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Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir.

ABSTRACT: Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) currently under review by the US Food and Drug Administration for marketing approval. The in vitro, protein-adjusted 90 % inhibitory concentration (IC90) of dolutegravir for wild-type virus is 0.064 ?g/ml, and it retains in vitro anti-HIV 1 activity across a broad range of viral phenotypes that are known to confer resistance to the currently marketed INSTIs, raltegravir and elvitegravir. Dolutegravir has a terminal elimination half-life of 13-14 h and maintains concentrations over the in vitro, protein-adjusted IC90 for more than 30 h following a single dose. Additionally, dolutegravir has low inter-subject variability compared with raltegravir and elvitegravir. A plasma exposure-response relationship has been well described, with antiviral activity strongly correlating with trough concentrations. Phase III trials have assessed the antiviral activity of dolutegravir compared with efavirenz and raltegravir in antiretroviral (ARV)-naive patients and found that dolutegravir achieved more rapid and sustained virologic suppression in both instances. Additionally, studies of dolutegravir activity in patients with known INSTI-resistant mutations have been favourable, indicating that dolutegravir retains activity in a variety of INSTI-resistant phenotypes. Much like currently marketed INSTIs, dolutegravir is very well tolerated. Because dolutegravir inhibits the renal transporter organic cation transporter 2, reduced tubular secretion of creatinine leads to non-progressive increases in serum creatinine. These serum creatinine increases have not been associated with a decreased glomerular filtration rate or progressive renal impairment. Dolutegravir's major and minor metabolic pathways are uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 (CYP)-3A4, respectively, and it neither induces nor inhibits CYP isoenzymes. Thus dolutegravir has a modest drug interaction profile. However, antacids significantly decrease dolutegravir plasma exposure and should be separated by 2 h before, or 6 h after, a dolutegravir dose. In summary, dolutegravir is the first of the second-generation INSTIs and exhibits a predictable pharmacokinetic profile and a well-defined exposure-response relationship. Dolutegravir retains activity despite the presence of some class-resistant mutations and achieves rapid and sustained virologic suppression in ARV-naive and ARV-experienced patients. Clinically, dolutegravir is poised to become a commonly used component of antiretroviral regimens.

SUBMITTER: Cottrell ML

PROVIDER: S-EPMC3805712 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir.

Cottrell Mackenzie L ML Hadzic Tanja T Kashuba Angela D M AD

Clinical pharmacokinetics 20131101 11

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) currently under review by the US Food and Drug Administration for marketing approval. The in vitro, protein-adjusted 90 % inhibitory concentration (IC90) of dolutegravir for wild-type virus is 0.064 μg/ml, and it retains in vitro anti-HIV 1 activity across a broad range of viral phenotypes that are known to confer resistance to the currently marketed INSTIs, raltegravir and elvitegravir. Dolutegravir has a terminal e ...[more]

PMID: 23824675

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Project description: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.

Dataset Information

Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir.

Publications

Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir.

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