LEADING ARTICLE

Clin Pharmacokinet 2000 May; 38 (5): 377-392 0312-5963/00/0005-0377/$20.00/0 © Adis International Limited. All rights reserved.

Choosing the Right Nonsteroidal Anti-Inflammatory Drug for the Right Patient A Pharmacokinetic Approach Neal M. Davies1 and Neil M. Skjodt2 1 Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia 2 Respiratory Research Group, University of Calgary, Calgary, Alberta, Canada

Abstract

Effective use of the growing number of nonsteroidal anti-inflammatory drugs (NSAIDs), a group that has recently been augmented by the introduction of the selective cyclo-oxygenase-2 inhibitors, requires adequate knowledge of their pharmacokinetics. After oral administration, the absorption of NSAIDs is generally rapid and complete. NSAIDs are highly bound to plasma proteins, specifically to albumin (>90%). The volume of distribution of NSAIDs is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding. NSAID binding in plasma can be saturated when the concentration of the NSAID exceeds that of albumin. Most NSAIDs are metabolised by the liver, with subsequent excretion into urine or bile. Enterohepatic recirculation occurs when a significant amount of an NSAID or its conjugated metabolites are excreted into the bile and then reabsorbed in the distal intestine. NSAID elimination is not dependent on hepatic blood flow. Hepatic NSAID elimination is dependent on the free fraction of NSAID within the plasma and the intrinsic enzyme activities of the liver. Renal elimination is not an important elimination pathway for NSAIDs, except for azapropazone. The plasma half-life of NSAIDs ranges from 0.25 to >70 hours, indicating wide differences in clearance rates. Hepatic or renal disease can alter NSAID protein binding and metabolism. Some NSAIDs with elimination predominantly via acylglucuronidation can have significantly altered disposition. Pharmacokinetics are also influenced by chronobiology, and many NSAIDs exhibit stereoselectivity. There appear to be relationships between NSAID concentration and effects. At therapeutically equivalent doses, NSAIDs appear to be equally efficacious. The major differences between NSAIDs are their therapeutic half-lives and safety profiles. NSAIDs undergo drug interactions through protein binding displacement and competition for active renal tubular secretion with other organic acids. When choosing the right NSAID for the right patient, individual patientspecific and NSAID-specific pharmacokinetic principles should be considered.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a structurally diverse group of therapeutic agents encompassing the salicylates, pyrazoles,

oxicams, fenamates, arylacetic acids and arylpropionic acids. Although there are differences between all of these agents in structure, NSAIDs have

378

many pharmacokinetic, pharmacodynamic and physicochemical similarities. Do NSAIDs differ in major ways? Why are there so many? These are reasonable questions that clinicians often ask. The pharmacokinetics of NSAIDs encompass a wide scientific and clinical scope, but this review will focus on clinically relevant NSAID pharmacokinetics. What determines the clinical utility and basic pharmacokinetics of NSAIDs will be reviewed. Clinical strategies for rationally selecting an appropriate NSAID at the right dose for specific patients with musculoskeletal disorders and selected other diseases will be discussed. The clinician must still recall that initial, adjunctive or alternative analgesics [e.g. local measures, paracetamol (acetaminophen) or opioids] may reduce the risk of NSAID toxicity and provide alternative symptom relief. 1. Determining the Clinical Utility of a Nonsteroidal Anti-Inflammatory Drug (NSAID) 1.1 Cyclo-Oxygenase Isoenzyme Inhibition

Cyclo-oxygenase (COX) metabolises arachidonic acid to prostaglandin H2, which in turn is metabolised to various other prostaglandins, prostacyclins and thromboxanes. Each of these daughter mediators has potent, complex and widespread inflammatory or thrombotic effects. Each may influence other immune cells or systems. NSAIDs inhibit the synthesis of prostaglandins via the inhibition of COX, resulting in anti-inflammatory, antipyretic and cytotoxic effects. Inhibition of prostaglandin synthesis is a major, but not the only, mechanism of NSAID action. COX consists of at least 2 very different isoenzymes.[1,2] COX-1 is a constitutively expressed (e.g. routinely synthesised) ‘cellular housekeeping’ isoenzyme found in many tissues. COX-1 regulates such functions as gastric cytoprotection and vascular homeostasis.[1] COX-2 is an inducible isoenzyme that is expressed in response to many stimuli, including cytokines, endotoxins, hormones, growth factors and mitogens. COX-2 is also con© Adis International Limited. All rights reserved.

Davies & Skjodt

stitutively expressed in brain neurons[1,3] and parts of the kidney.[1-3] The relative potencies of different NSAIDs as inhibitors of COX-1 or COX-2 are extremely variable. This COX selectivity is important in determining both the therapeutic and toxic effects of NSAIDs. It is postulated that inhibition of COX-1 reduces synthesis of cytoprotective compounds such as some prostacyclins, whereas inhibition of COX-2 can reduce inflammation and cell growth. Potent COX-2 inhibition may decrease cellular inflammation in rheumatic disorders. NSAIDs with high COX-1 : COX-2 inhibition are expected to cause more gastrointestinal (GI) toxicity. GI toxicity and the highly individual response often seen with NSAID therapy may be determined in part by the nature of the isoenzymes involved in a specific patient’s inflammatory condition and the differential efficacy of various NSAIDs to inhibit that isoenzyme form.[4] That the COX-1 : COX-2 selectivity of an NSAID correlates with its toxic or therapeutic effects is an attractive hypothesis to which several caveats must be applied. The results of cellular or animal experiments should be related cautiously to the clinical situation. Cellular models do not control for the type of NSAID formulation administered or organ- or tissue-specific NSAID effects. The relative COX-1 : COX-2 selectivity of an NSAID will depend on the laboratory model used. In vitro investigations of NSAID mechanisms of action are frequently conducted in media devoid of albumin. There may be other as yet unidentified COX isoenzymes. Other COX-independent effects may also mediate both NSAID toxicity and therapeutic effect. As expected, the discovery of the COX isoenzymes has prompted many pharmaceutical companies to search for molecules effective in inhibiting COX-2 with little or no effect on COX-1. Intensive efforts are now being made to develop selective inhibitors of COX-2, assuming that these agents will inhibit this isoform when it is induced at sites of inflammation, but will not inhibit prostaglandin synthesis in other tissues where COX-1 is constitutively expressed. COX plays a major role in the Clin Pharmacokinet 2000 May; 38 (5)

