemic circulation through oxidative metabolism, it is reasonable to assume that the disposition of atomoxetine would be affected by impaired hepatic function. Recently, Chalon et al.[34] compared the pharmacokinetic parameters of atomoxetine in ten adults with hepatic impairment (six moderate, four severe) and ten age- and sex-matched healthy subjects, all being genotyped as CYP2D6 extensive metabolisers. Clin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

Systemic clearance of atomoxetine was significantly reduced in patients with hepatic impairment compared with healthy subjects. There was an increase in overall atomoxetine exposure (AUC∞ 1.58 versus 0.85 μg • h/mL) but no change in Cmax or peak exposure. Mean 4-hydroxyatomoxetine AUC from zero to time t (AUCt) and Cmax were increased approximately 7- and 2-fold, respectively, indicating a reduced rate of glucuronidation in individuals with hepatic impairment. For the glucuronide conjugate of 4-hydroxyatomoxetine, the mean half-life was longer and mean AUC∞ and Cmax values were also lower, similar to the type of differences noted for individuals lacking CYP2D6 activity.[28] Decreased atomoxetine clearance in hepatically impaired patients was correlated with decreased CYP2D6 activity (debrisoquine clearance) and decreased hepatic blood flow (sorbitol clearance). Chalon et al.,[34] concluded that for ADHD patients who have hepatic impairment, a dosage reduction is recommended. Initial doses of atomoxetine should be reduced to 25% or 50% of the normal dose for patients with moderate or severe hepatic impairment, respectively. 7. Conclusions Atomoxetine is a well-tolerated inhibitor of the presynaptic norepinephrine transporter, and is a drug that has shown notable efficacy for the treatment of ADHD in children, adolescents and adults. The metabolism, pharmacokinetics and absolute oral bioavailability of atomoxetine are influenced by the CYP2D6 polymorphism. The mean half-life of atomoxetine is approximately 5-fold longer (5.2 versus 21.6 hours) and its mean CL/F is about 10-fold slower (0.35 versus 0.03 L/h/kg) in poor metabolisers compared with extensive metabolisers. After single oral dose, the mean atomoxetine Cmax is 2fold higher in poor metabolisers compared with extensive metabolisers. At steady state after twicedaily dosing, the mean atomoxetine Cmax is approximately 5-fold higher and the mean plasma concentration is approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. © 2005 Adis Data Information BV. All rights reserved.

587

Atomoxetine is rapidly and completely absorbed after oral administration with a median tmax of 1–2 hours. The presence of food in the gastrointestinal tract does not affect the extent of atomoxetine absorption but does decrease Cmax (by 37% with a standard high-fat breakfast and by 9% with a more modest meal) and delays tmax by 3 hours. Pharmacokinetics of atomoxetine are linear over the range of doses studied in both extensive and poor metabolisers. The pharmacokinetics following once-daily and twice-daily dosage regimens are readily predictable from single-dose data. Despite greater systemic exposures experienced by poor metabolisers versus extensive metabolisers, there has been no clinical significance related to these pharmacokinetic differences. The same mean doses were found to be well tolerated and efficacious for atomoxetine, and atomoxetine dosage recommendations are the same regardless of CYP2D6 genotype or phenotype. In both extensive and poor metabolisers, the primary oxidative metabolite of atomoxetine is 4-hydroxyatomoxetine. This metabolite undergoes further metabolism, resulting in the formation of 4hydroxyatomoxetine-O-glucuronide, which is primarily excreted in the urine. As a result of either genetic polymorphism or pharmacologial inhibition, individuals may exhibit a poor metaboliser phenotype that is characterised by slower metabolic elimination and higher steady-state plasma concentrations of atomoxetine and N-demethylated metabolite compared with those observed in extensive metabolisers. Atomoxetine administration does not result in clinically significant inhibition or induction of the clearance of other drugs metabolised by CYP. In extensive metabolisers, selective inhibitors of CYP2D6 (paroxetine) increased atomoxetine steady-state plasma concentrations to exposures less than or similar to those observed in poor metabolisers. In vitro studies indicate that the coadministration of CYP inhibitors to individuals lacking CYP2D6 activity is not expected to increase the plasma concentrations of atomoxetine. Clin Pharmacokinet 2005; 44 (6)

588

Sauer et al.

