ABSTRACT
: Product labels for cobicistat with atazanavir or darunavir, and for elvitegravir/cobicistat/emtricitabine/tenofovir (alafenamide or disoproxil fumarate) were recently updated to state that these products are not recommended for initiation during pregnancy, and an alternative regimen is recommended for those who become pregnant during therapy with these products. Herein, we present the rationale for these recommendations, which are based on studies in pregnant women evaluating the pharmacokinetics and antiviral activity of darunavir/cobicistat or elvitegravir/cobicistat-containing antiretroviral regimens. In these studies, mean steady-state minimum concentrations in the second and third trimester versus postpartum of cobicistat, darunavir, and elvitegravir were reduced by 61-83%, 89-92%, and 82-86%, respectively. In the absence of data with atazanavir/cobicistat, we leveraged the available data with darunavir/cobicistat and elvitegravir/cobicistat to make recommendations for atazanavir/cobicistat. Darunavir/ritonavir and atazanavir/ritonavir remain viable treatment options for pregnant women.
Subject(s)
Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , Antiretroviral Therapy, Highly Active/methods , Cobicistat/administration & dosage , Cobicistat/pharmacokinetics , HIV Infections/drug therapy , Pregnancy Complications, Infectious/drug therapy , Female , Humans , Pregnancy , Treatment OutcomeABSTRACT
The article by Adkison et al. described sorbitol effects on lamivudine exposures. The results indicate a plausible mechanism for lower lamivudine exposures in pediatric patients receiving the solution formulation with concomitant medications containing sorbitol. In this commentary, we discuss lower lamivudine exposures in pediatric patients receiving the solution formulation, the impact of sorbitol on lamivudine exposures, and the US Food and Drug Administration's (FDA's) decision to increase the dose of the lamivudine solution for all pediatric patients.
Subject(s)
Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , Lamivudine/administration & dosage , Lamivudine/pharmacokinetics , Sorbitol/administration & dosage , Sweetening Agents/administration & dosage , Administration, Oral , Age Factors , Anti-HIV Agents/adverse effects , Biological Availability , Child , Child, Preschool , Drug Dosage Calculations , Humans , Lamivudine/adverse effects , Pharmaceutical Solutions , Risk Assessment , Sorbitol/adverse effects , Sweetening Agents/adverse effects , United States , United States Food and Drug AdministrationABSTRACT
Elbasvir/grazoprevir demonstrated high sustained virologic response rates 12 weeks after the end of treatment (SVR12) across five clinical trials in subjects infected with chronic hepatitis C virus (HCV) genotype 1, including those with advanced chronic kidney disease (CKD), and GT4. Despite favorable results overall, the US Food and Drug Administration (FDA) encountered challenging regulatory issues due to the limitations of clinical trial data in certain subpopulations. In GT1a-infected subjects, baseline NS5A resistance-associated polymorphisms emerged as the strongest baseline characteristic associated with diminished SVR12 rates following 12 weeks of elbasvir/grazoprevir treatment. The decision for recommending 16 weeks of elbasvir/grazoprevir + ribavirin in this population and for extrapolating these recommendations to patients with advanced CKD was based on benefit-versus-risk analyses using the available data. Conversely, FDA had insufficient data to define a specific elbasvir/grazoprevir treatment regimen for GT1a-infected subjects with baseline NS5A resistance-associated polymorphisms who failed prior treatment with pegylated interferon + ribavirin (PR) and either boceprevir, simeprevir, or telaprevir. For GT4 PR-experienced patients, leveraging of data in related populations and additional pooled analyses were employed to support labeling for elbasvir/grazoprevir. This article describes FDA's rationale for labeling determinations in situations where limited data made these decisions challenging.
Subject(s)
Antiviral Agents/administration & dosage , Benzofurans/administration & dosage , Hepatitis C, Chronic/drug therapy , Imidazoles/administration & dosage , Quinoxalines/administration & dosage , Antiviral Agents/therapeutic use , Drug Combinations , Genotype , Hepacivirus/genetics , Humans , Renal Insufficiency, Chronic/drug therapy , Ribavirin/administration & dosage , Ribavirin/therapeutic use , Treatment OutcomeABSTRACT
Hypoglycemia was not previously known to be a linezolid-associated adverse reaction. A case report describing symptomatic hypoglycemia in a linezolid recipient prompted a review of the US Food and Drug Administration Adverse Event Reporting System, which demonstrated a relationship between linezolid and hypoglycemia. A warning with this information was added to the linezolid package insert.