Choosing the Right NSAID

pathophysiology of rheumatoid arthritis and osteoarthritis. COX-2 is increased in synovial cells during inflammation.[5] Selective COX-2 inhibitors may provide significant new therapy.[6] Highly selective COX-2 inhibitors showed potent anti-inflammatory and analgesic effects in preliminary animal studies.[7] Will the theoretical advantages of selective COX-2 inhibitors produce real clinical benefits? Several COX-2 preferential inhibitors (i.e. nabumetone, etodolac and meloxicam) and more selective COX-2 inhibitors (i.e. celecoxib and rofecoxib) have been released. Only widespread use will confirm or refute their utility over COX nonselective NSAIDs. 1.2 Individual Response Variability

When used in equivalent doses, few if any therapeutic differences are noted amongst the NSAIDs in epidemiological studies. Hundreds of comparative clinical trails of different NSAIDs in rheumatic disorders have confirmed this conclusion.[8] There is, however, no doubt that individual patients may note significant differences in efficacy between different NSAIDs. Approximately 50% of patients respond to the first, 25% of nonresponders to the second and 10% of nonresponders to the third NSAID tried. Variable pharmacodynamics are probably responsible for an individual’s lack of response to a particular NSAID, as no discernible differences in pharmacokinetics between ‘responders’ and ‘nonresponders’ have been found.[9,10] In rheumatoid arthritis, pretreatment erythrocyte sedimentation rate and lymphocyte counts correlate with positive NSAID response.[11] Men, but not women, had decreased nocioception following ibuprofen administration; however, no gender specific differences in pharmacokinetics were noted.[12] Unfortunately, many diseases (e.g. rheumatoid arthritis) for which NSAIDs are used as anti-inflammatories/ analgesics occur more frequently in women than in men. 1.3 Adverse Effects

The clinical utility of a drug is determined as a compromise between therapeutic efficacy and ac© Adis International Limited. All rights reserved.

379

ceptable adverse effects. If a drug is effective but has intolerable toxicity, it is of no use to the patient. Given similar therapeutic effectiveness, tolerability is often the primary consideration in the choice of a particular NSAID. The promotion of the relative tolerability of an NSAID can be the principal determinant of its commercial success. The optimal way to prevent NSAID toxicity is to avoid NSAID use in high-risk patients. This is not always practical, given that many patients with arthritis require NSAIDs for daily functioning. The relative toxicity of NSAIDs is the subject of numerous studies with conflicting results in many cases. Many of these studies employ problematic case-control or cohort designs. Other studies rely on the voluntary or remote recall of adverse events. The use of laboratory testing, surveillance for drug interactions, dosage modification or antiulcer drugs are also often not reported or controlled. Can an understanding of pharmacokinetic and pharmacodynamics discern relative NSAID toxicity in clinical practice? Several incomplete answers have been established. A linear response between NSAID dose and upper GI bleeding has been demonstrated.[13] Ibuprofen appears to have a superior tolerability profile compared with other nonselective NSAIDs.[14] In contrast, indomethacin is more likely than other NSAIDs to be discontinued because of an adverse event.[14] Non-acetylated salicylates appear to be the least toxic of available nonselective NSAIDs.[14] Clinically, the newer NSAIDs nabumetone, etodolac and meloxicam appear to be less toxic, although serious GI and renal adverse effects do occur. A patient’s prior therapeutic and toxic responses to a given NSAID are presumed to predict future responses to that agent. 1.4 Formulation

NSAIDs can induce toxicity throughout the GI tract from mouth to anus.[14,15] Enteric coatings have been used to reduce local gastroduodenal NSAID toxicity. The enteric coating of several NSAIDs reduced endoscopic haemorrhage and inflammation in the stomach and duodenal bulb.[16,17] Enteric coatings increase distal mucosal exposure to NSAIDs Clin Pharmacokinet 2000 May; 38 (5)

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Davies & Skjodt

Table I. Chiral nonsteroidal anti-inflammatory drugs by class Arylpropionic acids Alminoprofen

Fenoprofen

Ketoprofen

Pranoprofen

Benoxaprofen

Flunoxaprofen

Loxoprofen

Suprofen

Bermoprofen

Flurbiprofen

Miroprofen

Tiaprofenic acid

Carprofen

Ibuprofen

Naproxen

Thioxaprofen

Cicloprofen

Indoprofen

Pirprofen

Ximoprofen

Arylalkanoic acids Butibufen

Etdolac

Indobufen

Metbufen

Clindanac

Flobufen

Ketorolac

Sulindac

Bumadizone

Oxyphenbutazone

Talnifumate

Nonacidic agents Azapropazone

where endoscopic monitoring is more difficult and greater toxicity predicted.[18] Similar proximal sparing and distal worsening of NSAID toxicity can also be predicted with sustained release formulations.[14,19] Difficulties diagnosing distal NSAID damage may increase the clinical severity of complications. A recent report revealed suspect diclofenac pill fragments at a distal site of ulceration and strictures.[20] sustained release, but not regular, diclofenac increased intestinal permeability in another study.[21] Preclinical experiments also demonstrate distal intestinal damage induced by sustained release and enteric-coated NSAIDs.[22] Experimental and clinical data both suggest that enteric-coated or sustained release NSAIDs may not reduce GI toxicity, but merely shift the problem distally. 1.5 Chirality

A structural feature known as chirality distinguishes certain NSAIDs from all others (table I). Chirality results when 3-dimensional repositioning produces different forms (enantiomers) of the same molecule. Most chiral NSAIDs are arylalkanoic acids. The most common and simplistic example of this chirality is an sp3-hybridised tetrahedral carbon atom to which 4 different atoms are attached. A chiral NSAID such as ibuprofen has 1 chiral carbon and exists as a pair of mirror image enantiomers. Although the chiral carbon atom predominates in pharmaceuticals, sulindac is an example of a racemic NSAID with a chiral sulfur atom. © Adis International Limited. All rights reserved.

