Steady state bioequivalence of generic and innovator formulations of stavudine, lamivudine, and nevirapine in HIV-infected Ugandan adults

Background: Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®). Methodology/Principal Findings: An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC0–12h and Cmax. Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8–1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine Cmax, 1.3 (0.99–1.71) and AUC0–12h, 1.1 (0.87–1.38); lamivudine Cmax, 0.8 (0.63–0.98) and AUC0–12h, 0.8 (0.65–0.99); and nevirapine Cmax, 1.1 (0.95–1.23) and AUC0–12h, 1.1 (0.95–1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters. Conclusions/Significant Findings: These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU

Steady State Bioequivalence of Generic and Innovator Formulations of Stavudine, Lamivudine, and Nevirapine in HIV-Infected Ugandan Adults

Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®)., 1.1 (0.95–1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical

Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. Methodology/Principal Findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl- CoA isomerase (PECI) on chromosome 6. Conclusions: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclearencoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis

The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs

Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Steady state bioequivalence of generic and innovator formulations of stavudine, lamivudine, and nevirapine in HIV-infected Ugandan adults.

BackgroundGeneric antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune) or the corresponding brand formulations (Epivir, Zerit, and Viramune).Methodology/principal findingsAn open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC(0-12h) and C(max). Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8-1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C(max), 1.3 (0.99-1.71) and AUC(0-12h), 1.1 (0.87-1.38); lamivudine C(max), 0.8 (0.63-0.98) and AUC(0-12h), 0.8 (0.65-0.99); and nevirapine C(max), 1.1 (0.95-1.23) and AUC(0-12h), 1.1 (0.95-1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.Conclusions/significant findingsThese findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical

Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms

ObjectiveNevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability.MethodsTwo doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r(GC)) to variability in nevirapine AUC(0-6 h). Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics.ResultsA significant r(GC) for nevirapine AUC(0-6 h) was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC(0-6 h) for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19).ConclusionThis study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics

Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms: towards addressing the missing heritability in pharmacogenetic phenotypes?

ObjectiveNevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability.MethodsTwo doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r(GC)) to variability in nevirapine AUC(0-6 h). Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics.ResultsA significant r(GC) for nevirapine AUC(0-6 h) was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC(0-6 h) for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19).ConclusionThis study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics