Matching One Sample According to Two Criteria in Observational Studies.

Multivariate matching has two goals: (i) to construct treated and control groups that have similar distributions of observed covariates, and (ii) to produce matched pairs or sets that are homogeneous in a few key covariates. When there are only a few binary covariates, both goals may be achieved by matching exactly for these few covariates. Commonly, however, there are many covariates, so goals (i) and (ii) come apart, and must be achieved by different means. As is also true in a randomized experiment, similar distributions can be achieved for a high-dimensional covariate, but close pairs can be achieved for only a few covariates. We introduce a new polynomial-time method for achieving both goals that substantially generalizes several existing methods; in particular, it can minimize the earthmover distance between two marginal distributions. The method involves minimum cost flow optimization in a network built around a tripartite graph, unlike the usual network built around a bipartite graph. In the tripartite graph, treated subjects appear twice, on the far left and the far right, with controls sandwiched between them, and efforts to balance covariates are represented on the right, while efforts to find close individual pairs are represented on the left. In this way, the two efforts may be pursued simultaneously without conflict. The method is applied to our on-going study in the Medicare population of the relationship between superior nursing and sepsis mortality. The match2C package in R implements the method.

Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver disease.

BACKGROUND AND OBJECTIVE: Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel's active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients. METHODS: This was a parallel-design, open-label, multiple dose study of 30 subjects, 10 with moderate hepatic impairment (Child-Pugh Class B) and 20 with normal hepatic function. Prasugrel was administered orally as a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MDs) for 5 days. Pharmacokinetic parameters (AUC(0-t), C(max) and t(max)) and maximal platelet aggregation (MPA) by light transmission aggregometry were assessed after the LD and final MD. RESULTS AND DISCUSSION: Exposure to prasugrel's active metabolite was comparable between healthy subjects and those with moderate hepatic impairment. Point estimates for the ratios of geometric least square means for AUC(0-t) and C(max) after the LD and last MD ranged from 0.91 to 1.14. MPA to 20 microm ADP was similar between subjects with moderate hepatic impairment and healthy subjects for both the LD and MD. Prasugrel was well tolerated by all subjects, and adverse events were mild in severity. CONCLUSION: Moderate hepatic impairment appears to have no effect on exposure to prasugrel's active metabolite. Furthermore, MPA results suggest that moderate hepatic impairment has little or no effect on platelet aggregation relative to healthy controls. Overall, these results suggest that a dose adjustment would not be required in moderately hepatically impaired patients taking prasugrel.

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.

Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently.

Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite (R-138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2-week washout between periods. Ketoconazole decreased R-138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34-61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R-138727 exposure or prasugrel's inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrel's active metabolite AUC0-24 (area under the concentration-time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.

Hepatic enzyme induction potential of acitretin in male and female Sprague-Dawley rats.

Certain retinoids have been shown in rats and mice to induce the hepatic cytochrome P-450 enzyme system, and evidence from our laboratory suggested that acitretin, the active primary metabolite of etretinate (a retinoid used in the treatment of psoriasis) may induce its own metabolism. To test this hypothesis, male and female Sprague-Dawley rats were orally pretreated with acitretin for 18 days (10 mg/kg/day) and intravenously dosed with acitretin on day 20 (0.8-0.9 mg/kg). Serial blood samples were taken through 24 h, after which the hepatic microsomal proteins were harvested. Plasma concentrations of acitretin and its main metabolite isoacitretin were determined by HPLC, and total hepatic cytochrome P-450 concentrations and activities were determined using standard methods. Systemic clearance (17.4 +/- 2.5 and 12.1 +/- 1.6 mL/min per kg in control males and females, respectively), volume of distribution at steady state (Vss = 1568 +/- 353 and 1589 +/- 488 mL in control males and females, respectively), and mean residence time (MRT = 1.50 +/- 0.23 and 2.22 +/- 0.70 h in control males and females, respectively) were unchanged by acitretin pretreatment. Systemic clearance was 44% higher in control males than females. Concentrations of total microsomal protein (13.8 +/- 1.6 and 8.4 +/- 1.2 mg/g of liver in control males and females, respectively) and total P-450 (0.433 +/- 0.041 and 0.425 +/- 0.104 nmol/mg microsomal protein in control males and females, respectively) were also unchanged by acitretin pretreatment, as were microsomal levels of methoxy-, ethoxy-, pentoxy-, and (benzyloxy)resorufin O-dealkylation (MROD, EROD, PROD, and BROD, respectively) (control males and females, respectively, expressed as pmol of resorufin formed/min per mg of microsomal protein: MROD = 37.7 +/- 4.5 and 30.6 +/- 4.2; EROD 276 +/- 40 and 208 +/- 59; PROD = 15.2 +/- 4.5 and 5.8 +/- 1.2; and BROD 93.7 +/- 24.4 and 15.5 +/- 3.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet function normalization after a prasugrel loading-dose: time-dependent effect of platelet supplementation.

