Darcy Mulford

Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function.

OBJECTIVES This study sought to determine whether known genetic, drug, dietary, compliance, and lifestyle factors affecting clopidogrel absorption and metabolism fully account for the variability in clopidogrel pharmacokinetics and pharmacodynamics. BACKGROUND Platelet inhibition by clopidogrel is highly variable. Patients with reduced inhibition have increased risk for major adverse cardiovascular events. Identification of factors contributing to clopidogrels variable response is needed to improve platelet inhibition and reduce risk for cardiovascular events. METHODS Healthy subjects (n = 160; ages 20 to 53 years; homozygous CYP2C19 extensive metabolizer genotype; no nicotine for 6 weeks, prescription drugs for 4 weeks, over-the-counter drugs for 2 weeks, and no caffeine or alcohol for 72 h; confined; restricted diet) received clopidogrel 75 mg/day for 9 days, at which time clopidogrel pharmacokinetic and pharmacodynamic endpoints were measured. RESULTS At steady-state, clopidogrel active metabolite (clopidogrel(AM)) pharmacokinetics varied widely between subjects (coefficients of variation [CVs] 33.8% and 40.2% for clopidogrel(AM) area under the time-concentration curve and peak plasma concentration, respectively). On-treatment vasodilator stimulated phosphoprotein P2Y(12) platelet reactivity index (PRI), maximal platelet aggregation (MPA) to adenosine phosphate, and VerifyNow P2Y12 platelet response units (PRU) also varied widely (CVs 32% to 53%). All identified factors together accounted for only 18% of intersubject variation in pharmacokinetic parameters and 32% to 64% of intersubject variation in PRI, MPA, and PRU. High on-treatment platelet reactivity was present in 45% of subjects. CONCLUSIONS Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite rigorous exclusion or control of known disease, polymorphisms (CYP2C19, CYP3A5, ABCB1, PON1), noncompliance, co-medications, diet, smoking, alcohol, demographics, and pre-treatment platelet hyperreactivity. Thus, as yet unidentified factors contribute to high on-treatment platelet reactivity with its known increased risk of major adverse cardiovascular events. (A Study of the Effects of Multiple Doses of Dexiansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants: NCT00942175).

A Randomized, 2-Period, Crossover Design Study to Assess the Effects of Dexlansoprazole, Lansoprazole, Esomeprazole, and Omeprazole on the Steady-State Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Volunteers

OBJECTIVES The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel. BACKGROUND Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel. METHODS A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y(12) platelet reactivity index, maximal platelet aggregation to 5 and 20 μmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units. RESULTS Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units. CONCLUSIONS Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole.

Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials.

ABSTRACT Background: Dexlansoprazole MR is a novel Dual Delayed Release formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing. Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR. Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n = 40), subjects received dexlansoprazole MR 60, 90, and 120 mg and lansoprazole 30 mg QD. In study 2 (n = 45), subjects received dexlansoprazole MR 30 and 60 mg and lansoprazole 15 mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure. Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma concentration–time profile following administration of dexlansoprazole MR was characterized by two distinct peaks and a prolonged drug exposure during the 24-h dosing interval. Approximate dose proportionality was observed for mean peak plasma concentration and area under the plasma–concentration time curve after administration of dexlansoprazole MR. In each study, doses of dexlansoprazole MR generally produced greater gastric acid suppression than lansoprazole. Based on the exposure–response analysis using combined data from these two trials, the predicted mean 24-h intragastric pH values were 4.06 and 4.35 for the dexlansoprazole MR 30- and 90-mg doses, respectively. The percent of time pH > 4 over 24 h values were 59.2% and 66.7% for dexlansoprazole MR 30 and 90 mg, respectively. No appreciable additional gain in the pharmacodynamic response was predicted for dexlansoprazole MR 120 mg. Despite combining data from two studies to evaluate a broader dose range, this analysis provided a reasonable estimate of the pharmacodynamic parameters and a good characterization of the dexlansoprazole MR exposure–response relationship. Conclusions: Dexlansoprazole MR, a proton pump inhibitor that uses Dual Delayed Release technology, produced a pharmacokinetic profile with a plasma concentration–time curve characterized by two distinct peaks and an extended duration of pharmacologically active dexlansoprazole concentration in plasma. Exposure–response analysis indicated a progressive increase in the pharmacodynamic response as dexlansoprazole MR doses increased from 30 to 90 mg.

