Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects.

The effect of the protease-activated receptor-1 (PAR-1) antagonist vorapaxar on human bleeding time is not known. This was a randomized, two-period, open-label trial in healthy men (n = 31) and women (n = 5). In period 1, subjects received 81 mg aspirin q.d. or a vorapaxar regimen achieving steady-state plasma concentrations equivalent to chronic 2.5 mg q.d. doses, for 7 days. In period 2, each group added 7 days of the therapy alternate to that of period 1 without washout. Bleeding time and platelet aggregation using arachidonic acid, ADP, and TRAP agonists were assessed. Bleeding time geometric mean ratio (90% CI) for vorapaxar/baseline was 1.01 (0.88-1.15), aspirin/baseline was 1.32 (1.15-1.51), vorapaxar + aspirin/vorapaxar was 1.47 (1.26-1.70), and vorapaxar + aspirin/aspirin was 1.12 (0.96-1.30). Unlike aspirin, vorapaxar did not prolong bleeding time compared with baseline. Bleeding time following administration of vorapaxar with aspirin was similar to that following aspirin alone.

Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease.

OBJECTIVE: The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment. METHODS: Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n = 12) or moderate renal impairment (n = 10) and matched healthy subjects with normal renal function (n = 10). The third protocol was an open-label, single-dose escalation (5, 10, 30 and 60 mg prasugrel) study in subjects with ESRD (n = 16) and matched healthy subjects with normal renal function (n = 16). Plasma concentrations of prasugrel's active metabolite were determined and pharmacokinetic parameter estimates were derived. Maximum platelet aggregation (MPA) was measured by light transmission aggregometry using 20 mum adenosine diphosphate as agonist. RESULTS: Across all studies, prasugrel's C(max) and AUC(0-t) were 51% and 42% lower in subjects with ESRD than in healthy subjects. AUC(0-t) did not differ between healthy subjects and subjects with moderate renal impairment. The magnitude of change and time-course profiles of MPA was similar for healthy subjects compared with subjects with moderate renal impairment and those with ESRD. Prasugrel was well-tolerated in all subjects. CONCLUSION: There was no difference in pharmacokinetics or PD responses between subjects with moderate renal impairment and healthy subjects. Despite significantly lower exposure to prasugrel's active metabolite in subjects with ESRD, MPA did not differ between healthy subjects and those with ESRD.

Vancomycin pharmacokinetics and Bayesian estimation in pediatric patients.

The vancomycin pharmacokinetic profile was characterized in six pediatric patients and the potential of nonlinear mixed effects modeling and Bayesian forecasting for vancomycin monitoring was explored using NONMEM V (1.1). Based on steady state serial vancomycin concentrations, the estimates of mean t1/2, Vd, and Cl derived by the Sawchuk and Zaske method (1) were 3.52 hours, 0.57 L/kg, and 0.12 L/h per kg, respectively. NONMEM analysis demonstrated that a weight-adjusted two-compartment model described individual patients' data better than a comparable one-compartment model. The two-compartment estimates of mean t1/2alpha, t1/2beta, Vss, and Cl were 0.80 hour, 5.63 hours, 0.63 L/kg, and 0.11 L/h per kg, respectively. The relatively long mean t1/2alpha suggests that peak vancomycin concentrations measured earlier than 4 hours postdose do not reflect postdistributional serum concentrations. NONMEM population modeling revealed that a weight-adjusted two-compartment model provided a better fit than a comparable one-compartment model. The resulting population parameters and variances were fixed in NONMEM to obtain Bayesian predictions of individual vancomycin serum concentrations. Bayesian estimation with either a single midinterval or trough sample has the potential to provide accurate and precise predictions of vancomycin concentrations. This should be evaluated using a vancomycin population pharmacokinetic model based on a larger sample of pediatric patients.

Investigation of a possible interaction between ciprofloxacin and cyclosporine in renal transplant patients.

BACKGROUND: Bacterial infection is a common complication during the first few months after renal transplantation. Ciprofloxacin, a fluoroquinolone broad-spectrum antibiotic, is used frequently in treating infections in the early posttransplant period. Evidence from in vitro studies has suggested that ciprofloxacin can antagonize the cyclosporine (CsA)-dependent inhibition of interleukin-2 production. Such an effect in renal transplant patients could antagonize the immunosuppressive activity of CsA and lead to rejection of the graft. METHODS: To investigate the possibility of a pharmacodynamic interaction between ciprofloxacin and CsA, we conducted a case-control study in 42 patients who had received a kidney transplant and who were prescribed ciprofloxacin in the first 1-6 months after transplantation and in their matched controls (two per case) who did not receive ciprofloxacin during the study period. RESULTS: There was a twofold greater incidence (P=0.008) of ciprofloxacin use at 1-3 months (65%) than was observed at 4-7 months (35%) after transplantation. The proportion of cases experiencing at least one episode of biopsy-proven rejection 1-3 months posttransplant (45%) was significantly greater (P=0.004) than that of controls (19%). Furthermore, there was a marked increase (P<0.001) in the incidence of rejection temporally associated with ciprofloxacin use among cases (29%) compared with that experienced by the controls (2%). CONCLUSIONS: The possibility that ciprofloxacin increases rejection rates in renal transplant patients may be of clinical importance and therefore warrants further investigation.