BACKGROUND: Hemostatic benefits of platelet transfusions in thienopyridine-treated acute coronary syndrome (ACS) patients may be compromised by residual metabolite in circulation. OBJECTIVES: To estimate the earliest time after a prasugrel loading-dose when added platelets are no longer inhibited by prasugrel's active metabolite. METHODS: Baseline platelet reactivity of healthy subjects (n=25, 30 ± 5 years, 68% male) on ASA 325 mg was tested using maximum platelet aggregation (MPA, ADP 20 µm) and VerifyNow(®) P2Y12 and was followed by a 60 mg prasugrel loading-dose. At 2, 6, 12 and 24 h post-dose, fresh concentrated platelets from untreated donors were added ex-vivo to subjects' blood, raising platelet counts by 0% (control), 40%, 60% and 80%. To estimate the earliest time when prasugrel's active metabolite's inhibitory effect on the added platelets ceases, platelet function in supplemented samples was compared across time-points to identify the time when effect of supplementation on platelet function stabilized (i.e. the increase in platelet reactivity was statistically similar to that at the next time-point). RESULTS: Supplemented samples showed concentration-dependent increases in platelet reactivity vs. respective controls by both MPA and VerifyNow(®) at all assessment time-points. For each supplementation level, platelet reactivity showed a sharp increase from 2 to 6 h but was stable (P=NS) between 6 and 12 h. CONCLUSIONS: The earliest measured time when supplemented platelets were not inhibited by circulating active metabolite of prasugrel was 6 h after a prasugrel loading-dose. These findings may have important implications for prasugrel-treated ACS patients requiring platelet transfusions during surgery.

Effect of rifampin on the pharmacokinetics and pharmacodynamics of prasugrel in healthy male subjects.

OBJECTIVE: Prasugrel is a thienopyridine antiplatelet agent for the prevention of atherothrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Since cytochrome P450 enzymes CYP3A4 and CYP2B6 play a major role in prasugrel's active metabolite formation, the effect of potent CYP induction by rifampin on the pharmacokinetics of prasugrel and on the pharmacodynamic response to prasugrel was evaluated in healthy male subjects. RESEARCH DESIGN AND METHODS: This was an open-label, two-period, fixed-sequence study conducted at a single clinical research center. In the first treatment period, subjects received prasugrel as an oral 60-mg loading dose (LD) on the first day followed by ten oral, 10-mg daily maintenance doses. After a 2-week washout period, subjects received oral rifampin alone (600 mg once daily) for 8 days, followed by coadministration of oral rifampin with prasugrel, given as a 60-mg LD on the first day followed by five daily 10-mg MDs. Blood collection for pharmacokinetic and pharmacodynamic analyses occurred after the LD and fifth MD of prasugrel in both periods. CLINICAL TRIAL SYNOPSIS: clinicalstudyresults.org ID #8976 RESULTS: Rifampin coadministration (600 mg daily) did not affect exposure to prasugrel's active metabolite (R-138727). However, at 2 and 4 h after the prasugrel loading dose (60 mg), rifampicin coadministration was associated with a 6-9 percentage point decrease (p < 0.01) in the magnitude of platelet inhibition; similarly, a 5-17 percentage point decrease (p < 0.05) was observed with rifampin coadministration during the prasugrel maintenance dose (10 mg) period. Post hoc in vitro experiments demonstrated a dose-dependent R-138727-rifampin interaction at the P2Y(12) level unrelated to enzyme induction. A limitation of this study is that while results of the in vitro post hoc study indicate a pharmacodynamic interaction with rifampin, the mechanism underlying this interaction has not been elucidated. CONCLUSIONS: Dose adjustment should not be necessary when prasugrel is administered with CYP inducers since formation of prasugrel's active metabolite is not affected by potent enzyme induction with rifampin.

Acitretin elimination in Sprague-Dawley rats pretreated with phenobarbital or beta-naphthoflavone.

Male Sprague-Dawley rats were pretreated with either phenobarbital (PB) or beta-naphthoflavone (BNF), after which acitretin (0.84-0.86 mg/kg) was administered intravenously and plasma was sampled with time. Animals were killed 24 hr after dosing, and livers were removed. Hepatic microsomal protein was isolated, frozen, and later used for quantitation of hepatic microsomal protein concentration, total cytochrome P450 concentration, and microsomal activities of methoxy-, ethoxy-, pentoxy-, and benzyloxyresorufin O-dealkylation (MROD, EROD, PROD, and BROD, respectively). Plasma concentrations of acitretin and its primary metabolite isoacitretin were quantified by reversed-phase HPLC. PB pretreatment increased the systemic clearance (CLs) of acitretin 33%, but did not statistically significantly affect the volume of distribution (Vss) or mean residence time (MRT). PB pretreatment increased hepatic microsomal protein and total P450 concentrations, and increased the activity of MROD 7-fold, EROD 8-fold, PROD 121-fold, and BROD 106-fold. BNF pretreatment increased acitretin CLs 152% and reduced MRT by two-thirds; Vss was unchanged. Hepatic microsomal protein and total P450 concentrations were increased after BNF pretreatment, as were the activities of MROD 20-fold, EROD 32-fold, PROD 1-fold, and BROD 6-fold. These results indicate that PB moderately induces acitretin CLs in Sprague-Dawley rats, but the magnitude of induction suggests that the predominant PB-inducible enzymes do not play a major role in acitretin elimination. BNF pretreatment substantially increased acitretin CLs in male Sprague-Dawley rats, which strongly implicates involvement of P4501A1 and/or 1A2, and suggests the potential for clinically relevant interactions between acitretin disposition and drugs and activities that induce these pathways.