Amount of Testosterone on Laundered Clothing After Use of Testosterone Topical 2% Solution by Healthy Male Volunteers.

INTRODUCTION: Testosterone 2% solution (Axiron) applied to armpit(s) is used for replacement therapy in men with a deficiency of endogenous testosterone. AIM: To determine the amount of testosterone on subjects' T-shirts 12 hours after applying testosterone solution, the residual testosterone on subjects' T-shirts after laundering, and the testosterone transferred to unworn textile items during laundering with worn T-shirts. METHODS: Healthy males ≥18 years old applied 2 × 1.5 mL of testosterone 2% solution to both axillae (total testosterone dose: 120 mg) and dressed in cotton long-sleeved T-shirts after a ≥3-minute waiting period. T-shirts were worn 12 hours before being removed and cut into halves, after which a 10 × 10 cm sample of each armpit area was excised for testosterone quantification before or after laundering with samples of unworn textiles. MAIN OUTCOME MEASURES: Testosterone on worn T-shirts before and after laundering, and on unworn textiles laundered with the worn T-shirts. RESULTS: Twelve subjects enrolled and completed, with only minor adverse events. Mean testosterone in unwashed worn T-shirts was 7603 µg, with high between-subject variability (3359 µg to 13,069 µg), representing 13% of the dose to 1 armpit. Mean testosterone in worn, laundered T-shirts was 260 µg (7.55 µg to 1343 µg), representing 3% of the dose to 1 armpit. Mean transferred testosterone to other textiles during laundering ranged from 69 µg on texturized Dacron 56T Double to 10,402 µg on 87/13 nylon/Lycra knit, representing 0.0382% to 5.78% of the dose to 1 armpit. CONCLUSION: Thirteen percent of the testosterone applied to axillae was transferred to T-shirts during wear. Ninety-seven percent of the transferred testosterone was removed from the T-shirts during washing, some of which was then absorbed to various degrees by other textiles. Clinical implications of these findings and biological activity of the remaining/transferred testosterone are unknown.

Effect of hepatic or renal impairment on the pharmacokinetics of evacetrapib.

PURPOSE: The aim of this study is to investigate the effect of hepatic or renal impairment on the pharmacokinetics of a single 130-mg evacetrapib dose. METHODS: Two open-label, parallel-design studies in males and females with normal hepatic function or Child-Pugh mild, moderate, or severe hepatic impairment, or with normal renal function or severe renal impairment. Non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time data. Evacetrapib safety and tolerability were assessed. RESULTS: Pharmacokinetic parameter estimates were comparable between controls and mildly hepatically impaired subjects. Geometric mean area under the concentration-time curve (AUC) was greater, half-life (t1/2) was longer, and maximum concentration (Cmax) was lower in subjects with moderate and severe hepatic impairment than in controls. Apparent clearance (CL/F) did not differ between controls and those with mild hepatic impairment, but CL/F decreased for moderate and severe impairment. Spearman correlation coefficient showed no relationship between CL/F and Child-Pugh score. In the renal study, AUC and t1/2 were similar between groups, while Cmax was 15 % lower in subjects with severe impairment. CL/F in severely renally impaired subjects differed by <6 % from that in controls. Spearman correlation coefficient showed no apparent relationship between CL/F and estimated creatinine clearance or glomerular filtration rate. Neither study noted changes in clinical laboratory parameters or clinically significant findings. Adverse event incidence was low, and all were mild or moderate in severity. CONCLUSION: Evacetrapib exposure did not differ between mild hepatic impairment and normal hepatic function, but increased along the progression from mild to moderate to severe hepatic impairment. Severe renal impairment did not affect evacetrapib exposure.

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-∞) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a (13) C-labeled IV microdose tracer at about 1/1000(th) the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.

Prasugrel in children with sickle cell disease: pharmacokinetic and pharmacodynamic data from an open-label, adaptive-design, dose-ranging study.

INTRODUCTION: This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel's active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition. SAFETY: No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited. CONCLUSIONS: Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.

Effect of deodorant and antiperspirant use and presence or absence of axillary hair on absorption of testosterone 2% solution applied to men's axillae.

