Review Article

Clinical Pharmacokinetics 14: 287-310 (1988) 0312-5963/88/0005-0287/$12.00/0 © ADIS Press Limited

All rights reserved.

Clinical Pharmacokinetics of Clonidine D.T. Lowenthal, K.M. Matzek and T.R. MacGregor Department of Geriatrics and Adult Development and Department of Pharmacology, Mt Sinai School of Medicine, New York, and Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield

Contents

Summary ................. ............................................... ......................................................................287 I. Clinical Pharmacology of Clonidine ... .......................... ................................................... ...... 288 1. 1 Mechanism of Action ............... ........................................................................................ 288 1.2 Haemodynamic Effects ..................................................................................................... 289 1.3 Clinical Pharmacodynamics ....................... .................................... ..................................290 2. Clinical Pharmacokinetics of Clonidine ................................................................................291 2. 1 Assay Techniques ............................................................................... ...............................291 2.2 Dosage Form Interrelationships ....................................... .......... ..... ......................... ..... ..292 2.3 Biopharmaceutical Properties of Transdermal Clonidine ............................................. 294 2.4 Transdermal Clonidine Pharmacokinetics ....................... ............................ ................... 296 2.5 Pharmacokinetics During Renal Failure ......................................................................... 299 2.6 Pharmacokinetics in the Elderly ................................ ...................................................... 301 3. Pharmacodynamics of Transdermal C10nidine .... .............. ........ .......................................... 301 3. 1 Hypotensive and Biochemical Effects ............................................... .............................. 301 3.2 Plasma Concentration-Effect Relationship .................................................. ,.................. 303 3.3 Effect of Age on Clinical Response ................................................................................. 306

Summary

Clonidine is a centrally active antihypertensive agent effective in the treatment of mild. moderate and severe hypertension. alone or in combination with other drugs. Use of oral c10nidine has often been limited by side effects which include dry mouth and drowsiness. Transdermal c10nidine was therefore developed as an alternative to oral therapy. Ideally, a drug administered at a constant rate into the systemic circulation should attain steady-state concentrations with less peak-to-trough fluctuation than that associated with intermittent oral dosing. In theory. transdermal administration should thus minimise the adverse effects associated with peak plasma drug concentration, while avoiding the potential for decreased efficacy associated with trough levels. Clonidine has been incorporated into a small, pliable adhesive cutaneous delivery device designed to provide therapeutically effective doses of drug at a constant rate for at least 7 days. The transdermal therapeutic system is a laminate consisting of an external film impermeable to moisture and to the drug, a thin layer of active drug dispersed within a highly drug-permeable matrix. a membrane with a controlled intrinsic permeability regulating the rate of delivery of drug to the skin. and an adhesive coating that attaches the system to the skin surface. The permeation of drug through the skin occurs primarily by diffusion. Application of the c10nidine transdermal system to both normotensive and hypertensive

Clinical Pharmacokinetics of Clonidine

288

subjects has consistently reduced systolic and diastolic blood pressures. Maximum reduction in blood pressure occurs 2 to 3 days after initial application. and is maintained for at least 7 days or until the system is removed. The rate at which clonidine is presented to the skin surface is controlled by the microporous membrane: this rate is the same for all strengths of transdermal clonidine. the amount of clonidine released being proportional to its surface area. Thus. the daily dose is regulated by the area of skin covered. Typically. steady-state plasma concentrations are reached on the fourth day after initial transdermal system application. The lack of dose dependency in half-life and renal clearance estimates emphasise that the transdermal absorption of clonidine is linear. The plasma clonidine concentration produced by a particular transdermal dose varies considerably between individuals as a result of interindividual variation in renal clearance. For this reason. it is recommended that dosages be titrated up from the smallest system (3.5cm 1) until the desired pharmacological effect has been obtained. Blood pressure returns to pretreatment values over 3 to 4 days after removal of the transdermal system. Because the decline in plasma clonidine concentrations is slower following cessation of transdermal delivery than with oral therapy. rebound hypertension which has been observed in some patients upon abrupt cessation of high doses of oral clonidine does not appear to be a problem with discontinuing transdermal clonidine therapy. Blood pressure control with the transdermal clonidine system has been demonstrated to be equal to or in some cases better than that achieved with oral clonidine. Side effects associated with oral clonidine have been reported to be substantially reduced or eliminated in many patients. Additionally. once weekly transdermal clonidine dosing offers the potential for improved patient compliance.

Clonidine (fig. 1) is a centrally acting antihypertensive drug which is effective in the treatment of mild, moderate and severe hypertension. The purpose of this article is to review the available pharmacokinetic data for clonidine and to examine relationships between steady-state plasma concentrations and clinical efficacy.

1. Clinical Pharmacology of Clonidine 1.1 Mechanism of Action

The proposed mechanisms underlying the antihypertensive activity of clonidine are multiple (Isaac 1980; Reid et al. 1977; Wood 1979). The hypotensive action of clonidine appears due mainly

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Fig. 1. Structural configuration of clonidine.

to stimulation of central postsynaptic aradrenergic receptors (Kobinger 1978; Kobinger & Walland 1967). In addition, clonidine, as a partial agonist of presynaptic arreceptors, may interfere with the peripheral regulation of noradrenaline (norepinephrine) release (Haeusler 1976). Efferent sympathetic neuronal vasoconstrictor tone to the heart, kidneys and peripheral vasculature is diminished, while vagal tone to the cardiovascular system is enhanced, resulting in a reduction in total peripheral resistance, renal vascular resistance, heart rate and arterial blood pressure (Onesti et al. 1971). A measurable humoral manifestation of the sympatholytic action of clonidine during long term administration is a reduction in plasma catecholamines, especially noradrenaline (Hadeland et al. 1972; Mitchell & Pettinger 1981). Plasma noradrenaline concentrations are synchronously reduced with each decrease in blood pressure and increase in plasma clonidine concentration (Arndts et al. 1983; Louis et al. 1983; Thananopavarn et al. 1982). A significant correlation between clonidine dosing mean arterial pressure and reduced

289

Clinical Pharmacokinetics of C10nidine

noradrenaline excretion has been observed (Wing et a1. 1977). Suppression of plasma renin activity also contributes to the antihypertensive action of clonidine (Manhem et a1. 1982; Pettinger et a1. 1976; Wing et a1. 1977). The mechanism of this effect is debatable, but is most likely both central- and peripheral-mediated sympathetic inhibition. It has been suggested that renin suppression within the kidney is mediated by an inhibitory a-adrenoceptor mechanism (Houston 1982; Weber et al. 1976). The rapid reduction of blood pressure in patients with normal and high renin hypertension may be related to an acute inhibition of renin-angiotensin pressure mechanisms as well as a reduction in sympathetic tone. Clonidine has been found to reduce urinary aldosterone excretion in some studies. There is a positive correlation between plasma renin activity and decreased urinary aldosterone excretion (Houston 1982; Weber et a1. 1976); a significant decrease in aldosterone excretion is believed to reduce the development of fluid retention that would otherwise blunt the antihypertensive effect. Suppression of aldosterone, presumably secondary to the inhibition of angiotensin II and concurrent suppression of renin by clonidine, probably results in a greater reduction in blood pressure than from suppression of renin alone (Weber et a1. 1976). Aldosterone excretion has been reported to be decreased in clonidine responders but increased in clonidine non-responders (Niarchos et a1. 1978). Clonidine does not significantly alter glucose tolerance in diabetic patients. Administration of clonidine 0.4 mg/day for 6 weeks resulted in no significant change in fasting blood sugar or glucose tolerance (Sung et a1. 1971). In a total of 153 patients, no patient developed glucose intolerance, and in 3 patients with diabetes mellitus, control of blood sugar was unaltered (Houston 1982). Clonidine may suppress the hypoglycaemia-induced elevation of plasma adrenaline, but does not appreciably delay glucose recovery (Guthrie 1984; Guthrie et a1. 1983; Hadeland et a1. 1972; Pettinger 1980).