Metabolism and Excretion of [14C] Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase, in Healthy Male Subjects

Absorption, metabolism, and excretion of one 80 mg oral dose of [14C] febuxostat ([thiazole‐4‐14C] 2‐[3‐cyano‐4‐isobutoxyphenyl]‐4‐methyl‐5‐thiazolecarboxylic acid) were studied in 6 healthy subjects. Mean cumulative recovery in excreta was 94% (49% urine and 45% feces) of the dose over 9 days; 87% of the dose was profiled. Seventeen radioactive peaks were observed in urine and fecal chromatograms. Unchanged febuxostat contributed to a combined total in excreta of 10% to 18% of the dose, indicating that it was extensively metabolized and well absorbed. Metabolites were 67M‐1 (10%) and 67M‐2 (11%) hydroxylated febuxostat, febuxostat acyl‐glucuronide (30%), 67M‐4 di‐carboxylic acid (14%), 67M‐1 sulfate conjugate (3%), and dehydrated 67M‐1/67M‐2 acyl‐glucuronide (0.5%). Febuxostat and these metabolites accounted for 82% of profiled dose; unidentified peaks individually contributed <1.3% of the dose. Febuxostat and total radioactivity plasma Cmax values were observed at 0.5 hour postdose, suggesting that febuxostat was quickly absorbed. At 4 hours postdose, plasma chromatographic profiles contained 6 peaks: febuxostat (85%), 67M‐1 (4%), 67M‐2 (5%), febuxostat acyl‐glucuronide (4%), 67M‐4 (1%), and 67M‐1 sulfate (0.5%). Compared to total radioactivity, febuxostat accounted for 94% at Cmax and 83% of the area under the concentration‐time curve (AUC) values. Based on the whole blood to plasma total radioactivity, little radioactivity was associated with red blood cells.

The effect of time-of-day dosing on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR: evidence for dosing flexibility with a Dual Delayed Release proton pump inhibitor

Aliment Pharmacol Ther 31, 1001–1011

Drug interaction studies with dexlansoprazole modified release (TAK-390MR), a proton pump inhibitor with a dual delayed-release formulation: results of four randomized, double-blind, crossover, placebo-controlled, single-centre studies.

AbstractBackground and objective: Most proton pump inhibitors are extensively metabolized by cytochrome P450 (CYP) isoenzymes, as are many other drugs, giving rise to potential drug-drug interactions. Dexlansoprazole modified release (MR) [TAK-390MR] is a modified-release formulation of dexlansoprazole (TAK-390), an enantiomer of lansoprazole, which employs an innovative Dual Delayed Release™ technology designed to prolong the plasma dexlansoprazole concentration-time profile following once-daily oral administration. As with lansoprazole, dexlansoprazole is metabolized mainly by CYP3A and CYP2C19. Based on in vitro studies, dexlansoprazole has the potential to inhibit activity of these isoenzymes and also may induce human hepatic CYP1A and CYP2C9 activity. To determine whether dexlansoprazole has an effect on these isoenzymes in vivo, drug interaction studies with dexlansoprazole MR were conducted. Methods: Four separate randomized, double-blind, two-way crossover, placebo-controlled, single-centre studies were conducted in healthy volunteers to evaluate the effect of dexlansoprazole on the pharmacokinetics of four test substrates (diazepam, phenytoin, theophylline [administered as intravenous aminophylline] and warfarin), which were selected based on in vitro and/or in vivo data that suggest a potential drug interaction with CYP isoenzymes or potentially coadministered narrow therapeutic index drugs. In each study, dexlansoprazole MR 90 mg or placebo was administered once daily for 9 or 11 days in each period. Subjects received a single dose of test substrate in each study period. Pharmacokinetic parameters of the test substrates were estimated using noncompartmental methods. A conclusion of no effect of dexlansoprazole MR on the test substrate was made if the 90% confidence intervals (CIs) for the ratios of the central values for the observed maximum plasma drug concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of test substrate administered with dexlansoprazole MR versus placebo were within 0.80–1.25 based on an analysis of variance model. The potential for a pharmacodynamic interaction was also assessed for warfarin using prothrombin time, measured as the international normalized ratio. Routine safety assessments were conducted in these studies. Results: Mean Cmax and AUC values were generally similar for each test substrate when administered with multiple once-daily doses of dexlansoprazole MR or placebo. The 90% CIs for the bioavailability of these test substrates administered with dexlansoprazole MR relative to that obtained when the substrates were administered with placebo were within the bioequivalency range of 0.80–1.25, indicating that multiple doses of dexlansoprazole MR had no effect on the pharmacokinetics of these drugs. Additionally, dexlansoprazole MR had no effect on the pharmacodynamics of warfarin. Administration of these drugs with dexlansoprazole MR 90 mg or placebo was well tolerated; the only serious adverse event, which led to a subject’s discontinuation from the study, was considered unrelated to study drugs. Conclusions: Coadministration of dexlansoprazole MR with diazepam, phenytoin or theophylline did not affect the pharmacokinetics of these drugs, and therefore is unlikely to alter the pharmacokinetic profile of other drugs metabolized by CYP2C19, CYP2C9, CYP1A2 and perhaps CYP3A. Additionally, dexlansoprazole MR coadministered with warfarin did not affect the pharmacokinetics of the warfarin enantiomers and had no effect on the anticoagulant activity of warfarin. Dexlansoprazole MR was well tolerated in these trials of healthy subjects.