Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

AIM: To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODS: Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTS: Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (ΔQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 µg ml(-1) (range 1.1-2.8) vs. 1.4 µg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTc I relationship was steeper in women (30 ms per µg ml(-1) vs. 23 ms per µg ml(-1) in men; P = 0.0135). CONCLUSIONS: The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.

Antiviral Information Management System (AIMS): a prototype for operational innovation in drug development.

This article presents a prototype for an operational innovation in knowledge management (KM). These operational innovations are geared toward managing knowledge efficiently and accessing all available information by embracing advances in bioinformatics and allied fields. The specific components of the proposed KM system are (1) a database to archive hepatitis C virus (HCV) treatment data in a structured format and retrieve information in a query-capable manner and (2) an automated analysis tool to inform trial design elements for HCV drug development. The proposed framework is intended to benefit drug development by increasing efficiency of dose selection and improving the consistency of advice from US Food and Drug Administration (FDA). It is also hoped that the framework will encourage collaboration among FDA, industry, and academic scientists to guide the HCV drug development process using model-based quantitative analysis techniques.

Population pharmacokinetics of perphenazine in schizophrenia patients from CATIE: impact of race and smoking.

The goal of the study was to characterize population pharmacokinetics (PPK) for perphenazine in patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Patients (n = 156) received 8 to 32 mg of perphenazine daily for 14 to 600 days for a total of 421 plasma concentrations measurements. Nonlinear mixed-effects modeling was used to determine PPK characteristics of perphenazine. One- and 2-compartment models with various random effect implementations and mixture distributions were evaluated. Objective function values and goodness-of-fit plots were used as model selection criteria. Age, weight, sex, race, smoking, and concomitant medications were evaluated as covariates. A 1-compartment linear model with proportional error best described the data. The population mean clearance and volume of distribution for perphenazine were 483 L/h and 18 200 L, respectively. Race and smoking status had significant impacts on perphenazine clearance estimates. In addition, the estimated population mean clearance was 48% higher in nonsmoking African Americans than in nonsmoking other races (512 L/h vs 346 L/h). Active smokers eliminated perphenazine 159 L/h faster than nonsmokers in each race. Clearances for smoking African Americans versus smokers in other races were 671 L/h versus 505 L/h, respectively.

Population pharmacokinetic model of the pregabalin-sildenafil interaction in rats: application of simulation to preclinical PK-PD study design.

PURPOSE: Preliminary evidence has suggested a synergistic interaction between pregabalin and sildenafil for the treatment of neuropathic pain. The focus of this study was to determine the influence of sildenafil on the pharmacokinetics (PK) of pregabalin with the objective of informing the design of a quantitative pharmacodynamic (PD) study. METHODS: The pharmacokinetics were determined in rats following 2-hr intravenous infusions of pregabalin at doses of 4 mg/kg/hr and 10 mg/kg/hr with and without a sildenafil bolus (2.2 mg) and steady state infusion (12 mg/kg/hr for 6 h). This PK model was utilized in a preclinical trial simulation with the aim of selecting the optimal sampling strategy to characterize the PK-PD profile in a future study. Eight logistically feasible PK sampling strategies were simulated in NONMEM and examined through trial simulation techniques. RESULTS: A two-compartment population PK model best described pregabalin pharmacokinetics. Significant model covariates included either a binary effect of sildenafil administration (30.2% decrease in clearance) or a concentration-dependent effect due to sildenafil's active metabolite. CONCLUSIONS: Analysis of simulations indicated that three post-PD samples had the best cost/benefit ratio by providing a significant increase in the precision (and minor improvement in bias) of both PK and PD parameters compared with no PK sampling.

The effect of reporting methods for dosing times on the estimation of pharmacokinetic parameters of escitalopram.

The objective of this study was to compare population pharmacokinetic models of escitalopram developed from dosage times recorded by a medication event monitoring system (MEMS) versus the reported times from patients with diagnosed depression. Seventy-three patients were prescribed doses of 10, 15, or 20 mg escitalopram daily. Sparse blood samples were collected at weeks 4, 12, 24, and 36 with 185 blood samples obtained from the 73 patients. NONMEM was used to develop a population pharmacokinetic model based on dosing records obtained from MEMS prior to each blood sample time. A separate population pharmacokinetic analysis using NONMEM was performed for the same population using the patient-reported last dosing time and assuming a steady-state condition as the model input. Objective function values and goodness-of-fit plots were used as model selection criteria. The absolute mean difference in the last dosing time between MEMS and patient-reported times was 4.48 +/- 10.12 hours. A 1-compartment model with first-order absorption and elimination was sufficient for describing the data. Estimated oral clearance (CL/F) to escitalopram was statistically insensitive to reported dosing methods (MEMS vs patient reported: 25.5 [7.0%] vs 26.9 [6.6%] L/h). However, different dosing report methods resulted in significantly different estimates on the volume of distribution (V/F; MEMS vs patient reported: 1000 [17.3%] vs 767 [17.5%] L) and the absorption rate constant K(a) (MEMS vs patient reported: 0.74 [45.7%] vs 0.51 [35.4%] h(-1)) for escitalopram. Furthermore, the parameters estimated from the MEMS method were similar to literature reported values for V/F ( approximately 1100 L) and K(a) ( approximately 0.8-0.9 h(-1)) arising from traditional pharmacokinetic approaches.