1.2 Haemodynamic Effects Clonidine produces haemodynamic effects that are mediated through both the heart and the peripheral vasculature system. The acute administration of clonidine reduces supine blood pressure, cardiac output, heart rate and stroke volume, with no consistent change in peripheral resistance. Administration of clonidine to patients in the upright position, however, causes a significant reduction in total peripheral resistance (Onesti et a1. 1971). The decrease in cardiac output is primarily due to decreased venous return to the right heart, secondary to systemic venodilation and bradycardia (Brest 198(}). Cardiac output gradually returns to normal over 4 to 6 weeks with continued administration of clonidine (Houston 1982) despite the continued reduction in total peripheral resistance. Magorien et a1. (1985) reported a significant reduction in preload (left ventricular filling pressure), and afterload (systemic blood pressure) after administration of clonidine, without marked alterations in other central and regional haemodynamic variables in patients with congestive heart failure. Following a 0.2mg oral dose, renal, hepatic and limb blood flow were unaltered, while reductions were noted in heart rate (10%), mean system pressure (14%) and pulmonary capillary wedge pressure (27%). Cardiac index and systemic vascular resistance fell slightly. Higher doses of clonidine (O.4mg) generally elicited similar haemodynamic effects; however, systemic vascular resistance was significantly diminished (21%) and cardiac index remained unchanged. There is no evidence of decreased myocardial contractility or an increase in pulmonary artery pressure following oral administration of clonidine (Pettinger 1980). Clonidine does not interfere with increases in cardiac output and oxygen consumption during exercise, and therefore exercise-induced hypotension rarely occurs (Muir et a1. 1969; Pettinger 1980). Significant alterations in renal plasma flow, renal blood flow, and glomerular filtration rate have not been reported (Fillastre et a1. 1973; Green et a1. 1984; Hossmann & Specht 1983; Hulter et a1. 1979; Onesti et a1. 1971), while renal vascular resistance

Clinical Pharmacokinetics of Clonidine

is reduced (Cohen et al. 1979; Rudd & Blaschke 1985). Renal blood flow and glomerular filtration rate remained unchanged, despite reductions in systemic blood pressure and cardiac output (Bock et al. 1982; Itskovitz 1980; Onesti et al. 1969). Mild sodium and water retention has been observed during clonidine therapy (Onesti et al. 1971), but reported inhibition of antidiuretic hormone release by clonidine during long term use is inconclusive (ltskovitz 1980; Pettinger 1980). Campesi and Massry (1983) reported a significant decrease in plasma volume and exchangeable sodium in hypertensive patients with normal renal function during treatment with clonidine. Thananopavarn et al. (1982) reported no sodium or change in measured intravascular volume during long term clonidine therapy.

290

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Pharmacodynamic studies of clonidine in both normotensive volunteers and in hypertensive subjects have demonstrated the antihypertensive effects of clonidine to be dose dependent. Significant correlations between drug effect and plasma clonidine concentrations have been observed (Kanto et al. 1982; Velasquez et al. 1983). The antihypertensive effect of clonidine follows the time course of plasma concentrations (fig. 2), and a therapeutic window has been proposed for the optimal effect (Davies et al. 1977; Wing et al. 1977). The blood pressure response is usually correlated with plasma concentrations between 0.2 and 2.0 J,Lg/L (Anavekar et al. 1982; Dollery et al. 1976; Frisk-Holmberg et al. 1984; Mroczek et al. 1973; Wing et al. 1977). At plasma concentrations above 1.5 to 2.0 J,Lg/L the antihypertensive effect of clonidine appears to be attenuated (Davies et al. 1977; FriskHolmberg et al. 1978; Wing et al. 1977b) and at plasma concentrations above 4 J,Lg/L no blood pressure reduction is observed (Wing et al. 1977). However, at levels exceeding 10 J,Lg/L mild hypertensive responses have been observed (Domino et al. 1986; Wing et al. 1977). It has been suggested that vasoconstriction mediated by peripheral postsynaptic and a-adrenergic

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1.3 Clinical Pharmacodynamics

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Fig. 2. Mean clonidine plasma concentration (L':,) and mean change in systolic (e) and diastolic (0) blood pressure (BP) in 5 healthy subjects administered 300#9 oral clonidine. From 001lery et al. (1976). with permission.

receptors may diminish the centrally-induced antihypertensive action (Wing et al. 1977b). Interindividual variation in sensitivity to the antihypertensive effects of clonidine have been reported (Davies et al. 1977). The effect on heart rate does not appear to be dose related. Clonidine consistently causes sedation and dry mouth, both of which are believed to be centrally mediated. A close relationship (fig. 3) exists between plasma drug concentration, degree of sedation and reduction in salivary flow (Dollery et al. 1976; Keranen et al. 1978). Decreased saliva production and sedation are maximal 1 to 2 hours after an oral dose, corresponding to peak plasma clonidine concentrations of 1.5 to 2.0 J,Lg/L (Anavekar et al. 1982; Kanto et al. 1982; Louis et al. 1983; Wing et al. 1977). A linear relationship between reduction in salivary flow and plasma clonidine has been observed (Wing et al. 1977). During long term

Clinical Pharmacokinetics of Clonidine

291

angiotensin II, have been reported to occur 24 to 72 hours after abrupt cessation of oral clonidine therapy (Houston 1981, 1982; Weber 1980). There appears to be a direct relationship between the daily clonidine dose and the occurrence of the withdrawal syndrome (Houston 1981). Several studies have confirmed the observation that an excessive rise in blood pressure and/or withdrawal symptoms rarely occur after discontinuation of clonidine when the total daily dose is less than 1.2mg (Houston 1981). To date, there have been few reports of rebound hypertension following cessation of transdermal clonidine therapy (Weber 1986).

oral dosing, some tolerance to the sedative and salivary flow effects has been observed (Wing et al. 1977). Hogan et al. (1981) observed attenuation of side effects with long term clonidine administration, with no correlation between plasma concentrations and incidence of side effects. Peripheral a-adrenergic stimulation is not significant except in the presence of high serum clonidine concentrations (Mroczek et al. 1973). Clonidine overdose can produce severe cardiorespiratory dysfunction and coma (Artman & Boerth 1983). Upon overdose, bradycardia, hypotension, pallor, arrhythmias and hypertension have been observed. The effect of clonidine overdose appears to depend upon the balance between central and peripheral a-adrenergic stimulation (Algren & Rodgers 1984; Domino et al. 1986). Rapid blood pressure elevation to pretreatment levels and generalised increases in sympathetic activity, with elevated serum and urinary catecholamines and high circulating levels of renin and

2. Clinical Pharmacokinetics of Clonidine 2.1 Assay Techniques Eight assays for clonidine in plasma are described in the literature. These are divided into the techniques of radioimmunoassay (RIA), gas chro-

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Fig. 3. Clonidine plasma concentration following administration of a single 300,ug oral dose in 2 subjects (top panel). Lower panel shows reported degrees of dryness of the mouth (e) and sedation (Ll) following administration of a single 300,ug oral clonidine dose, according to the following rating scale: 0 none; 1 some; 2 moderate; 3 severe; 4 intolerable. From Keranen et al. (1978),

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Clinical Pharmacokinetics of Clonidine

matography with mass spectrometry (GC/MS) and gas chromatography with electron capture detection (GC/ECD). Because the oral therapeutic dose of clonidine is generally 0.2 to 0.6 mg/day and clonidine is highly lipophilic, with a large volume of distribution, the resulting plasma concentrations at these therapeutic doses are in the submicrogram range to an upper level of approximately 2 p,g/L. The lower limit of therapeutic efficacy presents a problem in the analysis of clonidine in plasma for a single dose bioavailability study, but poses only minor problems, mostly instrumentation capability, for therapeutic drug monitoring. 2.1.1 Gas Chromatography with Electron Capture Detection Chu et al. (1979) developed a GC/ECD assay for clonidine in both plasma and urine. Diperfluoroacyl derivatives of clonidine and the 4-methyl analogue (as the internal standard) were formed and an extraction process was developed that permitted quantification to 25 ng/L from a 4ml plasma sample. The assay demonstrated the capability of easily following plasma concentrations after a single dose of 300p,g clonidine. The primary difficulty in this assay is the extraction procedure which uses a 4ml plasma sample, necessitating at least IOml of blood to be drawn per timepoint with no possibility of duplicate analysis. Edlund (1980) has also reported a GC/ECD assay for clonidine. The method consists of buffered serum being extracted on silica columns, alkylated with pentafluorobenzyl bromide, purified by extraction, and analysed by glass capillary GC/ECD. This procedure is difficult and few laboratories are equipped with capillary gas chromatographs with electron capture detectors. The extraction procedure is quite lengthy and calls for extraction on a silica column, which has not yet become a standard procedure within the therapeutic drug monitoring industry. Again, 5ml of plasma is needed, necessitating large sampling with little chance of analysing duplicate samples if a timepoint appears to be incorrect. The assay is capable of quantitating plasma concentrations in the nanogram per litre region.

