Pharmacokinetic analysis of nevirapine extended release 400 mg once daily vs nevirapine immediate release 200 mg twice daily formulation in treatment-naïve patients with HIV-1 infection.

Background: VERxVE data showed non-inferior virologic efficacy with extended release nevirapine (NVP-XR) dosed 400 mg once daily (QD) versus immediate release nevirapine (NVP-IR) 200 mg twice daily in a double-blind, non-inferiority study in treatment-naïve HIV-1-positive patients.

Objective: To study the pharmacokinetics (PK) of the NVP formulations and identify possible associations with demographic factors.

Methods: Patients with viral load ≥1000 copies/mL and CD4+ count > 50- <400 cells/mm (males) and >50- <250 cells/mm (females) at screening received NVP-IR 200 mg QD during a 14-day lead-in and were then stratified by baseline viral load and randomized to NVP-XR or -IR.

Pharmacokinetics, safety, and tolerability of faldaprevir in patients with renal impairment.

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.

Mass balance and metabolite profiling of steady-state faldaprevir, a hepatitis C virus NS3/4 protease inhibitor, in healthy male subjects.

The pharmacokinetics, mass balance, and metabolite profiles of faldaprevir, a selective peptide-mimetic hepatitis C virus NS3/NS4 protease inhibitor, were assessed at steady state in 7 healthy male subjects. Subjects received oral doses of 480 mg faldaprevir on day 1, followed by 240 mg faldaprevir on days 2 to 8 and 10 to 15. [14C]faldaprevir (240 mg containing 100 μCi) was administered on day 9.

Steady-state pharmacokinetics of nevirapine extended-release tablets in HIV-1-infected children and adolescents: an open-label, multiple-dose, cross-over study.

Background: To compare steady-state (ss) pharmacokinetic targets of nevirapine extended-release (NVP-XR) tablets once-daily (QD) with immediate-release (NVP-IR) tablet or oral suspension twice-daily in HIV-1-infected children and adolescents.

Methods: Phase I, open-label, multidose, cross-over study with optional extension phase, in 85 patients 3 to <18 years of age, previously on an NVP-IR-based regimen for ≥18 weeks with baseline viral load <50 copies/mL. Patients were stratified by age, treated with NVP-IR twice-daily for 11 days, then NVP-XR QD for 10 days.

Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor.

The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested).

Bioavailability of extended-release nevirapine 400 and 300 mg in HIV-1: a multicenter, open-label study.

Background: Nevirapine (NVP) is a widely used non-nucleoside reverse transcriptase inhibitor. A once-daily extended-release (XR) formulation would potentially increase adherence and thus efficacy.

Objective: The aim of this study was to investigate the steady-state bioavailability of 2 once-daily tablet formulations of NVP XR (containing 25% or 20% hypromellose; NVP XR25 and NVP XR20, respectively) in 400- or 300-mg tablets compared with twice-daily immediate-release (IR) NVP 200-mg tablets.

Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice-daily in treatment-naive HIV-1-infected patients.

Background: This study (VERxVE) compared the efficacy and safety of the new nevirapine extended-release (NVP XR) formulation dosed once daily with NVP immediate release (IR) twice daily in treatment-naive patients.

Methods: Randomized, double-blind, double-dummy, parallel group study of HIV-1-infected adult patients with baseline viral load (VL) ≥ 1,000 copies/ml and CD4(+) T-cell count of >50-<400 (males) and >50-<250 cells/mm(3) (females). Patients stratified by baseline VL (≤ 100,000/>100,000 copies/ml) were randomized 1:1 to NVP XR 400 mg once daily (plus placebo) or NVP IR 200 mg twice daily (plus placebo), both combined with tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine 200 mg once daily.

Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection.

Background & Aims: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.

Methods: Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28.

In vitro-in vivo correlation for nevirapine extended release tablets.

An in vitro-in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC-MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin.

Assessment of nevirapine bioavailability from targeted sites in the human gastrointestinal tract.

This study investigated absorption of nevirapine (NVP) from targeted sites of the gastrointestinal tract using remotely activated capsules and gamma scintigraphy. A total of 24 participants were randomized to receive 50 mg NVP orally as a suspension or via remotely activated capsules for release into the ascending colon. The 24 participants were then rerandomized into parallel groups of n = 8 for drug release into the ileum, jejunum, or descending colon.

Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C.

BILN-2061, a specific and potent peptidomimetic inhibitor of the HCV NS3 protease, has recently been shown to markedly lower serum hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1 in three 2-day proof of principle studies. The aim of the current study was to assess the antiviral efficacy of BILN-2061 in patients with genotypes 2 and 3 HCV infection. The antiviral efficacy, pharmacokinetics, and tolerability of 500 mg twice-daily BILN-2061 given as monotherapy for 2 days in 10 patients chronically infected with non-genotype 1 HCV (genotype 2: n = 3; genotype 3: n =7) and minimal liver fibrosis (Ishak score 0-2) were assessed in a placebo-controlled (placebo n = 2), double-blind pilot study.

Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients.

Background And Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection.

Pharmacokinetic comparison of an angiotensin II receptor antagonist, telmisartan, in Japanese and western hypertensive patients using population pharmacokinetic method.

The objectives of this study were to develop a population pharmacokinetic (PPK) model for telmisartan based on the pooled data obtained from the different racial populations and then to identify the factors that affect the pharmacokinetics of telmisartan for the comparison between the regions. A PPK model was established based on the data of 1343 subjects in 12 clinical trials. The PK profiles of telmisartan were described with a 2-compartment model with first-order absorption.

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients.

Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.

The p38 mitogen-activated protein kinase (MAPK) participates in intracellular signaling cascades resulting in inflammatory responses. Therefore, inhibition of the p38 MAPK pathway may form the basis of a new strategy for treatment of inflammatory diseases. However, p38 MAPK activation during systemic inflammation in humans has not yet been shown, and its functional significance in vivo remains unclear.