title: Population Pharmacokinetics of Boosted-Elvitegravir in HIV-Infected Patients.
abstract: Elvitegravir (EVG) is an HIV strand transfer integrase inhibitor approved for the treatment of HIV infection as a part of antiretroviral regimens containing cobicistat (COBI) or ritonavir (RTV) as a booster. The population pharmacokinetics of EVG in treatment-naive and -experienced HIV patients was determined, and the effects of demographic, biometric, and formulation covariates on EVG pharmacokinetics (PK) were evaluated. Data from 31 clinical studies (25 in healthy subjects, 6 phase 1b to phase 3 in HIV-1-infected patients) with COBI-boosted EVG studies (as EVG/co or EVG/COBI/FTC/TDF single-tablet regimen) or RTV-boosted EVG studies (EVG/r) were analyzed using NONMEM. The effect of the covariates age, sex, race, health status (healthy volunteers vs HIV patients), weight, body mass index (BMI), body surface area (BSA), creatinine clearance (estimated GFR), and formulation were evaluated. EVG PK, with COBI or RTV, was described by a 2-compartment model, with first-order absorption and elimination and an absorption lag time. A statistically significant, but not clinically relevant, effect of BSA on EVG clearance (CL) was observed. Coadministration of atazanavir or lopinavir with EVG/r had an effect on EVG CL consistent with the known interaction with these agents. No other covariate had a meaningful effect on EVG PK. EVG PK was well described in a population PK model with HIV-infected patients, with low PK variability and no relevant effect of demographic or biometric covariates.
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, 94404.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Custodio
authors.affiliation: Ziba Drug Development Partners, San Carlos, CA, 94070.
authors.forename: Toufigh
authors.initials: T
authors.lastname: Gordi
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, 94404.
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, 94404.
authors.forename: Kah Hiing J
authors.initials: KH
authors.lastname: Ling
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, 94404.
authors.forename: Srini
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D019427:HIV Integrase / Q000097:blood; D019428:HIV Integrase Inhibitors / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000008:administration & dosage* / Q000097:blood*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: Clinical Pharmacology (CPH); HIV/AIDS; metabolism; pharmacokinetics and drug; pharmacometrics; population pharmacokinetics