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BACKGROUND & AIMS Telaprevir (VX-950), a hepatitis C virus (HCV) NS3.4A protease inhibitor, has shown strong antiviral activity in phase 1 clinical studies. Because of high levels of HCV replication and the low fidelity of HCV polymerase, selection of resistant isolates during therapy may occur. METHODS A highly sensitive sequencing method was developed(More)
UNLABELLED Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa-2a for 14 days. Previously untreated patients with genotype(More)
In patients chronically infected with hepatitis C virus (HCV) strains of genotype 1, rapid and dramatic antiviral activity has been observed with telaprevir (VX-950), a highly selective and potent inhibitor of the HCV NS3-4A serine protease. HCV variants with substitutions in the NS3 protease domain were observed in some patients during telaprevir dosing.(More)
A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18(More)
This study was performed to develop a new nonparametric approach for the estimation of robust tissue-to-plasma ratio from extremely sparsely sampled paired data (ie, one sample each from plasma and tissue per subject). Tissue-to-plasma ratio was estimated from paired/unpaired experimental data using independent time points approach, area under the curve(More)
Bayesian methods for estimating the dose response curves with the one-hit model, the gamma multi-hit model, and their modiied versions with Abbott's correction are studied. The Gibbs sampling approach with data augmentation and with the Metropolis algorithm is employed to compute the Bayes estimates of the potency curves. In addition, estimation of the(More)
To develop a data supplementation [i.e., a pharmacokinetic/pharmacodynamics (PK/PD) knowledge creation] approach for generating supplemental data to be used in characterizing a targeted unexplored segment of the response surface. The procedure for data supplementation can be summarized as follows: 1) statement of the objective of data supplementation for(More)
An integrative population pharmacokinetics (PPK)-based approach was used to characterize the effect of hepatic impairment on clobazam PK and its major metabolite in systemic circulation, N-desmethylclobazam (N-CLB). At therapeutic clobazam dosages, N-CLB plasma concentrations are 3-5 times greater than the parent compound. PK data from clinical trials in(More)
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