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2.1.2 Gas Chromatography with Mass Spectrometry The next series of assays consists of GC/MS. This is the method of choice for any laboratory that has such equipment as it should give highly reproducible results. The first mass spectrometric assay was the method devised by Keranen et al. (1978). This assay was developed to measure plasma concentrations following administration of a single 300p,g clonidine dose in healthy subjects. In this study clonidine was isolated from 4ml of serum with 50ng of deuterium-labelled clonidine as the internal standard. The extraction procedure is quite lengthy and is followed by an on-column methylation and analysis by GC/MS. Again, the high volume of plasma needed per sample makes this assay quite difficult to use. Davies et al. (1979) described a mass spectrometric assay for clonidine in which isotopically labelled analogues of clonidine were synthesised and used as the internal standards. The procedure for making deuterium and I3C-labelled clonidine has been described (Hughes & Baille 1980). This assay previously used a large amount of plasma but has since been revised (Murray et al. 1981). An extraction procedure after derivatisation was added, which reduced background 'noise'. 2.1.3 Radioimmunoassays There are 3 radioimmunoassays available for measuring clonidine in human plasma. The first method, which Arndts et al. (1979) developed, used a tritium label. Subsequently, Arndts et al. (1981) described an RIA that employed an 1251 label, permitting quantitation to 10 ngjL, and eliminated the need for an extraction step. This assay was later modified by Farina et al. (1985), and it now has a detection limit of 2 ngjL, based on a 200p,1 sample. It is possible to analyse a hundred samples in triplicate per day using less than 1.0ml of plasma per sample.

2.2 Dosage Form Interrelationships The purpose of a dosage formulation is to deliver the active ingredient of a drug to its site of action in an amount sufficient to elicit a desired

Clinical Pharmacokinetics of Clonidine

pharmacological response. The ease of use and portability of dosage formulations are important criteria for clinical efficacy, as they influence patient compliance and acceptability. Dosage formulations have a marked effect on the pharmacokinetic and pharmacodynamic properties of clonidine. 2.2.1 Intravenous Infusion Following intravenous infusion, clonidine exhibits a multiphasic pharmacokinetic profile consistent with rapid but extensive distribution (Arndts et al. 1983; Davies et al. 1977; Frisk-Holmberg et al. 1981; MacGregor et al. 1985b). Clonidine is highly lipid soluble, readily penetrating extravascular sites as well as the central nervous system. This results in a large apparent steady-state volume of distribution of approximately 2 L/kg (Davies et al. 1977). The degree to which clonidine is bound in vitro by plasma or serum, primarily to human serum albumin, varies within the range of 20 to 40% (Heckner 1979; Hulter et al. 1979). There seems to be no change in plasma protein binding in patients with end-stage renal disease (Hulter et al. 1979). Clonidine readily crosses the placenta and its concentrations are equal in maternal serum and umbilical cord serum (Hartikainen-Sorri et al. 1987). Amniotic fluid concentrations are up to 4 times those found in serum. This is probably due to the inefficiency of the fetal liver in metabolising drugs and the high proportion of clonidine that is normally excreted unchanged. Clonidine concentrations in milk are roughly twice those in maternal serum, in serum of newborns concentrations are about half those found in the mothers (Hartikainen-Sorri et al. 1987). Clonidine metabolism in humans follows a relatively minor elimination pathway (Darda et al. 1978). The major metabolite formed, p-hydroxyclonidine, is present at less than 10% of the concentration of the unchanged drug, but can cause confusion in assay development (Arndts et al. 1979) because of its close structural similarity to the parent drug. Clonidine is cleared primarily by renal mechanisms (Arndts et al. 1983; MacGregor et al. 1985b)

293

with a mean renal clearance of 167 mlfmin (10 LI h) out of a mean total body clearance of 250 mlf min (15 L/h). It has been postulated that the drug not cleared by metabolic or renal pathways is enterohepatically recycled (Arndts et al. 1983). Mass balance excretion studies using 14C-labelled clonidine in humans showed 72% of the radioactivity was excreted in the urine within 96 hours, and 40 to 50% of the total radioactivity was unchanged clonidine (Darda et al. 1978). Following intravenous infusion of 'cold' clonidine (0.2mg) to 12 healthy volunteers, 42% of the dose was recovered as unchanged clonidine in the urine (MacGregor et al. 1985b). ·Arndts et al. (1983) recovered 60% unchanged drug in the urine following a 0.15mg intravenous infusion over 10 minutes. The harmonic mean terminal half-life of clonidine following intravenous infusion in healthy volunteers and hypertensive patients with normal renal function is approximately 8 to 13 hours [Davies et al. 1977 (5 male volunteers); FriskHolmberg et al. 1978 (15 male patients, 6 female patients); MacGregor et al. 1985b (12 male volunteers)], although one research group has reported a half-life of 20 hours (Arndts et al. 1983) in 7 volunteers (3 female). 2.2.2 Oral Administration The pharmacokinetics of oral clonidine have been reviewed previously (Arndts et al. 1983; Lowenthal 1980). Clonidine HCl when given as a tablet is well absorbed by the gastrointestinal tract, with an absolute bioavailability of75 (Davies et al. 1977) to 95% (Arndts et al. 1983; MacGregor et al. 1985b). Because of rapid absorption of clonidine HCI in a tablet form, the oral plasma clonidine concentration curve parallels the intravenous curve after reaching a peak at 1 to 2 hours (Arndts et al. 1983; Cohen & Katz 1978; Dollery et al. 1976). Pharmacokinetic data following single and multiple oral dosing of clonidine have been inconsistent. Davies et al. (1977) proposed a 2-compartment model for clonidine disposition, with a rapid distribution phase and an elimination half-life ranging from 5.2 to 13.0 hours following administration of a single 0.3mg dose. Dollery et al. (1976)

Clinical Pharmacokinetics of C10nidine

described plasma clonidine concentrations in normotensives, following an oral dose of 0.3mg, as fitting a I-compartment open model, with peak concentrations achieved within 1.5 hours and halflife ranging from 6 to 23.4 hours (mean half-life, 12. 7 hours). A change in pharmacokinetics during long term clonidine therapy has been suggested by FriskHolmberg et al. (1978, 1981). An increase in plasma clearance and decreased bioavailability, as well as an increase in half-life from 8 hours following a single dose to 14 hours following multiple dosing, was observed (Frisk-Holmberg et al. 1981). However, following a single 0.3mg oral dose, the plasma concentration-time profile of clonidine reported by Wing et al. (l977b) was similar to that reported by Davies et al. (1977), and half-lives following multiple doses (0.15mg 3 times/day) did not differ significantly from those following single doses. Amdts et al. (1983) observed no change in clonidine bioavailability after multiple dosing in normotensives and also found dose-linear behaviour, but reported an elimination half-life of 20 to 25.5 hours after single and multiple doses. Transdermal clonidine exhibits pharmacokinetic properties consistent with rate-limiting drug input to the systemic circulation. Since the transdermal formulation has only recently been introduced for clinical practice, its pharmacokinetic and biopharmaceutical properties are discussed in detail (sections 2.3 and 2.4). 2.3 Biopharmaceutical Properties of Transdermal Clonidine As specific drug assays for clonidine have become easier and afforded greater sensitivity, the pharmacokinetics of the drug have undergone further study (Amdts 1983; Amdts et al. 1983). These studies have shed light on, among other things, the pharmacokinetics of transdermally delivered clonidine. The clonidine transdermal system (CatapresTTS®) is a 4-layer laminate (Chandrasekaran et al. 1980) consisting of: an occlusive protective backing; a gelled, mineral oil-polyisobutylene-clonidine

294

reservoir lamina that is the source of the clonidine for the constant delivery rate; a microporous membrane that controls the constant dosage rate; and a gelled, mineral oil-polyisobutylene-clonidine contact adhesive layer by which the system is attached and which primes the skin with drug. Prior to use, a protective liner covering the adhesive layer is removed and discarded. The occlusive protective backing protects the system contents from environmental influences (water, light, air, dirt) and maintains the proper skin hydration for drug delivery. Because of the occlusive nature of the backing, use of an overlay does not affect the release properties of the system. The clonidine suspension in the reservoir layer assures zero-order delivery as long as the concentration in the reservoir is saturated (i.e. a constant concentration). For the clonidine transdermal system, this saturation is maintained in vivo for at least 7 days (MacGregor et al. 1985a; Shaw 1984), but probably not beyond 9 or 10 days (MacGregor et al. 1985a). The rate at which drug is presented to the skin surface is controlled by the microporous membrane. This membrane also acts as a 'fail-safe' mechanism for individuals who would rapidly absorb clonidine from an ointment or a skin-controlled device. This rate of presentation is the same for all strengths of transdermal clonidine, so that the daily dose is manipulated by the area of skin coverage. The sizes of the system (3.5, 7.0 and 1O.5cm 2) were chosen empirically to cover the antihypertensive therapeutic range by delivering clonidine at dosage rates of 100, 200 and 300 /lgl day (Shaw 1984). The non-aqueous contact adhesive was chosen for its adherence ability, minimal drug solubility, and the minimal transport resistance it offers the drug (Chandrasekaran & Shaw 1977). The dosage form is designed to provide ratecontrolled, continuous administration of drug over 7 days. Figure 4 illustrates the rate of release of clonidine from the transdermal system in vitro, using water at 32°C as the receptor solution. It is evident that the rate of release of drug from the system is approximately 5 times greater in the first 8

