BACKGROUND Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 viro-logic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.)

Remdesivir (RDV), a single diastereomeric monophosphoramidate prodrug that inhibits viral RNA polymerases, has potent in vitro antiviral activity against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). RDV received the US Food and Drug Administration (FDA)’s emergency use authorization in the United States and approval in Japan for treatment of patients with severe coronavirus disease 2019 (COVID‐19). This report describes two phase I studies that evaluated the safety and pharmacokinetics (PKs) of single escalating and multiple i.v. doses of RDV (solution or lyophilized formulation) in healthy subjects. Lyophilized formulation was evaluated for potential future use in clinical trials due to its storage stability in resource‐limited settings. All adverse events were grade 1 or 2 in severity. Overall, RDV exhibited a linear profile following single‐dose i.v. administration over 2 hours of RDV solution formulation across the dose range of 3–225 mg. Both lyophilized and solution formulations provided comparable PK parameters. High intracellular concentrations of the active triphosphate (~ 220‐fold to 370‐fold higher than the in vitro half‐maximal effective concentration against SARS‐CoV‐2 clinical isolate) were achieved following infusion of 75 mg or 150 mg lyophilized formulation over 30 minutes or 2 hours. Following multiple‐doses of RDV 150 mg once daily for 7 or 14 days, RDV exhibited a PK profile similar to single‐dose administration. Metabolite GS‐441524 accumulated ~ 1.9‐fold after daily dosing. Overall, RDV exhibited favorable safety and PK profiles that supported once‐daily dosing.

GS-9350 is a new chemical entity under development as a potent, mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) isoforms. Its intended use is to increase the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. Unlike ritonavir, which is in current clinical use for this purpose, GS-9350 is devoid of anti-HIV activity. The pharmacokinetics of GS-9350 and its efficacy in increasing systemic exposure of the probe CYP3A substrate midazolam were examined in a study involving single- and multiple-dose escalations of GS-9350 from 50 to 400 mg. Single-dose escalation from 50 to 400 mg resulted in a 164-fold increase in GS-9350 exposure, whereas multiple-dose escalation in the dosage range of 50-300 mg resulted in a 47-fold increase in exposure. GS-9350 potently inhibited midazolam apparent clearance (95% reduction), similar in effect to ritonavir 100 mg. GS-9350 was generally well tolerated at all doses, and there was no evidence of dose-limiting toxicity. Establishing proof-of-concept, GS-9350 is currently under phase II development as a potential alternative to ritonavir for use with antiretroviral agents (including the HIV integrase inhibitor elvitegravir) that are often prescribed along with a "booster" drug.

Ledipasvir-sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir-sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371-378).

Elvitegravir is a potent, boosted, once-daily, HIV integrase inhibitor with antiviral activity against wild-type and drug-resistant strains of HIV. Because elvitegravir is metabolized primarily by cytochrome P450 (CYP) 3A enzymes, coadministration with a strong CYP3A inhibitor such as ritonavir or cobicistat (also known as GS-9350), an investigational pharmacoenhancer, substantially increases (boosts) elvitegravir plasma exposures and prolongs its elimination half-life to ∼9.5 hours, allowing once-daily administration of a low 150 mg dose. Boosting also results in low intra- and intersubject pharmacokinetic variability and high elvitegravir trough concentrations (∼6- to 10-fold above the concentration producing 95% inhibition of wild-type HIV-1 virus [IC95] of 45 ng/mL [protein binding-adjusted]), which is the pharmacokinetic parameter best associated with its antiviral activity. Data from extensive evaluation of the potential for boosted elvitegravir to undergo drug-drug interactions with other antiretroviral agents or concomitant medications indicate the absence of clinically relevant interactions or the need for dose modification in several cases, except for dose reduction of elvitegravir from 150 to 85 mg when coadministered with atazanavir/ritonavir or lopinavir/ritonavir. Dose adjustments for maraviroc and rifabutin, when each is coadministered with boosted elvitegravir, are consistent with their observed interactions with other ritonavir-boosted agents. The presence of a strong CYP3A inhibitor such as ritonavir or cobicistat renders the potential for increase in systemic exposures of CYP3A substrates coadministered with boosted elvitegravir. This article reviews a comprehensive pharmacology programme, including drug-drug interaction studies, mechanistic and special population studies, that has allowed a thorough understanding of elvitegravir clinical pharmacokinetics and its impact on pharmacodynamics.

COBI affects eGFR but not the actual GFR. The time to onset, magnitude, and time to resolution of changes in eGFR are consistent with altered proximal tubular secretion of creatinine through inhibition of drug transporters.

Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.

Remdesivir (RDV, Veklury ® ) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug–drug interaction potential based on available in vitro and clinical data in healthy volunteers. Following single-dose intravenous administration over 2 h of an RDV solution formulation across the dose range of 3–225 mg in healthy participants, RDV and its metabolites (GS-704277and GS-441524) exhibit linear pharmacokinetics. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. Based on pharmacokinetic bridging from animal data and available human data in healthy volunteers, the RDV clinical dose regimen of a 200-mg loading dose on day 1 followed by 100-mg maintenance doses for 4 or 9 days was selected for further evaluation of pharmacokinetics and safety. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. Mathematical drug–drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug–drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-00984-5.