Pharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis.

OBJECTIVE: We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis. METHODS: Patients (N = 1690) in a randomized, double-blind, placebo-controlled phase 3 trial received a 96-hour infusion of placebo (n = 840) or drotrecogin alfa (activated) (n = 850), 24 microg x kg(-1) x h(-1). Plasma samples from 680 patients were collected for pharmacokinetic assessment. Pharmacodynamic effects on activated partial thromboplastin time, D-dimer, protein C, and interleukin 6 were analyzed by drotrecogin alfa (activated) steady-state plasma concentration (C(ss)) quartile. RESULTS: Transient endogenous activated protein C concentrations above 10 ng/mL were observed in 11 placebo-treated patients (3.3%). In drotrecogin alfa (activated)-treated patients, the median C(ss) was 44.9 ng/mL and the median plasma clearance (CL(p)) was 40.1 L/h. C(ss) was reached within 2 hours after the infusion was started. Plasma concentrations were below the assay quantitation limit of 10 ng/mL within 2 hours after the infusion was stopped in 92% of patients. CL(p) increased with increasing body weight, so infusion rates should be based on predose body weight. Mean CL(p) associated with age, sex, or baseline hepatic or renal function differed by less than 30% from the mean CL(p) in all patients and resided within the interquartile range of CL(p) in all patients. Dose adjustment is not required on the basis of these factors alone or in combination. No correlation was detected between C(ss) quartile and bleeding risk or the magnitudes of effect on biomarkers of coagulopathy (D-dimers and protein C) and inflammation (interleukin 6). CONCLUSIONS: Plasma concentrations of drotrecogin alfa (activated) attain steady state rapidly after the infusion is started and decline rapidly after the infusion is stopped. The infusion rate should be based on predose body weight and not on any other demographic or baseline clinical covariate.

Two-stage randomization designs in drug development.

One challenge in oncology drug development is to determine whether a new agent to the care of patients should be added concurrently as a new component to standard of care (SOC) induction treatment, used sequentially as an extended maintenance treatment after SOC induction for patients responding to induction therapy, or used in both the induction and the maintenance settings. A two-stage randomization design (TSRD) addresses these questions simultaneously. In such trials patients are initially randomized to two induction therapies, followed by another randomization to maintenance therapy contingent upon disease remission under induction therapy. We survey recently proposed methods for analyzing time-to-event endpoints in TSRDs and discuss several issues related to the use of TSRDs including sample size calculation and multiplicity. An alternative drug development strategy is to perform several single randomization designs (SRDs) comparing induction and maintenance regimens, respectively. We present a simulation study, which compares TSRDs to several strategies based on SRDs in terms of total sample size and time to reach clinical decisions.

Cox regression methods for two-stage randomization designs.

Two-stage randomization designs (TSRD) are becoming increasingly common in oncology and AIDS clinical trials as they make more efficient use of study participants to examine therapeutic regimens. In these designs patients are initially randomized to an induction treatment, followed by randomization to a maintenance treatment conditional on their induction response and consent to further study treatment. Broader acceptance of TSRDs in drug development may hinge on the ability to make appropriate intent-to-treat type inference within this design framework as to whether an experimental induction regimen is better than a standard induction regimen when maintenance treatment is fixed. Recently Lunceford, Davidian, and Tsiatis (2002, Biometrics 58, 48-57) introduced an inverse probability weighting based analytical framework for estimating survival distributions and mean restricted survival times, as well as for comparing treatment policies at landmarks in the TSRD setting. In practice Cox regression is widely used and in this article we extend the analytical framework of Lunceford et al. (2002) to derive a consistent estimator for the log hazard in the Cox model and a robust score test to compare treatment policies. Large sample properties of these methods are derived, illustrated via a simulation study, and applied to a TSRD clinical trial.

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.

OBJECTIVE: To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]). DESIGN: Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study. SETTING: A total of 164 medical centers in 11 countries. PATIENTS: A total of 1,690 patients with severe sepsis. MEASUREMENTS AND MAIN RESULTS: We report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a > or = 20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality. CONCLUSIONS: The administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.