Clinical Pharmacokinetics of Clonidine

6.0

Fig. 4. Mean flux of clonidine (± SO. n = 10) from CatapresTIS" into infinite sink of water during 7-day functional lifetime of dosage form. From Shaw (1984). with permission.

hours, when the drug is being released from the adhesive, than the rate of release during the remainder of the 168-hour lifetime of the system, when the drug released comes from the reservoir (Shaw et al. 1984). This initial burst of drug from the adhesive in vitro primes the skin with drug (Chandrasekaran et al. 1980). The diffusional barrier properties of the skin dampen the sharp spike of drug seen in vitro (Berner 1985), resulting in a smooth, gradual plasma drug concentration rise to steady-state (MacGregor et al. 1985a; Shaw 1984) and continuous steady-state plasma drug concentrations upon system replacement (MacGregor et al. 1985a). Since the initial absorption of drug from the adhesive represents only 13 to 19% (fig. 5) of the total drug released over the 7 days of use, the term 'loading dose' used to describe the adhesive concentration is a pharmacokinetic misnomer. If a loading dose of clonidine is needed, concomitant oral clonidine administration should be considered during the first 2 days of transdermal use (Byyny et al. 1987). Following the initial release of drug from the adhesive with the application of each new system, the microporous membrane controls the release rate of dissolved drug from the saturated reservoir. To ensure that the system, and not the skin, controls the administration of drug to the systemic circulation, the system must deliver less drug per unit

295

area than the skin is capable of absorbing (Shaw and Chandrasekaran 1979). Because of the complex nature of drug transport from a polymeric device through an in vivo multilayer organ such as skin, exact models of drug transport, and therefore pharmacokinetic absorption models, are difficult to construct. To understand how the extent and nature of variability in skin permeability affects the overall in vivo release rate, a series of studies has been performed. Under occlusion, the surface temperature ofhuman skin ranges from 30 to 37"C in different regions of the body; these regions being (in ascending order of average temperature), thigh, forearm, back, chest, postauricular area (Shaw & Chandrasekaran 1979). Changes in skin temperature might be expected to modify the rate of drug released from a transdermal system as well as the permeability of skin. Hopkins et al. (1985) reported a diminution in clonidine release when a transdermal system was applied to the thigh compared with either an upper arm or chest site. Large changes in skin temperature for short periods, as might be expected from soaking in a hot tub, will have an influence on any dermal preparation. Assuming the activation energy for most drugs (Flynn et al. 1974) ranges between 7 and 20 kCalfmole (an extreme case) and the temperature of a hot tub is 45"C (also an extreme case), theoretically the flux of drug from any dermal system would double for the 15 to 30 minutes that the site is immersed in hot water. This would be equivalent to switching from a CatapresTTS®-1 to a Catapress-TTS®-2 for 15 to 30 minutes; however, clinical effects would be expected to be negligible. The release characteristics from the transdermal system were optimised using intact skin sites. Shaving of the site prior to application will strip off the stratum corneum and thereby interfere with the capacity of the skin to maintain a drug gradient (Shawet al. 1984). Evidence of altered transdermal release characteristics upon shaving was demonstrated by Hopkins et al. (1984) in one individual with high plasma clonidine concentrations following application to a freshly shaved chest. However,

Clinical Pharmacokinetics of Clonidine

controlled studies to elucidate the impact of shaving have not been carried out. The skin should be viewed as an anatomically complex perfused organ system that is regulated from within as well as environmentally. Although it is widely understood that the extent of perfusion varies with anatomical site (Guyton 1971), very few authors consider the tremendous changes in blood flow that take place within anyone anatomical site during a 24-hour period. At present, there is no direct technique for quantitation of total cutaneous blood flow, but stimuli such as heat, exercise, daily routine, barometric pressure and concurrent vasoactive drugs all alter the blood flow significantly. Cardiac output generally tends to increase 50 to 75% in the heat (rise of less than 50°C), but occasionally much lower or higher values are seen, particularly when conditions are extreme (Rowell 1974). Exercise studies in conditioned and nonconditioned athletes show initial periods of vasoconstriction followed by vasodilation based on the degree of conditioning (Greenleaf et a1. 1979; Stephenson et a1. 1984). Just the effort of a short walk after 8 hours of sleep in the non-conditioned patient will cause marked changes in cutaneous blood flow. Variations in cutaneous blood flow of 40% have been observed during sleep and the awake state because of blood flow redistribution to transport oxygen to the skeletal muscles of movement (Kaufman et a1. 1973). In humans, mild falls in barometric pressure, altering right arterial mean pressure without measurably changing heart rate or pulse pressure (Rowell 1975), can cause marked cutaneous and muscle vasoconstriction ('shivering' phenomena). The assumption in all transdermal transport models to date is that blood flow is sufficient at all times to carry drug away from the skin, i.e., 'sink' conditions exist at the vascular bed. However, a 'depot' of drug at the site of clonidine drug absorption has been suggested (MacGregor et a1. 1985a; Popli et a1. 1986; Shaw et a1. 1984). If this depot of drug does exist at the site of absorption, then pharmacokinetic models of transdermal drug absorption (Chandrasekaran et a1. 1978; Guy & Hadgraft 1985) constructed to date are too sim-

296

plistic. Evidence for a skin depot effect includes the persistence of drug absorption for approximately 12 hours following system removal (Popli et a1. 1986; MacGregor et a1. 1985a; Shaw et a1. 1984) and a slight increase in observed plasma clonidine concentrations immediately following removal (MacGregor et a1. 1985a), presumably from increased blood flow to the site due to adhesive friction. The duration and extent of this skin depot would vary with each individual wearer, but would not be expected to persist to a significant degree longer than 24 hours. As a general precaution it is recommended practice to move the site of application with each weekly dose. 2.4 Transdermal Clonidine Pharmacokinetics Factors such as site of application, dose titration, extent of system release and reproducibility of blood concentrations with long term application have an effect on the clinical pharmacokinetics of a transdermally delivered drug. Transdermally delivered clonidine was developed as an alternative to oral therapy. Whereas the typical oral regimen is 0.1 to 0.3mg twice daily, transdermally delivered clonidine can be administered once a week at system sizes of 3.5, 7.0 and 1O.5cm 2 for a programmed dose delivery rate of 0.1 to 0.3 mg/day. Transdermally delivered clonidine gives steady-state plasma concentrations similar to oral therapy without the 'peak and valley' effect (fig. 5). Following application of 5cm 2 transdermal clonidine to 17 normotensive volunteers, plasma concentrations of 400 ng/L were obtained on the third day of therapy (Shaw 1984). This mean plasma clonidine concentration remained constant through tout the next 4 days of system use. In the same 17 normotensive volunteers (random assignment crossover study design) oral clonidine 0.1 mg every 12 hours produced mean trough plasma drug concentrations of 400 ng/L. Peak plasma clonidine concentrations at steady-state measured on the fourth day of therapy (fig. 5) were 800 ng/L, giving a peak-to-trough ratio of 2, as is predicted for a drug being administered according to half-life.

297

Clinical Pharmacokinetics of Clonidine

t I

I

,

I

,

,

74

76

78

80

82

84

Time (h)

Fig. 5. Mean clonidine plasma concentrations (± SE, n = 17) on day 4 of use of either Catapres TIS· (e) or oral Catapres (A). Arrows indicate administration of oral doses. From Shaw (1984), with permission.

For a drug delivered transdermally at a zeroorder rate for 7 days, half-life is not as useful a parameter as total body clearance for determining the steady-state drug concentrations obtained. With transdermal clonidine, clearance varies among individuals, but is consistent within each individual (MacGregor et al. 1985a). For this reason doses should be titrated up from the smallest system (3.5cm 2 ) until the desired pharmacological effect is obtained. Because clearance is constant within individuals for transdermal clonidine, there is dose linearity when progressing from 3.5cm 2 through to 7.0cm 2 to the maximum size of lO.5cm 2 (MacGregor et al. 1985a). This should also hold for application of multiple systems, and limited data through to a size of 17.5cm2 seems to support this assumption (Klein et al. 1985). For long term therapeutic use in hypertension, various anatomical sites of application are needed to prevent potential skin irritation. MacGregor et al. (l985a) demonstrated that this could be accomplished if the patient progressively applied systems across the arms and chest (fig. 6). Hopkins et al. (1984, 1985) demonstrated that the thigh is not a favourable site. Their study also demonstrated that

the arm and chest had statistically significant differences in permeability (in descending order of permeability: chest, upper arm, thigh); that the thigh retains drug longer after system removal, suggesting a drug partitioning effect; and that shaving a hairy site prior to application causes rapid drug absorption and high plasma drug concentrations. The discrepancy between the two studies with respect to chest vs arm as a site of drug delivery is difficult to resolve. The populations chosen were different: 8 normotensive male volunteers in the study of MacGregor et al. (1985a) and 9 normotensive male volunteers and 3 normotensive female volunteers in the study of Hopkins et al. (1984). A clinically important difference between the two sites has yet to be reported. The standard recommended replacement time for the clonidine system is once a week. One major question encountered in clinical practice with dosing every 7 days is what would happen if the patient forgot for a day or two to remove the system. In one study 8 subjects wore the 3.5cm2 system for II days, and a decline in plasma mean clonidine concentrations was not seen until the tenth day (MacGregor et al. 1985a) [fig. 6]. Of the 8 subjects studied, 7 showed no perceivable decline in plasma clonidine concentrations through all II days, and I subject showed a significant decline after day 7. In another subject, plasma concentrations declined only after clonidine had been administered via the chest for 7 days. Thus, it can be expected in therapeutic use to be only a minor problem if systems are left on a day or two past the recommended removal date. MacGregor et al. (1985a) have shown that 20 to 40% of the drug remains in the transdermal system at II days (table I), the amount required to drive the drug from the system to the skin at a zero-order rate. In the 2 subjects in table I with declining plasma clonidine concentrations after 7 days (subjects 7 and 8), the percentage of the amount of drug in the system appeared to have reduced below the required threshold, and zero-order release was not maintained. The recommended 7-day replacement period for transdermal clonidine is conservative in order to cover all patients, as the reservoir still

298

Clinical Pharmacokinetics of Clonidine

r-

0.7

applied

:J" 0.6

~ c:

0.5

~

0.4

0

OIl 0

c: 0

0 OIl

0.3

c: '6 0.2 ·2 0

U 0.1 0 0

6 2 4 8 Time following first application (days)

10

12

Fig. 6. Time course of mean (± SE) plasma clonidine concentrations in 8 subjects receiving drug via a 3.5cm2 system on the arm (0) or chest (0) for 11 days (4 days past manufacturer's recommended removal date). From MacGregor et al. (1985a), with permission.

Table I. Percentage of clonidine dose (calculated after system residual analysis) released from transdermal system after 11 days' wear on chest or arm (from MacGregor et al. 1985) Subject no.

1 2 3 4 5 6 7 8 Mean ± SD

% Released arm

chest

62.7 54.9 51.9 68.8 51.0 75.6 72.6 81.7 64.9 ± 11.6

64.6 78.0 80.2 64.8 49.4 54.4 83.1 87.5 70.3 ± 14.0

contains approximately 50% of the drug load after 7 days' use (MacGregor et al. 1985a). Treatment of hypertension is a long term process. It is assumed that once a plasma steady-state concentration of c10nidine is reached using the transdermal system, it will be maintained with subsequent application offresh systems ofthe same size. This assumption was tested (MacGregor et al. 1985a) by multiple system changeover at steadystate with intensive sampling to evaluate c10nidine

plasma concentrations for the following 24 hours. There were no substantial increases or decreases in concentration during this time (fig. 7) with rises and falls in plasma concentrations being of the same magnitude as during studies in which there was no system changeover (see fig. 6, for example) and intense sampling occurring during the day. Evaluation of the 8 a.m. time point for each day showed no significant differences between plasma concentrations which were all within the range of 0.3 to 0.4 ILgfL, as would be expected with a 3.5cm2 system. In a limited study, Boekhorst and van Tol (1985) demonstrated that plasma c10nidine concentrations during transdermal therapy were not significantly different at 1 year from concentrations measured after 4 weeks of therapy. These studies suggest that once a patient is titrated to a desired system size, the plasma c10nidine steady-state concentrations achieved will be maintained for an extended period on that regimen. Although plasma c10nidine half-life estimates for individuals using transdermal delivery are not clinically useful, half-life estimates following system removal do serve as a useful research tool. The lack of dose dependency in the half-life and renal

299

Clinical Pharmacokinetics of Clonidine

clearance estimates emphasises that the transdermal absorption of clonidine is dose linear (MacGregor et al. I 985a). The half-life estimates observed of 14 to 26 hours (MacGregor et al. 1985a; Popli et al. 1986; Shaw 1984) are consistent with the concept that drug input to the systemic circulation is the rate-limiting step. Following system removal, plasma clonidine concentrations remain constant for 8 to 12 hours (MacGregor et al. 1985a; Popli et al. 1986; Shaw 1984), suggesting a skin depot effect. It has been suggested that this depot effect is useful in transdermal delivery to maintain plasma drug concentrations during system changeover (Berner 1985; MacGregor et al. 1985a). Because the decline in plasma clonidine concentrations is slower following cessation of transdermal than with oral treatment, Shaw et al. (1984) postulated that abrupt 'rebound hypertension' due to treatment discontinuation will be minimised. Because the apparent elimination half-life for transdermal clonidine is longer than the apparent elimination half-life of orally administered clonidine, the time to reach steady-state plasma concentrations will be longer for the transdermal preparation. Generally, steady-state plasma con-

centrations for transdermally administered clonidine are reached on the fourth day after initial application (MacGregor et al. 1985a; Shaw 1984). In summary, the steady-state plasma clonidine concentrations obtained following transdermal application are a function of the rate of delivery through the skin and clearance of the drug from the systemic circulation. Because the delivery rate is the slowest step, rather than elimination in oral therapy, and varies to some extent with the site of application, theoretical guidelines based on pharmacokinetic principles are difficult to construct for the conversion from oral therapy to transdermal therapy. Clinical efficacy and judgement should be the guide. From a pharmacokinetic perspective, patients should be titrated upward from the 3.5cm 2 size at weekly intervals. However, if a patient is being changed from an oral 0.3mg twice daily regimen, clinical rather than pharmacokinetic considerations should form the basis of judgement. 2.5 Pharmacokinetics During Renal Failure Approximately 50% of a clonidine dose is eliminated unchanged by the healthy kidney (Arndts et al. 1983; Davies et al. 1977; Dollery et al. 1976;

0.6

::J

~

0.5

c:

0.4

(I)

0.3

2 ~ c: u

t

il

i

c: 0

u (I)

c:

0.2

'6

·c 0 13 0.1 0 0

2 4 Time (days)

6

8

10

12

Fig. 7. Time course of mean (± SE) plasma clonidine concentrations in 8 subjects receiving drug via consecutively administered 3.5cm 2 transdermal systems at 0, 4 and 7 days. ~ = application; t = removal. From MacGregor et al. (1985a), with permission.

Clinical Pharmacokinetics of Clonidine

MacGregor et al. 1985b). Renal clearances of clonidine exceeding the glomerular filtration rate have been observed in some patients, suggesting renal tubular secretion of the drug (Davies et al. 1977). Considerable intersubject variability in renal clearance and total body clearance for oral (Davies et al. 1977; Hogan et al. 1981) and transdermal (MacGregor et al. 1985b) clonidine has also been observed. The half-life of clonidine is approximately 12 hours following oral or intravenous administration. As would be expected, the elimination halflife is prolonged in patients with compromised renal function. In the presence of severe renal insufficiency, the half-life may increase to greater than 40 hours (Fillastre et al. 1973; Hulter et al. 1979). Changes in endogenous creatinine clearance have generally been found to be predictive of decreases in the rate of elimination of drugs excreted by the kidney (Bennett et al. 1980). However, the need for adjustment of drug dosage in patients with end-stage renal disease is not only dependent upon the degree of renal impairment and percentage of drug cleared unchanged by the kidney, but also upon the therapeutic index of the particular drug (Bennett et al. 1980; Bjornsson 1986). The antihypertensive effect of clonidine follows the time course of plasma clonidine concentrations (see section 1.3); the blood pressure response is usually correlated with plasma levels between 0.2 and 2.0 J.Lg/L (Anavekar et al. 1982; Dollery et al. 1976; Frisk-Holmberg et al. 1984; Mroczek et al. 1973; Wing et al. 1977b). Above 1.5 to 2.0 J.Lg/L the antihypertensive effect of clonidine is reported to be attenuated (Davies et al. 1977; Frisk-Holmberg et al. 1978; Wing et al. 1977), possibly due to vasoconstriction mediated by peripheral postsynaptic a-adrenoceptors (Kobinger & Walland 1967). Interindividual variation in sensitivity to the antihypertensive effects of clonidine has been reported (Davies et al. 1977). The concentrationeffect relationship observed in patients with compromised renal function is markedly different from that seen in patients with normal renal function. Lowenthal et al. (1987) reported that 7 patients with end-stage renal disease, in whom clonidine con-