Many of the chiral NSAIDs are marketed as racemates (i.e. a mixture of enantiomers) [table I]. Naproxen is the only NSAID to be internationally marketed and clinically used as a pure (S)-enantiomer. (S)-Ibuprofen has been available in Austria since 1994, and (S)-ketoprofen has been recently marketed in Spain. Several other stereochemically pure NSAIDs are currently under clinical development. Some NSAIDs (e.g. fenoprofen, ibuprofen) undergo a unidirectional inversion of the ‘inactive’ (R)-enantiomer to the ‘active’ (S)-enantiomer. Thus, stereospecific assay methods are required to study individual enantiomers. It may be misleading to relate either toxicity or efficacy to the racemic rather than enantiomeric drug concentration. The arylalkanoic acid derivatives etodolac and ketorolac have much lower plasma concentrations of the ‘active’ (S)-enantiomer than the ‘inactive’ (R)enantiomer.[23-26] The (S)-enantiomers of chiral NSAIDs were thought to possess almost all of the pharmacological activity of the racemate. However, more recent studies have demonstrated pharmacological effects of the (R)-enantiomers and their metabolites.[27] The toxicity of racemic ibuprofen would depend on the 1-way conversion of its (R)to (S)-enantiomer. Administering only (S)-ibuprofen would allow more uniform prediction of toxicity and therapeutic effectiveness.[28] Enantiomers and racemates have different physical properties. The individual enantiomers of NSAIDs have greater water solubility than their racemates.[29] An enantiomer may have more rapid Clin Pharmacokinet 2000 May; 38 (5)

Choosing the Right NSAID

absorption and consequently a shorter onset of analgesia. For acute pain and fever, enantiomer formulations may be superior to racemates. Stereochemically pure NSAIDs may provide safer and more efficacious alternatives to the currently marketed racemic NSAIDs. Excellent reviews are available describing the stereoselective pharmacological, pharmacodynamic and pharmacokinetic behaviours of chiral NSAIDs.[23-26] 1.6 Chronobiology

Clinicians and patients are well aware that some symptoms of chronic arthropathies vary within a day and between days. Such a pattern of morning stiffness is a major diagnostic criterion for rheumatoid arthritis. There is ample evidence that the pharmacodynamics and pharmacokinetics of a drug vary with time of day of administration because of physiological circadian rhythm.[30] Rheumatoid arthritis symptoms might be better relieved by administering analgesics so as to have peak effectiveness over peak periods of pain.[31] The majority of patients with rheumatoid arthritis have maximal pain in the evening. The absorption of ketoprofen is circadian with the most rapid absorption, slowest elimination and greatest area under the concentration-time curve (AUC) in the morning.[32] Ketoprofen may be of particular benefit to patients with predominant morning pain. Not surprisingly, morning and evening ketoprofen regimens resulted in better analgesia than morning and noon regimens.[32] Indomethacin has demonstrated chronobiological variation in pharmacokinetics (fig. 1). Maximum plasma concentrations are lower following evening compared with morning administration because of differences in volume of distribution (Vd) and will peak as peak plasma concentration.[33] Paradoxically, indomethacin has better analgesia with night compared with morning ingestion despite lower morning plasma concentrations.[34] NSAID adverse effects are greater after morning rather than evening administration.[30,35] NSAID effectiveness increases when administered a few hours before the peak of pain.[36] Evening doses are © Adis International Limited. All rights reserved.

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more effective in patients with predominantly nocturnal or early morning pain, whereas morning or midday doses are more effective in patients with greater afternoon or evening pain.[30,35] 2. Pharmacokinetic Properties 2.1 Absorption

NSAIDs are most often administered orally, but they are also administered topically, intraocularly, intravenously, intramuscularly and rectally. Conventional tablets, sustained release preparations, creams, gels, suppositories and eye drops are all commercially available. Although most NSAIDs are weak acids and can be absorbed via the stomach, the large surface area of the small intestine makes this the major absorptive site for orally administered NSAIDs. The absorption of NSAIDs from the GI tract has been well reviewed.[37] There has been considerable recent interest in the development of topical NSAIDs. When applied topically, these drugs are formulated to penetrate the skin barrier in sufficient amounts to reach the joints and muscles and exert therapeutic activity. Topically applied NSAIDs generally demonstrate very low concentrations in plasma and prolonged absorption rates. After topical application, some of the NSAID also reaches the systemic circulation. Concomitant drug therapy may create problems with drug absorption. There is concern that H2 antagonists, antacids and proton pump inhibitors will elevate gastric pH, altering gastric absorption of NSAIDs. The presence of food in the stomach can raise the pH from between 1 and 3 to between 3 and 5, changing the gastric concentration of an ionised drug. Peak concentration, but not AUC, often changes with acid suppression. The effects of other drugs and food may be greater with short term compared with long term NSAID administration. GI dysfunction may be increased in the elderly, but since NSAIDs are absorbed via passive diffusion they are not significantly affected.[37] The rate and extent of NSAID absorption are often difficult to measure because of the lack of intravenous forClin Pharmacokinet 2000 May; 38 (5)

97

99.7

99.8

95

>99.0

98-99

>90

98.7

99.2

99

99

>99 for 6-methoxy-2- 22.5-30 naphthylacetic acid

99

>99.5

>99

87

93.1 95.4 for sulindac sulfide

98

NR

Celecoxib

Diclofenac

Diflunisal

Etodolac

Flurbiprofen

Ibuprofen

Indomethacin

Ketoprofen

Ketorolac

Meloxicam

Mefenamic acid

Nabumetone

Naproxen

Oxaprozin

Piroxicam

Rofecoxib

Sulindac

Tiaprofenic acid

Tenoxicam

Vd (L/kg)

© Adis International Limited. All rights reserved.

0.12-0.15

0.4-1.0

NR

1.3

0.12-0.15

0.20

0.10

0.83

NR

0.1-0.2

0.48

0.11

0.12

0.15

0.1

0.4

0.10

0.12

5-6.4

0.102/70kg

0.036-0.084

NR

0.09

0.0024

0.0024

0.0042

NR

NR

0.0072

0.033

0.072

0.0024

0.045

0.018

NR

0.0066

0.22

0.36-0.48

0.6-3.6 (ASA) 4.2 (salicylate)

CL/F (L/h/kg)

Insignificant

<5

50-10

1

<5

<5

<1

Insignificant

<6

<0.25

5-10

<1

60-70

<1

2-3

Negligible

<5

<1

2

<2

Renal excretion (% unchanged)

CL/F = oral clearance; NR = not reported; t1⁄2β = elimination half-life; Vd = volume of distribution.

60

1.5-2.5

7 16 for sulindac sulfide

16-18

30-86

50-60

12-15

3-4

13-20

2.4-8.6

2-4

4.5-6

2-2.5

3-6

7

5-20

1-2

11-16

14-20 min (ASA) 0.15 2-15 min (salicylate)

85-95 for ASA

Aspirin (acetylsalicylic acid) [ASA]

t1⁄2β (h)

Bound in plasma (% of plasma total)

NSAID

Active metabolite(s)

Oxidation

Conjugation

Oxidation, reduction

Cytosolic enzymes

Oxidation

Oxidation, conjugation

Conjugation, oxidation

Oxidation

Conjugation

Oxidation

Conjugation

Conjugation

Oxidation, conjugation

Oxidation

Oxidation

Oxidation, conjugation

Conjugation, sulfation

Oxidation

Conjugation

No

No

Yes

No

No

Yes

No

Yes

No

No

No

No

No

No

No

No

No

No

No

Hydrolysis, conjugation to Yes amino acid and glucuronidation

Primary metabolic pathways

Table II. Pharmacokinetic properties of commonly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs)[39-41]

0

0

Extensive

NR

0

0-35

0

0

0

Extensive

0

0

Extensive

0

0

0

5-10

10-20

NR

0

Biliary excretion (% of total drug)

382 Davies & Skjodt

Clin Pharmacokinet 2000 May; 38 (5)

Choosing the Right NSAID

mulations for many NSAIDs. However, absorption is generally complete after oral administration, with the exceptions of aspirin (acetylsalicylic acid) and diclofenac. A recent report has suggested there may be a subset of patients who are unable to absorb enteric coated aspirin.[38] In addition, some disease states such as Crohn’s, diverticular disease and ulcerative colitis can affect both drug transit time and absorption.[37] Absorption may also influence the pharmacokinetics of NSAID enantiomers that undergo inversion.[28] (R)-Ibuprofen undergoes a unidirectional inversion to (S)-ibuprofen that appears to depend on the rate of drug absorption. If inversion takes place presystemically within the GI tract, then the longer that (R)-ibuprofen resides within the gut the more likely it is to undergo inversion. A significant positive correlation between the time to peak plasma concentration (tmax) and the S : R concentration ratio of ibuprofen has been observed.[28] Greater S : R AUC ratios in individuals with longer tmax values also support the correlation between absorption rate and ibuprofen enantiomer inversion.[28]

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that of plasma albumin and the Vd/F increases with dose. NSAIDs compete for binding sites with other highly plasma protein–bound drugs. If binding sites are occupied by other drugs, the plasma concentration of free and active NSAID increases at least transiently. The free plasma fraction of an NSAID may also be increased in various pathophysiological conditions (i.e. patients with secondary hypoalbuminaemia associated with active rheumatoid arthritis) [fig. 2].[42] 2.3 Synovial Fluid Distribution

The synovium is the most likely primary site of action for NSAIDs in rheumatoid arthritis, so synovial fluid NSAID concentrations are of clinical relevance. Some NSAIDs may become sequestered preferentially in the synovial fluid of inflamed joints, although there is large variability depending 6

0700h 1100h 1500h 1900h 2300h

5

The majority of NSAIDs share several physical properties in common: they are weakly acidic, lipophilic and bound extensively (>90%) to plasma albumin [table II]. Hence, only a small portion of the circulating drug in plasma exists in the unbound (pharmacologically active) form. NSAIDs, because of their acidic nature (typical pKa ≤6) are ionised at physiological pH. The apparent volume of distribution (Vd/F), determined after oral administration, is usually 0.1 to 0.3 L/kg, which approximates plasma volume. Tissue binding is appreciably less than plasma protein binding. As unbound drug is generally considered responsible for pharmacological effects, the extent of binding of NSAIDs to plasma proteins is an important determinant of their dispositions and actions. The binding of some NSAIDs (i.e. ibuprofen, naproxen, salicylate) is concentration-dependent because their plasma concentration approaches © Adis International Limited. All rights reserved.

Concentration (mg/L)

2.2 Plasma Distribution 4

3

2

1

0 0

1

2

4

6

8

10

Time (h) Fig. 1. Mean plasma indomethacin concentrations in 9 healthy

volunteers after a single dose of indomethacin 100mg administered at 0700, 1100, 1500, 1900 and 2300 hours (reproduced from Clench et al.,[33] with permission).

Clin Pharmacokinet 2000 May; 38 (5)

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Davies & Skjodt

Serum total naproxen (mg/L)

a

Time of active disease 8 Months later

120 100 80

60

40

30

Serum unbound naproxen (mg/L)

b 0.80 0.50 0.30 0.20

0.10 0.06

NSAIDs with long elimination half-lives, the concentrations in synovial fluid are lower than in plasma but closely parallel plasma concentrations. More studies are required to better characterise the relationship between the concentration of drug in plasma compared with other sites of action. The onset and duration of action of NSAIDs are often more accurately related to their concentration in synovial fluid rather than in plasma. The required frequency of NSAID administration cannot always be predicted from plasma half-lives. Twice daily administration of ibuprofen, ketoprofen, diclofenac or indomethacin is equally effective as more frequent administration.[45] Articular pharmacokinetics are important for determining the administration frequency of these drugs,[44] but are measured in only a few clinical studies. A therapeutic articular concentration of 150 to 300 mg/L has been suggested for aspirin in rheumatoid arthritis.[46] The clinical effectiveness (as demonstrated by decreases in morning stiffness and Lee’s functional index scores) and free synovial concentrations of naproxen are correlated.[47]

0.04

2.4 Elimination and Metabolism 0.02 0

2

4 6 8 Time (h)

10

12

Fig. 2. Naproxen concentration-time curves for total (a) and unbound (b) serum concentrations during long term therapy with

500mg twice daily in a patient with rheumatoid arthritis at the time of active disease and 8 months later when major improvements of disease activity had been achieved (reproduced from Van Den Ouweland et al.,[43] with permission).

on the NSAID and the administration schedule.[44] High plasma protein binding of NSAIDs decreases their transfer into synovial fluid. Indeed, the delayed distribution of NSAIDs into and out of synovial fluid may explain, in part, contrasting long durations of analgesia with shorter plasma half-lives. Plasma and synovial tmax values may be different and will vary with different NSAIDs. In the terminal phase of short half-life NSAIDs, such as ibuprofen, plasma concentrations show a good correlation with the concentration in synovial fluid. For © Adis International Limited. All rights reserved.

Most NSAIDs are metabolised by hepatic oxidation, hepatic conjugation, or both. The metabolites of some NSAIDs are active (i.e. aspirin, diclofenac and oxaprozin). Other NSAIDs, such as nabumetone and sulindac, are prodrugs whose metabolites are responsible for the pharmacodynamic effects of the drug. NSAID plasma elimination half-lives vary widely from 0.25 to 70 hours (table II). Differences in plasma elimination also determine administration frequency. First-pass hepatic clearance of NSAIDs is limited by blood flow delivering the drug to the liver, the rate of degradation by hepatic enzymes and the rate of excretion in bile. Usually enzymatic degradation is slower than hepatic blood flow delivering the drug, making the former the rate-limiting step in NSAID elimination. The plasma clearance of an NSAID is therefore the product of its unbound concentration and enzymatic degradation. Clin Pharmacokinet 2000 May; 38 (5)

Choosing the Right NSAID

Some NSAIDs undergo enterohepatic recirculation (table II). Some experimental evidence identifies biliary excretion as important in the pathogenesis of NSAID enteropathy,[48] whereas other data suggest major systemic contributions in NSAID enteropathy.[48] Several NSAIDs (i.e. aspirin, nabumetone) that do not undergo enterohepatic recirculation have all been found to induce enteropathy.[49] The toxicity of chiral NSAID enantiomers does not always agree with the extent of enterohepatic recirculation.[50,51] 3. Practical Recommendations for Administering NSAIDs 3.1 Optimal Analgesia

Many patients with chronic arthropathies require long term continuous treatment for adequate symptom control, whereas other patients take NSAIDs only intermittently. Compliance is better in patients with more severe symptoms and decreases with disease severity. Compliance may be less important if a sustained release formulation is used, or if an NSAID with a longer half-life is administered. For patients requiring long term therapy, formulations given once or twice daily may improve patient compliance. NSAIDs with a long half-life or a sustained release formulation may provide a therapeutic advantage in patients requiring long term therapy. Conversely, many patients need to use an NSAID only on an intermittent basis. In these patients compliance is less important, and the time to symptom relief (times to onset of and to maximal analgesia) is more relevant. regular release and rapid release formulations achieve more rapid analgesia than sustained release formulations. There are now rapid-onset formulations of several NSAIDs available. 3.2 Lowest Toxicity

There remains a dogma regarding the relationship between NSAID elimination half-lives and their toxicities. This hypothesis that the greater the half-life the greater the toxicity arose from post© Adis International Limited. All rights reserved.

385

market surveillance data.[52-57] However, there is no consistent pharmacokinetic data to support this assertion. Indeed, no correlation between NSAID adverse effects and half-lives has been suggested.[58] The lack of correlation is not surprising given its oversimplicity. Elimination half-life (t1⁄2β) is a composite function of the volume of distribution (Vd) and the total body clearance (CL) of the drug: t1⁄2β = 0.693 × Vd/CL

Although the Vd of NSAIDs is similar, the extent of their protein binding and clearance vary. Differing oxidation, conjugation, biliary excretion, enterohepatic recirculation and renal elimination are all of therapeutic relevance. Relating serum half-life to toxicity does not consider the influence of intrinsic pharmacological potency, as a molecule with a short half-life may have more or less potent effect than a molecule with a long half-life. For NSAIDs exhibiting nonlinear kinetics, the importance of plasma half-life, widely used by clinicians, is lost because this parameter is no longer a constant value. Consequently, there may be doseand exposure-related changes in the half-life of unbound drug. Relating serum half-life to toxicity does not explain how enantiomers of NSAIDs with equivalent half-lives have different toxicity profiles. Relating serum half-life to toxicity ignores that local NSAID toxicity may be determined by the local concentration of drug. Historically, benoxaprofen demonstrates how pharmacokinetics can affect pharmacodynamics. Pharmacokinetic studies indicated a t1⁄2β of 30 to 35 hours in healthy young adult volunteers,[59] and 54 to 353 hours in elderly patients with osteoarthritis.[60] Dosage selection based on young volunteers resulted in benoxaprofen accumulation in elderly patients. Consequently, fatal hepatic and GI toxicity occurred, leading to the withdrawal of benoxaprofen from the world market.[61,62] It is entirely possible that if age-related differences in benoxaprofen pharmacokinetics had been appreciated, toxicity could have been prevented (fig. 3). Reduced clearance will produce higher concentrations of drug in all tissues, as well as in plasma, unless the dosage Clin Pharmacokinet 2000 May; 38 (5)

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Davies & Skjodt

60 600mg (elderly patients n = 6) 600mg (healthy volunteers n = 20)

Concentration (mg/L)

50

40

30

20

10

0

0 3 5 7 12

24

36

48 60 Time (h)

72

96

120

Fig. 3. Mean plasma benoxaprofen concentrations in elderly patients and healthy volunteers.[60]

of the NSAID is reduced. Whether the peak plasma concentration of an NSAID or its AUC is a better determinant of toxicity remains to be answered. In the case of short half-life NSAIDs, an increase in administration frequency would be expected. Does this increased administration frequency increase toxicity or produce variable analgesia? Unfortunately, there are no definitive answers yet to these important questions. Systemic exposure, redistribution of the NSAID into the GI tract and enterohepatic recirculation may all affect toxicity. Once plasma steady-state is attained, more clearly defined control with less variation may also occur, but only with regular and frequent administration of short half-life drugs. NSAIDs with longer halflives do not achieve plateau plasma concentrations or maximal analgesia as fast as NSAIDs with short half-lives unless a loading dose is used. Changing a patient’s NSAID can be complicated: to either achieve a steady-state in, or remove the NSAID from, plasma requires greater than 3 half-lives. Toxicity may increase with concomitant NSAID administration, and plasma pharmacokinetics become complicated when more than 1 NSAID competes for the same binding sites. Therapeutic and toxic effects may be delayed. NSAID pharmacokinetics in inflamed synovium are poorly © Adis International Limited. All rights reserved.

described for single drugs, let alone multiple drug systems. There may be delays in appreciating either therapeutic or toxic effects from an NSAID. Concomitant changes in disease activity or symptom perception may be driving changes in therapy. The use of concomitant ‘disease-modifying’ agents (e.g. gold or methotrexate) may further complicate the assessment of therapeutic and toxic effects. Given this complexity, clinicians should be cautious in assigning therapeutic or toxic effects of NSAIDs until pharmacokinetic disposition is understood and other confounders are controlled. 4. Interpreting NSAID Pharmacokinetics Systematic shortcomings in pharmacokinetic studies of NSAIDs complicate their interpretation. Many studies report total (bound and unbound) drug concentrations, whereas only the unbound form is pharmacodynamically active. Other factors, in addition to total and unbound concentrations, influence the unbound concentration of a drug. Some NSAIDs exhibit dose-dependent nonlinear pharmacokinetics. Various disease states can change concentration-dependent protein binding, thereby altering NSAID distribution and clearance. Clin Pharmacokinet 2000 May; 38 (5)

Choosing the Right NSAID

387

4.1 Dose-Concentration Effects

There are essentially 4 types of dose-concentration relationships for NSAIDs that have been well reviewed: linear for both total and unbound (e.g. piroxicam); linear for total and nonlinear for unbound (e.g. salicylates); nonlinear for total and linear for unbound (e.g. naproxen); nonlinear for both total and unbound (e.g. oxaprozen).[61] Most NSAIDs do not exhibit concentration-dependent protein binding and have a linear dose-concentration relationship for total and unbound drug. NSAIDs such as naproxen and ibuprofen demonstrate nonlinear changes in plasma concentrations with varying doses. The clearance of unbound drug, however, remains constant and is independent of total concentration. Salicylate exhibits nonlinear total and linear unbound dose-concentration relationships. This pharmacokinetic paradox can be attributed to saturable plasma protein binding and capacity-limited metabolism of salicylate. Oxaprozin demonstrates marked concentration-dependent protein binding; however, at the same time it undergoes saturable metabolism. The inverse nonlinear unbound dose-concentration relationship of oxaprozin is clinically important. Accumulation of unbound drug is higher than predicted and, therefore, a rational recommendation considering unbound concentrations is to reduce the dosage whereas based on total drug concentrations it would be to increase the dosage.[63] Naproxen is another excellent example for which assessment of disposition using total drug concentrations is misleading and can be clarified only by considering unbound drug concentrations. Unbound concentrations of naproxen are higher in elderly patients and those with active rheumatoid arthritis, whereas bound drug concentrations match those in healthy volunteers (table III).[64] If assessing total

naproxen concentrations, then there is no change in disposition with age. This is clearly misleading, as the elderly have only half the ability to clear naproxen compared with younger patients and dosages should reflect this. Likewise, naproxen pharmacokinetics in patients with rheumatoid arthritis at the time of active disease and during remission are markedly different (fig. 1). 4.2 Concentration-Effect Relationships

Relationships between NSAID concentrations in biological matrices and their efficacy or toxicity may be clinically important, but are as yet incompletely explored. When evaluating concentration-effect relationships, the finding of no correlation between the 2 parameters does not exclude important relationships. Measures of pain or inflammation could be too inexact to reveal a relationship. Unbound drug concentrations should be measured, although this may be technically prohibitive or impossible. Disease heterogeneity, disease severity and variation in target tissue uptake need to be accounted for or, ideally, controlled. Naproxen has well-described concentration-effect relationships. Apparently linear anti-inflammatory actions that depend on the dose or plasma concentration in patients with rheumatoid arthritis are evident.[65] A dose-response relationship in the range of 250 to 1500mg daily has been demonstrated for naproxen in patients with arthritis. A serum concentration-response relationship is evident for trough naproxen concentrations, with a good therapeutic response being associated with serum concentrations of naproxen above 50 mg/L. Patients with rheumatoid arthritis who have trough serum concentrations under 18 mg/L do not appear to have a clinical response to naproxen.[65] The clinical response to naproxen in rheumatoid arthritis patients to both dose (500, 1000 and 1500 mg/day)

Table III. Naproxen pharmacokinetic parameters in elderly and young patients who received 375mg twice daily for 9 days[64] No. of patients

Mean age (y) [range]

Clearance (L/h) bound drug

unbound drug

bound drug

unbound drug

10

29 (22-39)

0.547 ± 0.083

396 ± 155

14.0 ± 1.6

9215 ± 4402

10

71 (66-81)

0.496 ± 0.079

213 ± 64

12.1 ± 1.7

3882 ± 1804

© Adis International Limited. All rights reserved.

Volume of distribution (L)

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and naproxen concentrations was assessed using articular index, mean grip strength and analogue pain score. Linear clinical responses to trough plasma concentrations of total drug were noted, although clinical improvement was less significant with increased doses.[66] Decreases in morning stiffness and the Lee Index (a functional index of rheumatoid arthritis) correlate with the free concentration of naproxen in synovial fluid, which is the proposed site of action.[47] Pain scores, perhaps being more subjective and variable, did not vary with the synovial concentration of naproxen.[67] Several other variables have been shown to influence the clinical response to an NSAID, including the number of NSAIDs already used, duration of the disease and psychological factors.[68] More recently, the relationships between plasma and synovial fluid naproxen concentrations and prostaglandin concentrations in these fluids have been evaluated. The data for inhibition of platelet COX1–derived thromboxane B2 by plasma naproxen were fitted to a sigmoid maximum effect (Emax) model, with the mean concentrations of drug producing 50% of Emax (EC50) being 7.7 ± 4.4 mg/L and 25.3 ± 22 μg/L based on total and unbound concentrations of naproxen, respectively. Nonuniform reductions in serum or synovial prostanoid concentrations with increasing concentration of naproxen were reported, but many of the prostanoid concentrations were near the detection limit of the assay.[69] NSAID chirality may confound the assessment of concentration-effect relationships unless concentrations of the active enantiomer are studied. A significant correlation between clinical efficacy, as assessed by articular index in patients with rheumatoid arthritis, and total serum ibuprofen has been demonstrated.[70,71] Furthermore, the AUC of (S)ibuprofen correlated with improvement in disability, rest pain and physicians’ global assessment of arthritis severity in 45 patients with hip or knee osteoarthritis treated with ibuprofen for 4 weeks.[72] Mean concentrations and trough concentrations of (S)-ibuprofen also correlated with improvement in disability. The trough concentrations of (S)-ibuprofen also correlated with physicians’ global assessment. © Adis International Limited. All rights reserved.