INTRODUCTION: Testosterone 2% solution is applied to axillae and is indicated for testosterone replacement therapy in males deficient in endogenous testosterone. AIM: This open-label crossover study evaluated the effect of deodorant/antiperspirant use and presence or absence of axillary hair on absorption of testosterone solution. METHODS: Healthy males (N = 30; ≥50 years of age with baseline testosterone <400 ng/dL) were randomized to one of four treatment sequences involving six treatments. Each treatment consisted of one 1.5-mL dose of testosterone 2% solution (30 mg of testosterone) applied to each axilla. Axillae were unshaved or shaved, and were untreated or pretreated with deodorant/antiperspirant. MAIN OUTCOME MEASURES: Blood samples were taken over 72 hours after each dose for measuring serum testosterone concentrations. RESULTS: Profiles of mean testosterone concentrations were similar across treatments. For all treatments, area under the concentration-time curve through 24 hours (AUC[0-24] ) and 72 hours (AUC[0-72] ), and maximum total testosterone concentration (Cmax ) were similar except for 15% lower Cmax when treatment was applied after deodorant/antiperspirant to shaved vs. unshaved axillae (least squares mean, 531 ng/dL vs. 626 ng/dL, respectively; P = 0.011). This difference is not considered clinically significant. The 95% confidence intervals for AUC(0-24) , AUC(0-72) , and Cmax fell within the traditional bioequivalence limits of 0.8 to 1.25. Incidence of treatment-emergent adverse events (TEAEs) was low (<15%) in each treatment arm, and most TEAEs were mild. CONCLUSIONS: Absorption of testosterone 2% solution was unaffected by use of deodorant/antiperspirant or by the presence or absence of axillary hair. Testosterone solution was generally well tolerated.

Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients.

Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, ≥60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 ± 3.7 kg) and HBW (n = 38, 84.7 ± 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC(0-tlast), was calculated by noncompartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 µM adenosine diphosphate (ADP), and residual platelet aggregation to 5 µM ADP), VerifyNow(®) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC(0-tlast) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p ≤ 0.01), PRU (207 ± 68 vs. 152 ± 57, p < 0.001), and VASP-PRI (56 ± 18 vs. 39 ± 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9%) and VASP-PRI (65 vs. 27%). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC(0-tlast) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.

A phase 1 study of prasugrel in patients with sickle cell disease: pharmacokinetics and effects on ex vivo platelet reactivity.

AIMS: Prasugrel is a novel thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet-related ischaemia in sickle cell disease (SCD). Exposure to prasugrel's active metabolite (Pras-AM) and its antiplatelet activity in SCD have not been investigated. METHODS: Thirteen adult patients with SCD and an equal number of matched healthy control subjects were studied before and after 12 days of 5.0 or 7.5 mg day(-1) prasugrel treatment. Platelet reactivity was assessed by light transmission aggregometry (LTA), impedance aggregometry (MEA), VerifyNow® P2Y12, vasodilator-stimulated phosphoprotein (VASP) phosphorylation and Plateletworks. Exposure to Pras-AM was also assessed. RESULTS: At baseline, patients with SCD showed increased platelet reactivity vs. healthy control subjects with VerifyNow (408 vs. 323 P2Y12 reaction units (PRU), respectively, P = 0.003) and MEA (106 vs. 77 area under the aggregation curve (AU.min), P = 0.002); lower platelet reactivity index with VASP flow cytometry (59 vs. 79% platelet reactivity index (PRI), P = 0.018); and no significant differences with LTA, VASP enzyme-linked immunosorbent assay or Plateletworks. Relative to baseline, prasugrel significantly reduced platelet reactivity by all assays in both populations (all P < 0.05). Prasugrel was well tolerated, with no bleeding-related events in patients with SCD. The mean concentration-time profiles of Pras-AM were comparable between healthy subjects and patients with SCD following a single 10 mg prasugrel dose and following the 12th dose of 7.5 or 5 mg prasugrel. CONCLUSIONS: Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras-AM, and provide a basis for further study of prasugrel in patients with SCD.

Pharmacokinetic and pharmacodynamic effects of prasugrel in healthy Korean males.

Prasugrel is a thienopyridine for treatment of acute coronary syndromes in patients undergoing percutaneous coronary intervention. Higher concentrations of prasugrel's active metabolite (R-138727) have been observed in Asian than white subjects. The primary objective was to investigate pharmacokinetics of R-138727 in healthy Korean males. Thirty subjects were randomized (1:2) to a 60 or 30 mg loading dose, subsequently (1:1:1) to 10-, 7.5-, or 5-mg maintenance doses. R-138727 plasma concentrations were analyzed with liquid chromatography/mass spectrometry. Platelet aggregation was measured with Accumetrics VerifyNow. Mean (coefficient of variation) exposure to R-138727 was 600 ng·h/mL (16%) after 60 mg prasugrel and 283 ng·h/mL (17%) after 30 mg. After 10, 7.5, and 5 mg, mean exposures were 78.1 (24%), 58.4 (21%), and 38.3 ng·h/mL (24%). Pharmacokinetics were linear over this range. Daily 5 mg doses maintained a 65% (SD = 14.5%) inhibition of adenosine diphosphate-induced platelet aggregation; all other doses produced ≥90%. Prasugrel was well tolerated with no serious adverse events. Results are consistent with other studies of Asian subjects administered prasugrel. Although further guidance will be provided by a recently completed phase 3 study, these preliminary data suggest that dosing strategies approved for white patients with acute coronary syndromes are applicable to Asian patients.

Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants.

AIMS: This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel. METHODS: Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)]. RESULTS: Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001). CONCLUSIONS: Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.

The onset of inhibition of platelet aggregation with prasugrel compared with clopidogrel loading doses using gatekeeping analysis of integrated clinical pharmacology data.

The purpose of this analysis was to determine the time by which a prasugrel 60-mg loading dose (LD) achieved significantly greater inhibition of platelet aggregation (IPA) than the peak IPA after a clopidogrel 300-mg LD or 600-mg LD. Data were pooled from nine studies representing 587 individuals: 274 healthy subjects and 313 patients with stable coronary artery disease. The primary pharmacodynamic measure was IPA using 20 [mu]M adenosine-5'-diphosphate as the agonist. Gatekeeping analysis compared the peak IPA at 4, 6, and 24 hours after a clopidogrel 300-mg or 600-mg LD with IPA at various prior time points backwards after a prasugrel LD until a statistically nonsignificant difference was reached. Prasugrel 60-mg LD produced greater IPA by 30 minutes than the peak IPA after a clopidogrel 300-mg LD (P < 0.0001). Significantly greater IPA was achieved at 1 hour after prasugrel 60-mg LD compared with the peak IPA after 600-mg clopidogrel LD (P < 0.0001), regardless of sex, body weight, or age and as early as 30 minutes in the diabetic subgroup. A prasugrel 60-mg LD produces significantly faster onset and greater IPA compared with a clopidogrel 300-mg LD or 600-mg LD.

A comparison of the VerifyNow P2Y12 point-of-care device and light transmission aggregometry to monitor platelet function with prasugrel and clopidogrel: an integrated analysis.

We compared platelet function results obtained with the VerifyNow P2Y12 (VN-P2Y12) point-of-care device and the light transmission aggregometry (5 and 20 microM adenosine diphosphate) method using an integrated database of eight clinical trials with a total of 591 subjects. The study was performed in healthy subjects, patients with coronary artery disease, patients with end-stage renal disease, and patients with acute coronary syndrome after treatment with prasugrel or clopidogrel. Analyses focused on loading doses of 60 mg prasugrel or 600 mg clopidogrel and daily maintenance doses of 10 mg prasugrel or 75 or 150 mg clopidogrel. Similar patterns of platelet inhibition were observed for light transmission aggregometry versus VN-P2Y12 and assay results were well correlated (r approximately 0.7), although a sigmoidal model may more accurately represent the relationship between light transmission aggregometry and VN-P2Y12, because VN-P2Y12 was relatively less sensitive to low and high levels of inhibition. The percentage of poor responders was less with prasugrel compared with clopidogrel by both assays, but the percentages tended to differ between the assays. The VN-P2Y12 "BASE" channel appeared to be susceptible to high levels of P2Y12 blockade, which would underestimate the VN-P2Y12-reported percent inhibition in individuals who respond well to loading doses of thienopyridines. This integrated analysis supports the findings of earlier individual studies comparing these methodologies that assess platelet function.

The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects.

PURPOSE: Prasugrel is a novel thienopyridine prodrug metabolised to an active metabolite that binds irreversibly to the platelet P2Y(12) receptor and inhibits adenosine diphosphate (ADP)-induced platelet aggregation. We compared prasugrel pharmacokinetics, pharmacodynamics, and tolerability in healthy Chinese, Japanese, Korean and Caucasian subjects. METHODS: In an open-label, single-centre, parallel-design study, 89 healthy subjects (25 Chinese, 20 Japanese, 22 Korean and 22 Caucasian) aged 20-65 years were given a prasugrel 60-mg loading dose (LD) followed by daily 10-mg maintenance doses (MD) for 7 days and then 5-mg MD for 10 days. Plasma concentrations of prasugrel's active metabolite and inhibition of ADP-induced platelet aggregation (IPA) were determined. RESULTS: Mean exposure to prasugrel's active metabolite in all treatment regimens was higher in each of the Asian groups than in the Caucasian group, although there was considerable overlap between individual exposure estimates in Asians and Caucasians. The mean IPA was also higher in Asians than in Caucasians following a prasugrel 60-mg LD, although the difference did not consistently achieve statistical significance. Prasugrel 10-mg or 5-mg MD produced statistically significantly higher IPA in each Asian group compared with that in the Caucasians. Prasugrel was well tolerated during the LD and MD regimens by all groups. CONCLUSIONS: Mean exposure to the prasugrel active metabolite following prasugrel 60-mg LD and during daily 10-mg or 5-mg MD was higher in each of the Asian groups than in the Caucasian group, which resulted in greater platelet inhibition.