The results of the conventional pharmacokinetic analyses in adults, as well as conventional and population pharmacokinetic analyses in children, demonstrate that the pharmacokinetics of atomoxetine are similar between these age groups after adjustment for bodyweight. Weight-based dosage regimens (mg/kg) are recommended for paediatric patients. The pharmacokinetic parameters of atomoxetine were affected by moderate and severe hepatic insufficiency, and a dosage reduction is recommended in patients who have hepatic insufficiency. Pharmacokinetics of atomoxetine and its metabolites in individuals with end-stage renal disease suggest that no dosage adjustment is necessary. Overall, the pharmacokinetics and metabolism of atomoxetine are predictable based on an individual’s CYP2D6 phenotype. Both the efficacy and safety of atomoxetine have been demonstrated for the treatment of ADHD in children, adolescents and adults. As the first FDA-approved, nonstimulant pharmaceutical treatment for ADHD, atomoxetine represents a significant advance in the treatment of this disease. Furthermore, due to its novel mechanism of action, atomoxetine does not share the abuse potential associated with psychostimulant drugs. Acknowledgements The authors wish to thank Dr Richard F. Bergstrom from Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA, for his helpful guidance and insightful scientific comments. The authors also thank Ms Amanda J. Long for her contributions to the work presented herein. Finally, the authors thank Mr Nathan P. Sanburn for his editorial comments. At the time of preparation of this review all authors were employees of Eli Lilly and Company, Indianapolis, IN, USA.

References 1. Spencer T, Biederman J, Wilens T, et al. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. Child Adol Psychiatry 1996; 35: 409-32 2. Swanson JM, Sergeant JA, Sonuga-Barke EJS, et al. Attentiondeficit hyperactivity disorder and hyperkinetic disorder. Lancet 1998; 351: 429-33 3. Weiss G. Follow-up studies on outcome of hyperactive children. Psychopharmacol Bull 1985; 21: 169-77 4. Pary R, Lewis S, Matuschka PR, et al. Attention deficit disorder in adults. Ann Clin Psychiatry 2002; 14: 105-11 5. Adler LA, Chua HC. Management of ADHD in adults. J Clin Psychiatry 2002; 63 Suppl. 12: 29-35

© 2005 Adis Data Information BV. All rights reserved.

6. Barkley FA, Fischer M, Edelbrock CS, et al. The adolescent outcome of hyperactive children diagnosed by research criteria: I. An 8-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 1990; 29: 546-57 7. Munir K, Biederman J, Knee D. Psychiatric comorbidity in patients with attention deficit disorder: a controlled study. J Am Acad Child Adolesc Psychiatry 1987; 26: 844-8 8. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 1991; 148: 564-77 9. Spencer TJ, Biederman J, Wilens TE, et al. Overview and neurobiology of attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002; 63 Suppl. 12: 3-9 10. Volkow ND, Fowler JS, Wang G-J, et al. Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies. Eur Neuropsychopharmacol 2002; 12: 557-66 11. Giros B, Caron MG. Molecular characterization of the dopamine transporter. Trends Pharmacol Sci 1993; 14: 43-9 12. Patrick KS, Markowitz JS. Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder: a review. Hum Psychopharmacol 1997; 12: 527-46 13. Dackis CA, Gold MS. Addictiveness of central stimulants. Adv Alcohol Subst Abuse 1990; 9: 9-26 14. Markowitz JS, Patrick KS. Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet 2001; 40: 753-72 15. Pelham WE, Gnagy EM, Burrows-Maclean L, et al. Once-aday Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings [abstract]. Pediatrics 2001; 107: E105 16. Lyseng-Williamson KA, Keating GM. Extended-release methylphenidate (Ritalin LA). Drugs 2002; 62: 2251-9 17. Tulloch SJ, Zhang Y, McLean A, et al. SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration. Pharmacotherapy 2002; 22: 1405-15 18. Wu D, Otton SV, Inaba T, et al. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol 1997; 53: 1605-12 19. Nehra A, Mullick R, Ishak KG, et al. Pemoline-associated hepatic injury. Gastroenterology 1990; 99: 1517-9 20. Popper CW. Antidepressants in the treatment of attention-deficit/hyperactivity disorder. J Clin Psychiatry 1997; 58 Suppl. 14: 14-29 21. Wong DT, Threlkeld PG, Best KL, et al. A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain. J Pharmacol Exp Ther 1982; 222: 61-5 22. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 2002; 27: 699-711 23. Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998; 155: 693-5 24. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 2003; 53: 112-20 25. Michelson D, Faries DE, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with ADHD: a random-

Clin Pharmacokinet 2005; 44 (6)

Clinical Pharmacokinetics of Atomoxetine

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37. 38.

39.

40.

41.