Davies & Skjodt

Interestingly, when total (R plus S) was substituted for (S)-ibuprofen these variables demonstrated similar correlations. Recent in vitro evidence suggesting that (R)-ibuprofenoyl-CoA thioester, a metabolite of (R)-ibuprofen, inhibits COX-2 may help reconcile these findings.[73] In addition, a positive correlation has been demonstrated between total ibuprofen concentrations and analgesic effect in patients with mild to moderate pain subsequent to third molar extraction.[74] Total serum concentrations of ibuprofen at 1, 2 and 3 hours postdose correlated significantly with global analgesic response as measured by the percentage of the sum of the pain intensity scores. The highest correlation between serum concentrations and pain intensity difference values was at 1 hour postdose.[74] The absorption, subsequent bioavailability, resultant onset of analgesia and resultant magnitude of analgesia of ibuprofen was increased using soluble granular compared with standard tablet preparations in patients with osteoarticular pain.[75] Concentration-effect relationships are not confined to anti-inflammatory and analgesic effects. The peak antipyretic response of ibuprofen occurred 1 to 3 hours after peak plasma concentrations had been achieved. An anticlockwise hysteresis was evident upon plotting total, (R)- or (S)-ibuprofen plasma concentration versus mean temperature difference and joining the points in temporal order.[76] Concentration-effect relationships are extremely important when considering NSAID toxicity. Understanding of such relationships may prevent excessive dosages in patients with intractable symptoms. Systemic concentrations of piroxicam appeared to be higher in patients with acute upper GI haemorrhage than in controls.[77] Preclinical studies also suggest discernible dose- and concentration-effect relationships between plasma concentrations of NSAIDs and GI adverse effects.[49,78] 5. Disease and Chronobiology Effects 5.1 Rheumatoid Arthritis

Although there has been a trend towards earlier use of disease-modifying drugs in recent years, Clin Pharmacokinet 2000 May; 38 (5)

Choosing the Right NSAID

NSAIDs remain first-line therapy for the treatment of rheumatoid and other inflammatory arthropathies. One of the clinical manifestations of rheumatoid arthritis that can alter the disposition of these drugs is low serum albumin. Hypoalbuminaemia increases the Vd of several NSAIDs (e.g. ibuprofen, naproxen) if total (bound plus unbound) concentrations are assayed (fig. 3). Clinically, the rate of NSAID removal in rheumatoid arthritis would be expected to be increased when compared with healthy individuals if the fraction of free drug in blood increases and provided that hepatic function is not significantly altered. 5.2 Renal Failure

Hypoalbuminaemia and increased circulating binding inhibitors have been implicated in the reduced plasma protein binding of NSAIDs seen in renal failure. A number of NSAIDs such as naproxen demonstrate an increase in Vd attributable to a reduction in protein binding.[79] Patients with renal disease may not be able to eliminate an NSAID or its metabolites effectively. Renally-excreted NSAIDs such as azapropazone may accumulate in renal failure.[80] Ketoprofen and naproxen are mainly metabolised via the acylglucuronidation pathway, and also accumulate in renal failure. Accumulation may result from the binding of the acylglucuronidated conjugated metabolite to intact NSAID, thus reducing the clearance of the NSAID. In elderly patients with renal failure, glucuronide conjugates are slowly eliminated, and the ester glucuronide, which is unstable, can be hydrolysed back to the parent compound. NSAIDs undergoing glucuronidation should be avoided in patients with renal failure.[81] The clearance of several other NSAIDs (e.g. tenoxicam and piroxicam) that are metabolised via oxidative pathways does not appear to be affected by renal failure.[39] Renal impairment is a risk factor for NSAID-induced renal toxicity, whether or not the NSAID is retained in renal failure, and thus in general all NSAIDs should be used with extreme care in patients with renal failure. Particular attention to concomitant drug therapy is also crucial. Extreme cau© Adis International Limited. All rights reserved.

389

tion is warranted with drugs that decrease renal perfusion, such as ACE inhibitors. 5.3 Hepatic Disease

The first-pass extraction of NSAIDs by the liver is low and therefore a reduction in liver function is not expected to change the rate or the extent of NSAID absorption.[39] Patients with hepatic dysfunction may have a reduced synthesis of albumin. As with renal failure, hypoalbuminaemia will alter the Vd of an NSAID. Hepatic dysfunction may cause lower basal metabolic rates, which will decrease NSAID metabolism. NSAIDs that are mainly eliminated by hepatic oxidative metabolism may require dosage reduction, or should be avoided in the presence of significant liver disease (ibuprofen, piroxicam, tenoxicam, diclofenac, flurbiprofen, nabumetone, sulindac).[82] Elderly patients with concomitant hepatic dysfunction are at particular risk if given these NSAIDs.[83] All NSAIDs have been associated with idiosyncratic hepatic toxicity. 5.4 Elderly Patients

Several NSAIDs have reduced clearances in the elderly including diflunisal, ibuprofen, naproxen, ketoprofen, sulindac, ketorolac and nabumetone.[39] Dosage reduction is indicated in these patients. Particular caution should be exercised with coexistent renal or hepatic dysfunction.[39] Drug therapy is commonplace in the elderly, but accounts for considerable morbidity and expense. The withdrawal of benoxaprofen from the market in the early 1980s illustrates the importance of evaluating differential NSAID-induced toxicity in the elderly.[61,62] The pharmacokinetic differences of NSAID disposition in the elderly have been well reviewed.[84] Distinguishing the effects of aging from coexistent disease is often difficult. Some studies have demonstrated that the clearance of ibuprofen, naproxen, ketoprofen, sulindac, ketorolac and nabumetone is reduced in elderly volunteers,[84] although other studies demonstrate no differences in the clearance of indomethacin, piroxicam, tenoxicam, etodolac and tiaprofenic acid.[85] Clin Pharmacokinet 2000 May; 38 (5)