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 prasugrel's 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 > or =60 kg. Mean Pras-AM exposures for patients > or =75 years (10.5%) were 19% (90% CI: 1.11-1.28) higher compared with patients <75 years.

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 muM 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.

A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry.

Platelet inhibition as measured by vasodilator-stimulated phosphoprotein (VASP) and light transmission aggregometry (LTA) have shown concordance following dosing of clopidogrel. No reports have directly compared the VASP assay and LTA at the levels of P2Y(12) blockade after loading doses (LDs) of prasugrel or high dose clopidogrel (600 and 900 mg). The aim was to compare the VASP assay and LTA during the loading dose phase of a comparative study of prasugrel and clopidogrel. Prasugrel 60 mg LD/10 mg maintenance dose (MD) and clopidogrel 300 mg/75 mg and 600 mg/75 mg LD/MD regimens were compared in a 3-way crossover study in 41 healthy, aspirin-free subjects. Each LD was followed by seven daily MDs and a 14-day washout period. P2Y(12) receptor blockade was estimated using the VASP assay, expressed as platelet reactivity index (VASP-PRI). Platelet aggregation was assessed by light transmission aggregometry (20 and 5 microM ADP). Twenty-four hours after prasgurel 60 mg or clopidogrel 300 mg and 600 mg, respectively, VASP-PRI decreased from approximately 80% to 8.9%, 54.7%, and 39.0%, and maximal platelet aggregation (MPA) decreased from approximately 79% to 10.8%, 42.7%, and 31.2%, with an overall VASP:MPA correlation of 0.88 (p < 0.01). VASP assay responses after the clopidogrel LDs showed a wider range of values (300 mg: 0-93%; 600 mg: 0-80%) than prasugrel (0-13%); MPA responses followed a similar trend. Pearson's correlation suggested a strong agreement between VASP and LTA (20 microM ADP) for MPA (r = 0.86, p < 0.0001). VASP and LTA demonstrated concordance across the response range of P2Y(12) receptor blockade following thienopyridine LDs.

The use of the VerifyNow P2Y12 point-of-care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration.

Variability in response to antiplatelet agents has prompted the development of point-of-care (POC) technology. In this study, we compared the VerifyNow P2Y12 (VN-P2Y12) POC device with light transmission aggregometry (LTA) in subjects switched directly from clopidogrel to prasugrel. Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose (LD) followed by a 75 mg/d maintenance dose (MD) for 10 days. Subjects were then switched to a prasugrel 60 mg LD and then 10 mg/d MD for 10 days (n = 16), or to a prasugrel 10 mg/d MD for 11 days (n = 19). Platelet function was measured by LTA and VN-P2Y12 at baseline and after dosing. Clopidogrel 600 mg LD/75 mg MD treatment led to a reduction in P2Y(12) reaction units (PRU) from baseline. A switch from clopidogrel MD to prasugrel 60 mg LD/10 mg MD produced an immediate decrease in PRU, while a switch to prasugrel 10 mg MD resulted in a more gradual decline. Consistent with the reduction in PRU, device-reported percent inhibition increased during both clopidogrel and prasugrel regimens. Inhibition of platelet aggregation as measured by LTA showed a very similar pattern to that found with VN-P2Y12 measurement, irrespective of treatment regimens. The dynamic range of VN-P2Y12 appeared to be narrower than that of LTA. With two different thienopyridines, the VN-P2Y12 device, within a somewhat more limited range, reflected the overall magnitude of change in aggregation response determined by LTA. The determination of the clinical utility of such POC devices will require their use in clinical outcome studies.

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-infinity by 14% and 18%, respectively, and decreased hydroxybupropion Cmax and AUC0-infinity by 32% and 23%. These results are consistent with patients receiving prasugrel not requiring dose adjustments when treated with drugs primarily metabolized by CYP2B6.

Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel.