42.

ized, placebo-controlled dose-response study [abstract]. Pediatrics 2001; 108: E83 Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 2002; 159: 1896-901 Kratochvil CJ, Heiligenstein JH, Dittmann R, et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. Am Acad Child Adolesc Psychiatry 2002; 41: 776-84 Sauer JM, Ponsler GD, Mattiuz EL, et al. Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metab Dispos 2003; 31: 98-107 Farid NA, Bergstrom RF, Ziege EA, et al. Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects. J Clin Pharmacol 1985; 25: 296-301 Belle DJ, Ernest S, Sauer JM, et al. Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. J Clin Pharmacol 2002; 42: 1-9 Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, editor. Cytochrome P450: structure, mechanism, and biochemistry. New York: Plenum Press, 1995: 473535 Sachse C, Brockmoller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997; 60: 284-95 Agundez JA, Ledesma MC, Ladero JM, et al. Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin Pharmacol Ther 1995; 57: 265-9 Chalon S, Desager JP, DeSante K, et al. Effect of liver impairment on the pharmacokinetics of atomoxetine and its metabolites. Clin Pharmacol Ther 2003; 73: 178-91 Sauer JM, Long AJ, Ring B, et al. Disposition and metabolic fate of atomoxetine hydrochloride: clinical drug-drug interaction prediction and outcome. J Pharmacol and Exp Ther 2004; 308: 410-8 Witcher JW, Long AJ, Sauer JM, et al. Atomoxetine pharmacokinetics in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2003; 13: 5364 Strattera™ (atomoxetine) package insert (NDA 21-411). Indianapolis (IN); Eli Lilly and Co., 2003 Evans DAP, Maghoub A, Sloan TP, et al. A family and population study of the genetic polymorphism of the debrisoquine oxidation in a white British population. J Med Genet 1980; 17: 102-5 Steiner E, Bertilsson L, Sawe J, et al. Polymorphic debrisoquine hydroxylation in 757 Swedish subjects. Clin Pharmacol Ther 1988; 44: 431-5 DeSante K, Long A, Smith B, et al. Atomoxetine absolute bioavailability and effects of food, Maalox or omeprazole on atomoxetine bioavailability. AAPS Annual Meeting and Exposition; 2001 Oct 21-25; Denver Herman JL, Kou F, Sauer JM, et al. Tissue disposition of 14Ctomoxetine in male Fischer 344 rats following a single oral dose administration. Society for Whole-Body Autoradiography Meeting; 1999 Apr 18-20; St Louis Hamilton MM, Herman JL, Kou F, et al. Placental transfer and milk excretion in rats after a single oral 50 mg/kg dose of [14C]atomoxetine administered as the hydrochloride salt. European Society for Whole Body Autoradiography; 2000, Paris

© 2005 Adis Data Information BV. All rights reserved.

589

43. Ring BJ, Gillespie JS, Eckstein JA, et al. Identification of the human cytochromes P450 responsible for atomoxetine metabolism. Drug Metab Dispos 2002; 30: 319-23 44. Segel IH. Enzyme kinetics. New York: John Wiley and Sons, Inc., 1975 45. Oberlender R, Nichols DE, Ramachandran PV, et al. Tomoxetine and the stereoselectivity of drug action. J Pharm Pharmacol 1987; 39: 1055-6 46. Gehlert DR, Gackenheimer SL, Robertson DW. Localization of rat brain binding sites for [3H]tomoxetine, an enantiomerically pure ligand for norepinephrine reuptake sites. Neurosci Lett 1993; 157: 203-6 47. Gehlert DR, Schober DA, Gackenheimer SL. Comparison of (R)-[3H]tomoxetine and (R/S)-[3H]nisoxetine binding in rat brain. J Neurochem 1995; 64: 2792-800 48. Heil SH, Holmes HW, Bickel WK, et al. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend 2002; 67: 149-56 49. Wheeler WJ, Bymaster FP, Calligaro DO, et al. Strattera® (atomoxetine HCl), an inhibitor of the norepinephrine transporter. I: the preparation of C-14 labeled atomoxetine, and two of its metabolites; II: The preparation and biological evaluation of some additional putative metabolites of atomoxetine. In: Dean DC, Filer CN, McCarthy KE, editors. Synthesis and applications of isotopically labelled compounds. Vol 8. New York: John Wiley and Sons, Inc., 2004: 357-60 50. Fuller RW, Hemrick-Luecke SK. Antagonism by tomoxetine of the depletion of norepinephrine and epinephrine in rat brain by alpha-methyl-m-tyrosine. Res Commun Chem Path Pharmacol 1983; 41: 169-72 51. Mattiuz EL, Ponsler GD, Barbuch RJ, et al. Disposition and metabolic fate of atomoxetine hydrochloride: pharmacokinetics, metabolism, and excretion in the fischer 344 rat and beagle dog. Drug Metab Dispos 2003; 31: 88-97 52. Tidey JW, Bergman J. Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs. J Pharmacol Exp Ther 1998; 285: 116374 53. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry 2002; 63 Suppl. 12: 50-5 54. Wernicke JF, Allen AJ, Faries D, et al. Safety of tomoxetine in clinical trials [abstract]. Biol Psychiatry 2001; 49 (8 Suppl.): 159S 55. Spencer T, Heiligenstein JH, Biederman J, et al. Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002; 63: 1140-7 56. Wernicke JF, Faries D, Girod D, et al. Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf 2003; 26: 729-40 57. Chouinard G, Annable L, Bradwejn J. An early phase II clinical trial of tomoxetine (LY139603) in the treatment of newly admitted depressed patients. Psychopharmacologia 1984; 83: 126-8 58. Zerbe RL, Rowe H, Enas GG, et al. Clinical pharmacology of tomoxetine, a potential antidepressant. J Pharmacol Exp Ther 1985; 232: 139-43 59. Allen AJ, Wernicke JF, Dunn D, et al. Safety and efficacy of atomoxetine in pediatric CYP2D6 extensive and poor metabolizers. Biol Psychiatry 2001; 49 (8 Suppl.): 37S