300

centrations exceeded the 'therapeutic window' of 0.2 to 2.0 J.Lg/L, had diastolic blood pressure below 90mm Hg. No correlation between diastolic blood pressure response and plasma clonidine concentrations was observed. A similar phenomenon of elevated clonidine plasma concentrations and control of systemic arterial blood pressure in renally compromised patient populations has been reported (Hossmann & Specht 1983; Lowenthal et al. 1985, 1986b). There is clinical evidence suggesting altered 0'adrenergic responsiveness in patients with reduced renal function (Kersh et al. 1974; Nies et al. 1979; Pickering et al. 1972; Romoff et al. 1978). Reduced sympathetic activity has also been observed during long term haemodialysis, and may be due to a reduced number or decreased sensitivity of 0'1- and a2-adrenoceptors (Brodde & Daul 1984). Quantitative changes in central as well as peripheral presynaptic and postsynaptic a-receptors in chronic renal insufficiency may therefore explain the differences in the pharmacodynamic activity of clonidine between renal patients and hypertensives with normal kidney function. Transdermal drug absorption in the renal patient is a potential problem because of histopathological changes in the skin that are manifestations of the duration and severity of renal failure (Scoggins & Harlan 1967). Marked thickening of the stratum corneum, flattening of the dermoepidermal junction, a reduction in the number of prickle cell layers, and cytological changes have been observed in the epidermal layer. Dilation of capillaries and lymphatics with endothelial swelling is seen in patients with mild azotaemia progressing to dermal atrophy with loss of blood vessels, hair follicles and sebaceous sweat glands in advanced renal insufficiency (Rosenthal 1931). In addition, moderate thickening of venular walls in the superficial dermis has been observed in patients undergoing maintenance haemodialysis (Gilchrest 1975). Although the comparative bioavailability of dermally and enterally absorbed clonidine has not been determined in patients with chronic renal insufficiency, the pharmacodynamic response to the rate-controlled transdermal administration of clon-

301

Clinical Pharmacokinetics of Clonidine

Table II. Mean plasma clonidine concentrations at steady-state following transdermal administration with different system sizes in the elderly and young Reference

Age group (y)

Klein et al. 60-74 (1985) Weber et al. 26-68 (1984c) MacGregor 18-45 et al. (1985a)

Clonidine concentration (pg/L) 3.5cm 2

7.Ocm2

10.5cm2

0.22

0.52

0.73

0.30

0.80

1.02

0.39

0.84

1.05

idine is therapeutically equivalent to that of oral dosing (Lowenthal et al. 1983, 1985, I 986b, 1988; Paran et al. 1985; Saris et al. I 984). Plasma c1onidine concentrations achieved with the transdermal system were comparable in magnitude to those achieved with oral administration in chronic renal failure patients (Lowenthal et al. 1988). The results of these investigations suggest that in mild to moderate hypertensive patients with varying degrees of renal impairment blood pressure can be controlled with once weekly application of transdermal c10nidine as effectively as with oral c1onidine, assuming proper dose titration is carried out. 2.6 Pharmacokinetics in the Elderly Transdermal c10nidine monotherapy appears to be effective in elderly patients with mild hypertension. Klein et al. (1985) studied 20 elderly, mild hypertensives (aged 60 to 74 years) and found the efficacy oftransdermal c10nidine in this group (85%) was at least as good as in a younger group aged 26 to 68 years (60%) reported by Weber et al. (I984c). The mean plasma c10nidine concentrations for the 3 different system sizes obtained at the time of initial blood pressure control (at least 2 weeks of therapy) in the Klein et al. (1985) study are comparable (table II), but consistently lower than the values reported in the young volunteers (aged 18 to 45 years) by MacGregor et al. (I985a) or in the young hypertensives reported by Weber et al. (1984c).

Significant age-related alterations in the skin barrier function have been documented (Roskos et al. 1986), which may have an impact on any transdermal drug delivery system. Klein et al. (1985) noted a tendency to require increasing system sizes to maintain adequate blood pressure control in the elderly hypertensive. This may be related to changes in skin permeability, severity of blood pressure or concomitant use by the elderly of tricyclic antidepressants. This observation again points to the need for titration with increasing system sizes until efficacy is obtained, rather than reliance on plasma c10nidine concentrations.

3. Pharmacodynamics Clonidine

0/ Transdermal

Application of the c10nidine transdermal system to hypertensive patients consistently reduces systolic and diastolic blood pressures. Maximum reduction in blood pressure is achieved 2 to 3 days after initial application and maintained for at least 7 days or until the system is removed. Blood pressure returns to pretreatment values over 3 to 4 days. A sustained reduction in heart rate does not occur during therapy. The severe rebound hypertension that has been observed in some patients upon abrupt cessation of high doses of oral c10nidine does not appear to be a problem when discontinuing transdermal c10nidine (Weber & Drayer 1984; Weber et al. I 984c). 3.1 Hypotensive and Biochemical Effects Worldwide clinical trials have evaluated the hypotensive and biochemical effects of transdermal c10nidine (Kolloch et al. 1985; Lowenthal et al. 1986a; McMahon et al. 1984). Blood pressure control with the transdermal c10nidine system has been demonstrated to be equal or in some cases better than that achieved with oral c10nidine (figs 8 and 9). The substitution of transdermal for oral therapy has not been associated with any loss of efficacy (Holzer et al. 1985; Weber 1986), nor does responsiveness to transdermal c10nidine therapy appear to be related to sex, race, age or bodyweight

Clinical Pharmacokinetics of Clonidine

Systolic

302

dose appear to vary among individuals, probably a result of interindividual variation in renal clearance (Boekhorst & van Tol 1985; Drayer & Weber 1983; Groth et al. 1984; Mroczek 1983; Popli et al. 1983). No unequivocal correlation between transdermal dosage and prior oral therapy has been established (Lowenthal et al. 1986). The symptomatic side effects usually associated with peak plasma concentrations following oral administration of clonidine occur with less frequency and severity during transdermal therapy (fig. 10). Drowsiness and dry mouth are mild and usually reported early in treatment (Weber 1986; Weber et al. 1984b,c). Consistent with earlier experience with oral clonidine, it has been reported that transdermally administered clonidine produces a decrease in plasma noradrenaline (Golub et al. 1985). Plasma renin activity and aldosterone levels are also decreased during transdermal administration of clonidine (fig. ll) [Weber 1986]. Klein et al. (1985) reported no change in plasma glucose concentrations during transdermal clonidine treatment. No significant change has been reported in diabetic control as measured by fasting plasma glucose concentrations and by glycosylated haemoglobin (Guthrie 1985), with no significant change in the severity of insulin-induced hypoglycaemia or rate

Diastolic

Q.

!II

.S CI)

01

c:

os

.c u c:

os CI) ::2

I

2

4 Time (days)

6 0

I

2

I

4

6

Time (days)

Fig. 8. Time course of mean decreases (± SE, n = 17 except for day 6 when n = 12) in blood pressure (BP) during and after use of oral clonidine 1mg every 12 hours for 4 days. From Shaw (1984), with permission.

(Falkner et al. 1985; Frohlich 1987; Jeunemaitre et al. 1987; Klein et al. 1985; Schaller et al 1984, 1985; Weber et al. 1984a). Plasma clonidine concentrations achieved with the transdermal system are comparable in magnitude to those achieved with oral administration, falling well within the proposed therapeutic range of 0.2 to 2.0 f.Lg/L, but do not display the variability inherent in intermittent oral dosing. Plasma concentrations produced by a particular transdermal

Systolic

Diastolic

-2

c;

0

E

2

Q.

4

.S

6

:x:

.s !II CI)

01

c:

os

.c

~

8

u

c: 10 co CI)

::2 12

I

0

4 2 Time (days)

6

8

10

0

2 4 Time (days)

6

8

10

Fig. 9. Time course of mean (± SE, n = 17 except for day 10 when n = 16) decreases in blood pressure (BP) during use and after removal of Catapres-TTS . System was applied at day 0 and removed at day 7. From Shaw (1984), with permission.

