C. Steven Ernest

Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel.

Prasugrel pharmacodynamics and pharmacokinetics after a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MD) were compared in a 3-way crossover study to clopidogrel 600-mg/75-mg and 300-mg/75-mg LD/MD in 41 healthy, aspirin-free subjects. Each LD was followed by 7 days of daily MD and a 14-day washout period. Inhibition of platelet aggregation (IPA) was assessed by turbidometric aggregometry (20 and 5 μM ADP). Prasugrel 60-mg achieved higher mean IPA (54%) 30 minutes post-LD than clopidogrel 300-mg (3%) or 600-mg (6%) (P < 0.001) and greater IPA by 1 hour (82%) and 2 hours (91%) than the 6-hour IPA for clopidogrel 300-mg (51%) or 600-mg (69%) (P < 0.01). During MD, IPA for prasugrel 10-mg (78%) exceeded that of clopidogrel (300-mg/75-mg, 56%; 600-mg/75-mg, 52%; P < 0.001). Active metabolite area under the concentration-time curve (AUC0-tlast) after prasugrel 60-mg (594 ng·hr/mL) was 2.2 times that after clopidogrel 600-mg. Prasugrel active metabolite AUC0-tlast was consistent with dose-proportionality from 10-mg to 60-mg, while clopidogrel active metabolite AUC0-tlast exhibited saturable absorption and/or metabolism. In conclusion, greater exposure to prasugrels active metabolite results in faster onset, higher levels, and less variability of platelet inhibition compared with high-dose clopidogrel in healthy subjects.

Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects.

Study Objective. To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.

Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.

The purpose of this study was to characterize the effect of potent CYP2D6 inhibition by paroxetine on atomoxetine disposition in extensive metabolizers. This was a single‐blind, two‐period, sequential study in 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4‐hydroxyatomoxetine, and N‐desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased Css,max, AUC0–12, and t1/2 of atomoxetine by approximately 3.5‐, 6.5‐, and 2.5‐fold, respectively. After coadministration with paroxetine, increases in N‐desmethylatomoxetine and decreases in 4‐hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates.

Population Pharmacokinetic Analyses to Evaluate the Influence of Intrinsic and Extrinsic Factors on Exposure of Prasugrel Active Metabolite in TRITON‐TIMI 38

Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON‐TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrels active metabolite (Pras‐AM) concentrations from its 2 downstream inactive metabolites. Population‐based methods were then applied to Pras‐AM concentration data to characterize the PK. The potential influence of body weight, body mass index, age, sex, renal function, diabetes, tobacco use, and other disease status on Bayesian estimates of Pras‐AM exposures was assessed. The PK of Pras‐AM was adequately described by a multicompartmental model and consistent with results from previous studies. The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment. Pras‐AM mean exposure in patients weighing <60 kg (4.1%) was 30% (90% confidence interval [CI] 1.16–1.45) higher than exposure in patients ≥60 kg. Mean Pras‐AM exposures for patients ≥75 years (10.5%) were 19% (90% CI: 1.11–1.28) higher compared with patients <75 years.

Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel

ABSTRACT Objective: Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrels solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption. This study evaluated the influence of ranitidine coadministration on the pharmacokinetics and pharmacodynamics of the respective active metabolite of prasugrel and clopidogrel. Research design and methods: In this open-label, two-period, two-treatment, crossover study, 47 healthy male subjects were randomized to one of two study arms, receiving either prasugrel (60-mg loading dose [LD], 10-mg maintenance dose [MD] for 7 days; n = 23) or clopidogrel (600-mg LD, 75-mg MD for 7 days; n = 24). In one treatment period, subjects received prasugrel or clopidogrel alone, and in the alternate period received the same thienopyridine with ranitidine (150 mg twice daily, starting 1 day before the LD). Pharmacokinetic parameter estimates (AUC0−t last, Cmax, and tmax) and inhibition of platelet aggregation (IPA) by light transmission aggregometry were assessed at multiple time points after the LD and final MD. Results: Ranitidine had no clinically significant effect on the area under the plasma-concentration-time curve (AUC) and did not affect the time to Cmax (tmax) for active metabolites of either prasugrel or clopidogrel. It reduced the geometric mean maximum concentrations of active metabolite (Cmax) after a prasugrel and clopidogrel LD by 14% and 10%, respectively, but these differences were not statistically significant. When coadministered with a 60-mg prasugrel LD, ranitidine did not affect the time to, or magnitude of, peak IPA, but did result in a modest reduction at 0.5 h from 67.4 to 55.1% (p < 0.001). Ranitidine did not affect prasugrel IPA during MD. For clopidogrel, IPA was not affected by ranitidine. Prasugrel and clopidogrel were both well-tolerated, with/without ranitidine. Conclusions: Results from this study suggest that there is no significant drug–drug interaction between oral ranitidine therapy and concomitantly-administered prasugrel or clopidogrel.

Prasugrel, a New Thienopyridine Antiplatelet Drug, Weakly Inhibits Cytochrome P450 2B6 in Humans

Prasugrel, a thienopyridine prodrug, is hydrolyzed in vivo by esterases to a thiolactone followed by a single cytochrome P450 (CYP)‐dependent step to an active metabolite that is a potent inhibitor of adenosine diphosphate–induced platelet aggregation. This open‐label, multiple‐dose, 2‐period, fixed‐sequence study assessed CYP2B6 inhibition by prasugrel using bupropion as a probe substrate, where its active metabolite, hydroxybupropion, is almost exclusively formed by CYP2B6. Thirty healthy subjects received a single 150‐mg oral dose of sustained‐release bupropion. After a 7‐day washout, a 60‐mg prasugrel loading dose, followed by a 10‐mg daily maintenance dose for 10 days, was administered. Bupropion (150 mg) was given with prasugrel on day 7 of this phase. Prasugrel weakly inhibited CYP2B6 activity as it increased bupropion Cmax and AUC0‐∞ by 14% and 18%, respectively, and decreased hydroxybupropion Cmax and AUC0‐∞ by 32% and 23%. These results are consistent with patients receiving prasugrel not requiring dose adjustments when treated with drugs primarily metabolized by CYP2B6.

Inhibition of platelet aggregation with prasugrel and clopidogrel: an integrated analysis in 846 subjects.

This integrated analysis compared speed of onset, level of platelet inhibition, and response variability to prasugrel and clopidogrel in healthy subjects and in patients with stable coronary artery disease with data pooled from 24 clinical pharmacology studies. Data from subjects (N = 846) were categorized into the following treatment groups: prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD), clopidogrel 300 mg LD/75 mg MD, or clopidogrel 600 mg LD/75 mg MDs. Maximum platelet aggregation (MPA) and inhibition of platelet aggregation (IPA) to 5 and 20 μM ADP were assessed by turbidimetric aggregometry. A linear mixed-effect model compared the MPA and IPA between treatments over time points evaluated in the integrated database, and covariates affecting platelet inhibition were identified. Prasugrel 60 mg LD resulted in faster onset, greater magnitude, and more consistent levels of inhibition of platelet function compared to either clopidogrel 300 mg or 600 mg LDs. Greater and more consistent levels of platelet inhibition were observed with the prasugrel 10 mg MD compared to the clopidogrel 75 mg MD. This integrated analysis confirms the findings of earlier individual studies, that prasugrel achieves faster onset of greater extent and more consistent platelet inhibition compared to the approved and higher loading doses of clopidogrel. Gender, race, body weight, and age were identified as statistically significant covariates impacting platelet inhibition.