Prasugrel and clopidogrel, thienopyridine prodrugs, are each metabolized to an active metabolite that inhibits the platelet P2Y(12) ADP receptor. In this open-label, 4-period crossover study, the effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel were assessed in healthy subjects given single doses of prasugrel 60 mg and clopidogrel 300 mg with and without concurrent lansoprazole 30 mg qd. C(max) and AUC(0-tlast) of prasugrel's active metabolite, R-138727, and clopidogrel's inactive carboxylic acid metabolite, SR26334, were assessed. Inhibition of platelet aggregation (IPA) was measured by turbidimetric aggregometry 4 to 24 hours after each treatment. Lansoprazole (1) decreased R-138727 AUC(0-tlast) and C(max) by 13% and 29%, respectively, but did not affect IPA after the prasugrel dose, and (2) did not affect SR62334 exposure but tended to lower IPA after a clopidogrel dose. A retrospective tertile analysis showed in subjects with high IPA after a clopidogrel dose alone that lansoprazole decreased IPA, whereas IPA was unaffected in these same subjects after a prasugrel dose. The overall data suggest that a prasugrel dose adjustment is not likely warranted in an individual taking prasugrel with a proton pump inhibitor such as lansoprazole.

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. DESIGN: Open-label, randomized, crossover, two-arm, parallel-group study. SETTING: Single clinical research center in the United Kingdom. PARTICIPANTS: Sixty-nine healthy men aged 18-60 years. Intervention. Subjects received either a loading dose of prasugrel 60 mg followed by a maintenance dose of 10 mg/day or a loading dose of clopidogrel 300 mg followed by 75 mg/day. The drug was given as monotherapy for 10 days, and after a 6-day run-in period with atorvastatin 80 mg/day, the same dosage of atorvastatin was continued with the respective thienopyridine for 10 days. A 14-day washout period separated the treatment regimens. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected before and at various time points after dosing on days 1 and 11 for determination of plasma concentrations of metabolites and for measurement of platelet aggregation induced by adenosine 5'-diphosphate 20 microM and vasodilator-stimulated phosphoprotein (VASP). Coadministration of atorvastatin did not alter exposure to active metabolites of prasugrel or clopidogrel after the loading dose and thus did not alter inhibition of platelet aggregation (IPA). During maintenance dosing, atorvastatin administration resulted in 17% and 28% increases in the area under the plasma concentration-time curve (AUC) values of prasugrel's and clopidogrel's active metabolites, respectively. These small changes in AUC did not result in a significant change in IPA response to prasugrel but did result in a significant increase in IPA during clopidogrel maintenance dosing at some, but not all, of the time points on day 11. Coadministration of atorvastatin with either prasugrel or clopidogrel had no effect on VASP phosphorylation relative to the thienopyridine alone after the loading dose. CONCLUSION: Coadministration of atorvastatin 80 mg/day with prasugrel or clopidogrel did not negatively affect the antiplatelet response to either drug after a loading dose or during maintenance dosing. The lack of a clinically meaningful effect of high-dose atorvastatin on the pharmacodynamic response to prasugrel after the loading or maintenance dose indicates that no dosage adjustment should be necessary in patients receiving these drugs concomitantly.

Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects.

Prasugrel, a novel P2Y(12) antagonist, achieves faster onset and greater inhibition of platelet aggregation than clopidogrel 300 and 600 mg loading doses (LD). We studied the safety, time course, and level of platelet inhibition when switching directly from clopidogrel 75 mg maintenance dose (MD) to a prasugrel 60 mg LD/10 mg MD or 10 mg MD regimen. Healthy subjects (n = 39) on aspirin (81 mg/d) received a clopidogrel 600 mg LD followed by 10 days of clopidogrel MD (75 mg/d). Subjects were then randomized without a washout period to prasugrel 60 mg LD (n = 16) followed by 10 days of prasugrel MD (10 mg/d) or to prasugrel MD (10 mg/d, n = 19) for 11 days. Maximal platelet aggregation (MPA) to 20 microM ADP was measured by turbidimetric aggregometry. In subjects on clopidogrel 75 mg MD, mean MPA decreased from 39 to 12% by 30 minutes, and to 5% by 1 hour after a prasugrel 60 mg LD (p < 0.001 for both) and from 37 to 28% (p < 0.001) by 1 hour after a prasugrel 10 mg MD. During prasugrel MD, a new pharmacodynamic steady state MPA of approximately 24% (p < 0.01 vs. clopidogrel MD) occurred within four to five days of switching from clopidogrel. Changing from clopidogrel to prasugrel did not increase bleeding episodes or other adverse events. Switching directly from clopidogrel MD to either prasugrel LD or MD was well tolerated and resulted in significantly greater levels of platelet inhibition than a clopidogrel 75 mg MD.