Clinical Pharmacokinetics of Clonidine

Incidence of side effects ("!o)

o

5 10 15 20 25 30 35 40 45 50

Local prUritus Erythema

DrowSiness

Dry mouth Hyperplgmentation and rough skin DIzziness

Gastric upset

Fig. 10. Incidence of side effects with transdermal cl(>nidine (_) compared with expected incidence of side effects with oral clonidine (EJ). After McMahon et al. (1984).

of recovery (Guthrie et al. 1985; Wallin et al. 1985). Transdermal c10nidine has been reported to inhibit noradrenaline, adrenaline and renin responses to hypoglycaemia, and potentiates growth hormone response without affecting basal growth hormone levels. Basal cortisol levels or cortisol response to hypoglycaemia are unchanged.

303

Administration of transdermal c10nidine resulted in the reduction of diastolic blood pressure to less than 90mm Hg in 12 of 20 mildly hypertensive patients (Weber et al. 1984c). Mean plasma clonidine concentrations in all patients studied were 0.3 ± 0.06 ILg/L (n = 20),0.8 ± 0.16 ILg/L (n = 10), and 1.02 ± 0.1 ILgjL (n = 13) following transdermal application of total surface areas of 3.5, 7.0 and 1O.5cm 2, respectively. A significant correlation between plasma c10nidine concentration and change in blood pressure was not observed, nor were significant correlations between treatment-induced changes in plasma renin activity or urinary aldosterone excretion and changes in blood pressure apparent. 24-Hour urinary sodium excretion remained constant. Plasma concentrations of creatinine, urea nitrogen, sodium and potassium were unchanged (table III). When treatment with transdermal c10nidine was discontinued, blood pressure increased gradually during the course of 1 week to levels similar to pretreatment measurements. Popli et al. (1983) evaluated transdermal clonidine therapy in 17 moderately hypertensive patients controlled with hydrochlorothiazide 15mg daily and oral c10nidine (mean daily dose 0.36 ± 0.16mg). Trough to peak plasma c10nidine concentrations obtained just prior to and 4 hours after

2.0r

1.5

~

":;;

:g

'"C C

~

",:2

3.2 Plasma Concentration-Effect Relationship The effectiveness of transdermal c10nidine therapy in controlling blood pressure in patients with mild to moderate hypertension has been reviewed in detail elsewhere (Langley & Heel 1987). Clonidine plasma concentrations have been monitored with respect to haemodynamic response and biochemical indices in the following clinical trials.

1,0

• p

br ! 1I

10 Q)

c

e

~ en 0

B:c '" '
1*

Een~

-'"

< 0.05

l*i*

0> "-

Cl.~

Control

oC \:

-~

::;)~

5

4 12 Duration of treatment (wks)

Fig. 11. Mean (± SEM) plasma renin activity (0) and aldosterone excretion rate (e) in 12 hypertensive patients during 3 months of treatment with clonidine transdermal systems. From Weber et al. (1984c). with permission.

Clinical Pharmacokinetics of Clonidine

304

Table III. Laboratory values (mean ± SEM; n = 12) during treatment with transdermal clonidine. From Weber et at (1984c)

Placebo

1 month

3 months

Serum urea nitrogen 158 ± 9.0 158 ± 9.0 162 ± 10.0 (mg/L) 11 ± 0.4 13 ± 0.5 Serum creatinine 12 ± 0.4 (mg/L) 53 ± 3.()Il Serum uric acid 60 ± 4.0 63 ± 3.0 (mg/L) Serum sodium 141 ± 6.0 140 ± 0.9 141 ± 0.8 (mEq/L) 4.5 ± 1.0 4.6 ± 1.0 4.6 ± 1.0 Serum potassium (mEq/L) Urinary sodium 117 ± 14 145 ± 21 119 ± 13 (mEq/24 hours) a p

< 0.01.

the usual morning clonidine dose averaged 0.86 ± 0.54 p.g/L and 1.26 ± 0.56 p.g/L, respectively. Oral clonidine was discontinued and replaced by a 3.9cm2 transdermal system programmed to deliver approximately 0.2mg clonidine per day over a 7day period. The total surface area applied each week was increased as needed (to a maximum area of 11.7cm2) to lower blood pressure to the same level achieved by oral clonidine. 15 of the 17 patients responded adequately to transdermal clonidine (table IV). Mean steady-state plasma clonidine concentrations were 0.70 ± 0.31 p.g/L (n = 8), 0.99 ± 0.65 p.g/L (n = 5), and 1.38 ± 0.18 p.g/L (n = 2) after application ofsurface areas of 3.9, 7.8 and 11. 7cm2 , respectively. Steady-state plasma concentrations 4 hours, 4 days and 7 days after transdermal administration did not significantly differ from one another. Drowsiness, dry mouth and sedation appeared to be less pronounced during transdermal clonidine than during oral therapy. Boekhorst et al. (1987) evaluated the efficacy of transdermal clonidine in maintaining control of mild to moderate hypertension in 31 patients previously controlled by oral clonidine and a diuretic. The average clonidine concentrations observed with transdermal efficacy were 0.539 p.g/L (n = 14),0.771 p.g/L (n = 9), and 1.841 p.g/L (n = 8) for surface areas of3.5, 7.0 and 1O.5cm2, respectively. The av-

erage clonidine plasma concentration of 9 patients maintaining blood pressure control during transdermal therapy was 0.907 p.g/L after 4 weeks and 0.764 p.g/L after I year of treatment. There was no significant difference between the controlled blood pressure values during oral therapy and those measured after I year of transdermal clonidine therapy. Transdermal clonidine therapy was compared with placebo in a double-blind trial in 30 patients with mild essential hypertension over a 5-week period (Popli et al. 1985, 1986). Patients were initially treated with a 3.5cm2 clonidine transdermal system or matching placebo. Dosages were titrated as necessary by increasing the surface area of the transdermal system to 7.0 or 10.5cm2• Diastolic pressures of less than 90mm Hg were achieved in II of 15 patients treated with clonidine, but in only 4 of 15 placebo patients (p < 0.0 I). The transdermal clonidine group evidenced significantly larger decreases in both systolic and diastolic blood pressure. Blood pressure and plasma clonidine concentrations (mean 0.58 ± 0.06 p.g/L) were stable throughout a representative 7-day period. The mean daily clonidine dose calculated on the basis of delivery rates of 0.1, 0.2 and 0.3 mgt day for the 3.5, 7.0 and 1O.5cm2 systems, respectively, was 0.2 ± 0.2 mg/day. Six patients were controlled by a 3.5cm 2 system, 3 patients required the 7.Ocm2 system and 2 the 1O.5cm2 system. Four patients did not achieve adequate blood pressure control during treatment with the 1O.5cm 2 system. Plasma clonidine concentrations were determined at 0, 24 and 48 hours after discontinuation of transdermal clonidine therapy. A non-log-linear decline of plasma clonidine concentrations was reported by the authors, with plasma half-lives of 34 ± 4.8 and 21 ± 4.7 hours for the first and second days, respectively, of the post-clonidine period. No evidence of rebound hypertension was observed. Plasma noradrenaline levels obtained 48 hours after discontinuation of transdermal clonidine therapy were not increased relative to baseline. Burris and Mroczek (1986) assessed the antihypertensive efficacy of transdermal clonidine in

Clinical Pharmacokinetics of Clonidine

305

25 patients with mild to moderate essential hypertension. Transdermal clonidine (3.9cm2) was substituted for oral clonidine and transdermal dosages were titrated until adequate blood pressure control (seated diastolic blood pressure < 90mm Hg) was obtained. Seated morning blood pressure during transdermal therapy averaged 129/90 ± 15/ 5mm Hg, compared with 136/96 ± 12f7mm Hg (p < 0.01/0.001) during oral clonidine administration. Blood pressures measured in the afternoon were virtually identical during oral and transdermal therapy. There was, however, less morning-to-afternoon variability in blood pressure and plasma clonidine concentrations during transdermal therapy. During oral therapy there was a significant difference between pre-dose morning (0.91 ± 0.49 ~g/L) and post-dose afternoon (1.23 ± 0.56 ~g/L) plasma concentrations. Plasma clonidine concentrations remained stable throughout transdermal therapy; no significant difference was noted between morning (0.89 ± 0.49 ~g/L) and afternoon (1.04 ± 0.64 ~g/L) concentrations (p > 0.05). Average morning plasma clonidine concentrations were 0.65 ± 0.23 ~g/L, 0.80 ± 0.67 ~g/L, and 1.57 ± 0.43 ~g/L following application of surface areas of 3.9, 7.8, and II. 7cm 2, respectively. There was a significant correlation between the surface area applied and the observed plasma concentrations. Side effects associated with oral clonidine, including dry mouth, drowsiness and sexual dysfunction, were reduced during transdermal therapy. 21 hypertensive patients controlled on oral

clonidine (0.15mg twice daily) were treated with transdermal clonidine for an average 7.2 ± 6 months (Holzer et al. 1985). No significant differences between the oral clonidine treatment (mean blood pressure 146/86mm Hg, pulse rate 71 beats/ min) and transdermal clonidine therapy (mean blood pressure 153/86mm Hg, pulse rate 72 beats/ min) were observed. Clonidine plasma concentrations, however, were significantly higher during oral treatment (1.04 ± 0.6 ~g/L) and showed a distinctly greater daily variation than during transdermal therapy (0.64 ± 0.35 ~g/L). Klein et al. (1985) evaluated the efficacy of transdermal clonidine in elderly patients as monotherapy for mild hypertension. Adequate diastolic blood pressure response was achieved in 17 of the 20 patients. Mean plasma clonidine concentrations were 0.22 ± 0.13 ~g/L (n = 12), 0.52 ± 0.16 ~g/ L (n = 2), 0.73 ± 0.26 ~g/L (n = 5), 1.22 ± 0.3 ~g/L (n = 5), 2.14 ± 0.42 ~g/L (n = 2), and 0.86 ± 0.22 ~g/L (n = 5) for programmed delivery of clonidine doses of 0.1 to 0.6 mg/day. Plasma noradrenaline levels were reduced during clonidine therapy; however, the magnitude of the decrement in plasma catecholamine levels was not correlated with initial catecholamine levels, initial blood pressure or treatment-induced decrease in blood pressure. Fasting plasma glucose levels increased slightly from 98 ± 20 mg/dl (n = 13) at baseline to 118 ± 127 mg/dl (n = 13) during the course of clonidine therapy, but were not correlated with plasma clonidine or noradrenaline concentrations.

Table IV. Mean blood pressure values and plasma clonidine concentrations (± SO) in 15 hypertensive patients (receiving hydrochlorothiazide) during treatment with oral clonidine (measured immediately before and 4 hours after an oral dose) and during transdermal clonidine treatment (measured 4 hours. 4 days. and 7 days after application of a transdermal system). From Popli et al. (1983) Oral treatment pre-dose Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Plasma clonidine concentration

138 ± 13 88 ± 4 0.9 ± 0.5

(,ug/L) a

p

< 0.05 vs

pre-dose measurement

Transdermal treatment post-dose 129 ± 8 85 ± 5 1.3 ± 0.6 8

4h 132 ± 10

86 ± 5 0.8 ± 0.4

4 days 128 ± 10 83 ± 5 0.9 ± 0.5

7 days 129 ± 8 86 ± 6 0.8 ± 0.4

Clinical Pharmacokinetics of Clonidine

Kolloch et al. (1985) evaluated transdermal clonidine therapy in 13 patients. All patients were treated for 2 weeks with a placebo transdermal system followed by 4 weeks of transdermal clonidine therapy. Transdermal dosage was titrated as necessary to achieve adequate reduction of blood pressure. Mean plasma concentrations of clonidine following the application of 1 clonidine system per week were 0.3 f.Lg/L. Mean clonidine plasma concentrations doubled on average when the surface area applied was doubled. Overall, clonidine plasma concentrations indicated drug absorption to be continuous and uniform throughout the observation period. There was a significant reduction of systolic and diastolic blood pressures in the supine and standing positions, with only a minor effect on pulse rate. After 2 weeks of transdermal clonidine, mean sodium excretion had risen from 156 to 176 mEq/24h (p < 0.05). After 4 weeks of transdermal clonidine treatment, the plasma noradrenaline concentration decreased from 488 to 335 ng/L and the urinary excretion of noradrenaline fell from 20.6 to 13.1 f.Lg/24h (p < 0.001). Glomerular filtration rate did not change during treatment. No effect on plasma lipid profiles was observed after 2 to 4 weeks of transdermal therapy. 32 patients with essential hypertension were studied by Groth et al. (1984). After a washout period of 2 weeks, all patients were treated with a placebo transdermal system. At the end of 1 week it was replaced by a 3.5cm2 clonidine transdermal system. Patients showing a good response (diastolic blood pressure less than 95mm Hg) continued therapy with one 3.5cm 2 transdermal system changed at weekly intervals. The dosage of clonidine was titrated to 7.0cm 2 in non-responders, and if blood pressure control was inadequate at subsequent visits, hydrochlorothiazide 50 mg/day was added. Transdermal clonidine therapy was maintained for up to 19 months. Average systolic and diastolic blood pressure decreased significantly from 162/107 ± 15/ 5mm Hg to 145/91 ± 14/5mm Hg after 4 weeks of transdermal therapy, whereas placebo transdermal therapy resulted in no significant blood pressure changes. At the end of the titration period,

306

blood pressure was adequately controlled (diastolic blood pressure < 95mm Hg) in 28 of 32 patients. Six patients showed good blood pressure response to the 3.5cm 2 transdermal system, 14 patients required the 7.Ocm2 transdermal system, and diuretic therapy was necessary in 12 patients. It was observed that patients responding to the 3.5cm2 transdermal system had significantly lower blood pressure values at baseline than those requiring the 7.0cm 2 clonidine system plus hydrochlorothiazide for blood pressure control. No significant differences were observed between blood pressures at baseline in those patients who received the 3.5cm2 or 7.0cm 2 transdermal clonidine systems. Three days after initial application of a 3.5cm 2 clonidine transdermal system, mean plasma concentrations were 0.27 ± 0.9 f.Lg/L. After 7 days, just prior to the application of a new system, plasma clonidine com:entrations were nearly unchanged at 0.29 ± 0.07 f.Lg/L. Plasma concentrations ranged from 0.49 ± 0.15 to 0.57 ± 0.12 f.Lg/L following application of a 7.0cm2 system. Further measurements during the stable dose period showed no significant plasma clonidine fluctuations in either treatment group, with I exception. In this patient, blood pressure had been well controlled with transdermal clonidine for 8 weeks when treatment had to be discontinued because of intolerable fatigue and nightmares. Clonidine plasma concentration on the day of discontinuation from the study was 1.14 f.Lg/L, 3 times higher than expected during application of a 3.5cm2 system. 3.3 Effect of Age on Clinical Response Jeunemaitre et al. (1987) assessed the efficacy of transdermal clonidine in patients with mild uncomplicated hypertension. 17 young patients (mean age 26 years) and 18 elderly patients (mean age 68.5 years) were included in a double-blind placebo crossover study. The effect of transdermal clonidine or a transdermal placebo on blood pressure control was studied. One or two 3.5cm 2 transdermal systems were applied during the course of four 2-week periods.

Clinical Pharmacokinetics of Clonidine

In the younger patients treated with placebo, the average fall in systolic and diastolic pressures was 9.S ± 7.0 and 3.7 ± 6.0mm Hg, respectively, versus 14.7 ± 14 and 9.6 ± 10mm Hg when a 7.Ocm2 transdermal clonidine patch was applied. The differences in response between clonidine and placebo were significant (p < 0.005, p < 0.05). With clonidine, 13 of 17 young patients had blood pressures ofless than 140/90mm Hg versus only patients receiving placebo. There was no treatment-order interaction. In the older subjects, the fall in blood pressure was 3.2 ± 7/0.7 ± 6mm Hg with placebo and 12.5 ± 14/6.7 ± Smm Hg with transdermal clonidine (7.0cm 2). 12 of the IS older patients had blood pressure less than 160/90mm Hg on clonidine versus only 1 patient receiving placebo. The initial heart rate was more rapid in the group of younger patients than in the older patients. In the younger group the same reduction in heart rate occurred with placebo as with clonidine. Heart rate did not change with placebo but significantly decreased with clonidine in the older group. Mean clonidine concentrations were similar in both groups: 0.51 ± O.IS p.g/L in young patients (n = 14) and 0.49 ± 0.17 p.g/L (n = 13) in older patients following application of a 3.5cm2 system, and 0.S9 ± 2.6 and 0.91 ± 0.34 p.gfL, respectively, for a system of 7.0cm 2 • Age did not appear to affect the extent of clonidine absorption.

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Clinical Pharmacokinetics of Clonidine

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Authors' address: Professor D. T. Lowenthal. Mount Sinai School of Medicine, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029 (USA).