Integrated Analysis of Pharmacokinetic Data Across Multiple Clinical Pharmacology Studies of Prasugrel, a New Thienopyridine Antiplatelet Agent

An integrated analysis of pharmacokinetic (PK) parameter estimates for prasugrel, from 16 phase I clinical pharmacology studies, consolidated exposure estimates from 506 healthy male and female participants and evaluated the effect of specific intrinsic and extrinsic factors on exposure to prasugrels active metabolite (AM, R‐138727). A linear mixed effect model was fitted with study and subject nested within study as random effects and subject factors as fixed effects. Prasugrel AM exposure was similar in males and females, in participants <65 years and ≥65 years, in smokers and nonsmokers, in drinkers and nondrinkers of alcohol, and in Asians, Caucasians, and participants of African and Hispanic descent. Prasugrel AM exposure increased as body weight decreased and was 40% higher in participants <60 kg than in participants ≥60 kg. Exposure in Asians was 40% higher than that in Caucasians, but this difference could be explained by the lower overall weight of the Asian participants and a disproportionately large difference between ethnic groups in lighter participants, especially those ≤60 kg. These results characterize prasugrels PK across a range of studies and highlight body weight as the most influential covariate on prasugrel AM exposure, with implications for prasugrel maintenance dosing in clinical practice.

Relationship Between Exposure to Prasugrel Active Metabolite and Clinical Outcomes in the TRITON-TIMI 38 Substudy

In TRITON‐TIMI 38, levels of the prasugrel active metabolite (pras‐AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras‐AM was observed in low‐weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non—coronary artery bypass graft (CABG)–related TIMI‐related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras‐AM and clinical outcomes was assessed in 1159 prasugrel‐treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras‐AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras‐AM exposure was associated with a higher incidence of non‐CABG‐related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non‐CABG‐related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras‐AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras‐AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.

Effect of age on the pharmacokinetics and pharmacodynamics of prasugrel during multiple dosing: an open-label, single-sequence, clinical trial.

BackgroundA substantial portion of patients at risk for acute coronary syndrome (ACS) are >65 years old. Prasugrel is a novel antiplatelet agent approved for the treatment of ACS patients undergoing percutaneous coronary intervention, and will be used in this population.ObjectiveThis study assessed the effect of age ≥65 years on the pharmacokinetics (PK) and pharmacodynamics (PD) of the active metabolite (R-138727) of prasugrel in healthy subjects taking aspirin (acetylsalicylic acid).MethodsThis was an open-label, single-sequence trial conducted in a single clinical research centre in the UK. A total of 17 subjects aged 65–80 years and 15 subjects aged 20–39 years received a prasugrel 5-mg once-daily maintenance dose for 10 days followed by 10-mg once daily maintenance doses for 10 days. All subjects also received aspirin 75 mg daily. Serial blood samples were collected pre-dose and at various times post-dose for measurement of the active metabolite of prasugrel in plasma on days 10 and 20, following the last 5- and 10-mg prasugrel dose, respectively. PK parameters of the active metabolite of prasugrel included area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast), maximum plasma concentration (Cmax) and time to Cmax (tmax). Maximal platelet aggregation (MPA), assessed by light transmission aggregometry using adenosine diphosphate (ADP) 20 µmol/L, was assessed at baseline and on day 10 (5-mg maintenance dose) and day 20 (10-mg maintenance dose). Bleeding times (BTs) were determined on days −5, 1, 10, 11, 20 and 21 using a modified Ivy technique.ResultsAUClast did not differ significantly between age groups. The steady-state trough MPA to ADP 20 µmol/L during 10-mg maintenance dosing was 30.6% and 26.6% in elderly and young subjects, respectively. Mean MPA was consistently higher in elderly subjects compared with young subjects; however, differences were generally less than ten percentage points. BTs did not differ between the two populations during 5-mg maintenance dosing; however, during 10-mg maintenance dosing, BTs were up to 67% longer in young compared with elderly subjects. A higher frequency of minor bleeding during 10-mg maintenance dosing was observed in elderly subjects compared with young subjects.ConclusionsThese data indicate that prasugrel PK and MPA were similar in healthy subjects regardless of age. Compared with younger subjects, elderly subjects had shorter BTs but a greater frequency of mild bleeding-related adverse events.