390

Phase I metabolic reactions (i.e. oxidation, reduction and hydrolysis) may be decreased in the elderly and affect hepatic metabolism. Phase II metabolism (glucuronidation, acetylation and hydrolysis) are generally not affected. Physiological changes in the elderly consist of decreased hepatic blood flow, hepatic mass and enzymatic activity.[86] Hepatic enzyme activity can be reduced, and NSAIDs predominantly metabolised by oxidation have been shown to have longer plasma half-lives in elderly patients.[83] Glucuronide conjugates are eliminated slowly and the ester glucuronide can be hydrolysed back to the parent compound in elderly patients. Older patients often have impaired renal function. It has been found that in patients with renal failure, clearance of several NSAIDs (e.g. ketoprofen, naproxen) may be impaired.[81] The clinical significance of these metabolic changes in the elderly is not clear, but toxic NSAID accumulation may result. It is often prudent to initiate pharmacotherapy at a reduced dosage in elderly patients. 6. Drug Interactions It is important for clinicians to have knowledge regarding the pharmacokinetics of drugs being used in combination to anticipate the potential for interaction and minimise the consequences of an interaction if it occurs. Excellent reviews are available concerning NSAID drug interactions.[40,41,87] Multiple disease states are common in the elderly and as a result elderly patients frequently receive several medications concomitantly, increasing the possibility of drug interactions. With NSAIDs the most important interactions are pharmacodynamic in nature. NSAIDs may interact with antihypertensives (loop diuretics, thiazide diuretics, β-blockers and ACE inhibitors), antihyperglycaemics, digoxin, disease-modifying antirheumatic drugs and anticonvulsants.[40,41,87] Pharmacokinetic interactions include inhibition of renal lithium excretion, which can increase plasma lithium concentrations and the risk of toxicity.[40,41,87] NSAIDs also increase the risk of serious bleeding in patients taking warfarin by displac© Adis International Limited. All rights reserved.

Davies & Skjodt

ing warfarin from plasma protein binding sites, leading to higher free warfarin concentrations and therefore greater anticoagulation.[41,87] Some NSAIDs inhibit metabolism of phenytoin, thereby increasing plasma phenytoin concentrations and the risk of toxicity.[87] NSAIDs may reduce the clearance of methotrexate, thereby increasing plasma methotrexate concentrations and the risk of toxicity.[41,87] NSAIDs can cause or worsen azotaemia. If a patient is simultaneously receiving aminoglycosides, then aminoglycoside clearance can be reduced and toxic accumulation could ensue. NSAIDs can compete with other drugs for active proximal tubular secretion in the kidney (i.e. probenecid).[41,87] 7. Conclusions A clear understanding of NSAID pharmacokinetics for a given drug in a given patient are required to optimise therapy and minimise toxicity. Factors such as drug interactions, advanced age, organ impairment, dosage, formulation, chirality, chronobiology, protein binding and therapeutic half-life must all be considered. In the age of designer drugs and evidence-based therapy, further insightful study of pharmacokinetics may equally aid in improving patient outcomes. Acknowledgements Dr Skjodt is a clinical fellow of the Alberta Heritage Foundation for Medical Research.

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69. Day RO, Francis H, Vial J, et al. Naproxen concentrations in plasma and synovial fluid and effects on prostanoid concentrations. J Rheumatol 1995; 22: 2295-303 70. Greenan DW, Aarons L, Siddiqui M, et al. Dose-response study with ibuprofen in rheumatoid arthritis: clinical and pharmacokinetic findings. Br J Clin Pharmacol 1983; 15: 311-6 71. Greenan DM, Ferry DG, Ashworth ME, et al. The aspirinibuprofen interaction in rheumatoid arthritis. Br J Clin Pharmacol 1979; 8: 497-503 72. Bradley JD, Rudy AC, Katz BP, et al. Correlation of serum concentrations of ibuprofen stereoisomers with clinical response in the treatment of hip and knee osteoarthritis. J Rheumatol 1992; 19 (1): 130-4 73. Neupert W, Brugger R, Euchenhofer C, et al. Effects of ibuprofen enantiomers and its coenzyme A thioester on human prostaglandin endoperoxide synthases. Br J Pharmacol 1997; 122: 487-92 74. Laska EM, Sunshine A, Marrero I. The correlation between blood levels of ibuprofen and analgesic response. Clin Pharmacol Ther 1986; 40 (1): 1-7 75. Ceppi Monti N, Gazzaniga A, Gianesello V, et al. Activity and pharmacokinetics of a new oral dosage form of soluble ibuprofen. Arzneimittel Forschung 1992; 42: 556-9 76. Kauffman RE, Nelson MV. Effect of age on ibuprofen pharmacokinetics and antipyretic response. J Pediatr 1992; 121: 969-73 77. Wynne HA, Rawlins MD. Are systemic levels of nonsteroidal anti-inflammatory drugs relevant to acute upper gastrointestinal haemorrhage? Eur J Clin Pharmacol 1993; 44: 309-13 78. Davies NM, Jamali F. Influence of flurbiprofen dosage form on gastroenteropathy in the rat: evidence of shift in the toxicity site. Pharm Res 1997; 11 (6): 255-9 79. Held H. Elimination shalbwertszeiten und serum protein bindung des antirheumatikums naproxen bei niereninsuffizienz. Z Rheumatol 1979; 38: 111-9 80. Ritch AES, Perera WNR, Jones CJ. Pharmacokinetics of azapropazone in the elderly. Br J Clin Pharmacol 1982; 14: 116-9 81. Meffin PJ. The effects of renal dysfunction on the disposition of NSAIDs forming acyl-glucuronides. Agents Actions 1985; 17: 85-9 82. Brater CG. Drug-drug and drug-disease interactions with nonsteroidal anti-inflammatory drugs. Am J Med 1986; 80 (Suppl. 1A): 62-77 83. Richardson CJ, Blocka KLN, Ross SG, et al. Effects of age and sex on piroxicam disposition. Clin Pharmacol Ther 1985; 37: 13-8 84. Woodhouse KW, Wynne H. The pharmacokinetics of non-steroidal anti-inflammatory drugs in the elderly. Clin Pharmacokinet 1987; 12: 111-2 85. Orme M. NSAIDs in the healthy elderly. In: Famaey JP, Paulus HE, editors. Therapeutic applications of NSAIDs. New York (NY): Marcel Dekker, 1992: 191-210 86. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. Med Intell 1989; 321 (5): 303-9 87. Brouwers JRBJ, de Smet PAGM. Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet 1994; 27 (6): 462-85

Correspondence and offprints: Dr Neal M. Davies, University of Sydney, Faculty of Pharmacy, Sydney, NSW 2006, Australia. E-mail: [email protected]

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