Clin Pharmacokinet 2005; 44 (6)

590

60. Caccia S. Metabolism of the newer antidepressants: an overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 1998; 34: 281-302 61. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997; 32S: 1-21 62. Brøsen K, Hansen JG, Nielsen KK, et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 1993; 44: 34955 ¨ 63. Ozdemir V, Naranjo CA, Herrmann N, et al. Paroxetine potentiates the central nervous system side effects of perphenazine: contribution of cytochrome P4502D6 inhibition in vivo. Clin Pharmacol Ther 1997; 62: 334-47 64. Alderman J, Preskorn SH, Greenblatt DJ, et al. Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol 1997; 17: 284-91 65. Hemeryck A, Lefebvre RA, De Vriendt C, et al, editor. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Drug Metab Dispos 2001; 29: 656-63 66. Kobayashi K, Yamamoto T, Chiba K, et al. The effects of selective serotonin reuptake inhibitors and their metablites on S-mephenytoin 4′-hydroxylase activity in human liver microsomes. Br J Clin Pharmacol 1995; 40: 481-5 67. von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995; 15: 125-31

Sauer et al.

74. Sanburn N, Long A, Witcher J, et al. Co-administration of atomoxetine hydrochloride and midazolam results in no clinically significant drug-drug interaction. AAPS Annual Meeting and Exposition; 2001 Oct 21-25, Denver 75. Kronbach T, Mathys D, Umeno M, et al. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 1989; 36: 89-96 76. Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55: 481-5 77. Yuan R, Flockhart D, Balian J. Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol 1999; 39: 1109-25 78. Witcher JW, Kurtz DL, Sauer JM, et al. Pharmacokinetic/ pharmacodynamic relationship of atomoxetine exposure and efficacy in child and adolescent ADHD patients. Philadelphia (PA): American Psychiatric Association, 2002 79. Horai Y, Nakano M, Ishizaki T, et al. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther 1989; 46: 198-207 80. Zanger UM, Eichelbaum M. CYP2D6. In: Levy RH, Thummel KE, Trager WF, et al, editors. Metabolic drug interactions. New York: Lippincott Williams & Wilkins, 2000: 87-94 81. McLellan RA, Oscarson M, Seidegard J, et al. Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 1997; 7: 187-91

68. Jeppesen U, Gram LF, Vistisen K, et al. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996; 51: 73-8

82. Griese EU, Asante-Poku S, Ofori-Adjei D, et al. Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population. Pharmacogenetics 1999; 9: 715-23

69. Martin DE, Zussman BD, Everitt DE, et al. Paroxetine does not affect the cardiac safety and pharmacokinetics of terfenadine in healthy adult men. J Clin Psychopharmacol 1997; 17: 451-9

83. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002; 3: 229-43

70. Schmider J, Greenblatt DJ, von Moltke LL, et al. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation. Br J Clin Pharmacol 1997; 44: 495-8

84. Evans W, Relling M, Petros W, et al. Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children. Clin Pharmacol Ther 1989; 45: 568-73

71. Hemeryck A, De Vriendt C, Belpaire FM. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. Eur J Clin Pharmacol 1999; 54: 947-51

85. Relling M, Cherrie J, Schell M, et al. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects. Clin Pharmacol Ther 1991; 50: 308-13

72. Long A, Witcher J, Smith B, et al. Atomoxetine does not alter the plasma pharmacokinetics of desipramine in healthy subjects. AAPS Annual Meeting and Exposition; 2001 Oct 21-25, Denver 73. Spina E, Avenoso A, Campo GM, et al. Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects. Br J Clin Pharmacol 1997; 43: 315-8

© 2005 Adis Data Information BV. All rights reserved.

Correspondence and offprints: Dr Jennifer W. Witcher, Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Clin Pharmacokinet 2005; 44 (6)