title: Pharmacokinetics of Co-Formulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate After Switch From Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Healthy Subjects.
abstract: Elvitegravir (EVG), a HIV integrase inhibitor, is metabolized primarily by CYP3A, and secondarily by UGT1A1/3; Efavirenz (EFV), a HIV non-nucleoside reverse transcriptase inhibitor, is metabolized by Cytochrome P450 (CYP) 2B6 and induces CYP3A and uridine diphosphate glucuronosyltransferase (UGT) with residual effects post discontinuation because of long T1/2 (40-55 hours). This study evaluated the pharmacokinetics after switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF).
  
  
  
  Healthy subjects (n = 32 including n = 8 CYP2B6 poor metabolizers) received EVG/COBI/FTC/TDF (150/150/200/300 mg) on days 1-7, and after a washout, received EFV/FTC/TDF (600/200/300 mg) on days 15-28 and switched to EVG/COBI/FTC/TDF (150/150/200/300 mg) for 5 weeks (days 29-62). Pharmacokinetic assessments occurred on days 7, 28, 35, and 42; trough samples (Ctrough) were collected periodically until day 63. Safety was assessed throughout the study.
  
  
  
  Twenty-nine subjects completed with 3 adverse events leading to discontinuation; no grade ≥3 adverse events were reported. Post-EFV/FTC/TDF, mean EVG area under concentration (AUCtau) was 37% and 29% lower and mean Ctrough ∼3- and ∼5-fold above IC95, respectively, on days 35 and 42, and 7-8-fold above IC95 by 5 weeks. COBI AUCtau returned to normal by day 42. EVG glucuronide, GS-9200, AUCtau was higher (46% and 32% on days 35 and 42, respectively) postswitch. CYP2B6 poor metabolizers displayed higher EFV AUCtau and Cmax (125% and 91%, respectively) versus non-poor metabolizers, and lower EVG and COBI exposures. EFV Ctrough was >IC90 (10 ng/mL) in all subjects postswitch. FTC and tenofovir (TFV) exposures were unaffected.
  
  
  
  After EFV/FTC/TDF to EVG/COBI/FTC/TDF switch, EVG and/or EFV exposures were in an active range. These findings support further evaluation of switching regimens in HIV-1 patients.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA.
authors.forename: Srini
authors.initials: S
authors.lastname: Ramanathan
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Custodio
authors.forename: Xuelian
authors.initials: X
authors.lastname: Wei
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Marshall
authors.initials: M
authors.lastname: Fordyce
authors.forename: Ami
authors.initials: A
authors.lastname: Dave
authors.forename: Kah Hiing J
authors.initials: KH
authors.lastname: Ling
authors.forename: Javier
authors.initials: J
authors.lastname: Szwarcberg
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions; D000068257:Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069545:Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D000068257:Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D000069545:Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination