Pharmacokinetics and Drug Interaction Profile of Cobicistat boosted-elvitegravir with Atazanavir, Rosuvastatin or Rifabutin
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1 Pharmacokinetics and Drug Interaction Profile of Cobicistat boosted-elvitegravir with Atazanavir, Rosuvastatin or Rifabutin S Ramanathan, H Wang, T Stondell, A Cheng, and BP Kearney Gilead Sciences, Inc., USA 13th International Workshop on Clinical Pharmacology of HIV Therapy April 16-18, 2012 Barcelona, Spain Abstract #O_03
2 Introduction Elvitegravir (EVG) Profile: ~ -2.0 log 10 mean change in HIV-1 RNA over 10 days as monotherapy 1 High rates of efficacy, fewer CNS/psychiatric AEs as EVG/COBI/FTC/TDF (QUAD) vs. EFV/FTC/TDF (Atripla ) or Atazanavir/r + TVD in treatment-naïve patients 2,3 Metabolized primarily via CYP3A, secondarily via UGT1A1/3 Boosted substantially by COBI 150 mg similar to RTV mg EVG/r PK EVG 150 mg 85 mg with ATV; Rifabutin 300 mg QD 150 mg QOD 4 No data with newer (non-cyp3a) statins COBI Profile Potent CYP3A inhibitor, weak 2D6 inhibitor, no effects on other CYPs or UGT Similar inhibition as RTV of Pgp, BCRP (intestinal), OATP1B1/3 (liver) 1 DeJesus E, et al. JAIDS 43(1):1-5, 2006; 2 Sax et al. CROI, 2012; 3 DeJesus et al. CROI, 2012; 4 German et al. IWCPHT, 2008
3 Objective and Study Design Objective COBI-boosted EVG 85 mg plus ATV PK COBI-boosted EVG and statin (non-cyp3a) interaction Rosuvastatin minimally metabolized (CYP2C9) Substrate for BCRP, OATP1B1, OATP1B3 Dosing guidance for QUAD COBI-boosted EVG and dose-reduced rifabutin (150 mg QOD) Dosing guidance for QUAD Design Three cohorts with fixed-sequence crossover design Rosuvastatin given as single dose All other treatments given as multiple doses 3
4 Demographics and Safety Demographics across three cohorts Equal distribution by gender Roughly 80% white, 20% black Median age 35 years and BMI 28 kg/m 2 Safety Results No Grade 4 or serious adverse events (serious AEs) Five discontinuations during plus ATV Three Grade 3 hyperbilirubinemia, one Grade 3 rash, one Grade 2 abdominal pain AEs generally consistent with ATV product labeling Hyperbilirubinemia returned to baseline levels upon treatment discontinuation Other AEs: constipation and headache, mostly Grade 1
5 Elvitegravir and Rosuvastatin (ROS) PK EVG Concentration (ng/ml) 00 0 Rosuvastatin PK Mean (%CV) + ROS ROS GMR AUC inf (ng.hr/ml) 38 (40) 27 (41) 138 (114, 167) C max (ng/ml) 5.0 (41) 2.7 (55) 189 (148, 242) T 1/2 (hr) Median (Q1, Q3) 150/150 +ROS 10 mg 150/150 mg Mean ± SD (n=10) (17, 21) 21 (14, 27) ROS Concentration (ng/ml) /150 mg + ROS 10 mg ROS 10 mg Mean ± SD (n=10) No ROS dose adjustment with QUAD per US PI EVG, COBI PK unaffected
6 Elvitegravir and Atazanavir PK ATV Concentration (ng/ml) 00 0 Mean (%CV) AUC tau (ng.hr/ml) EVG 85 mg + ATV/co ATV/r 300/ mg EVG 85 mg + ATV/co 300/150 mg Mean ± SD (n=18 test, 7 ref.) ATV Exposures ATV/r GMR EVG Exposures EVG 85 mg + ATV/co GMR (40) (16) 90.5 (73.4,112) (35) (35) 117 (88, 156) C max (ng/ml) 4660 (37) 5780 (24) 76.1 (59.1, 97.9) 1790 (43) 2150 (41) 84.2 (61.8, 115) C tau (ng/ml) 751 (78) 743 (35) 80.5 (55.6, 117) 553 (49) 318 (49) 183 (117, 286) EVG Concentration (ng/ml) 00 0 EVG 85 mg + ATV/co 300/150 mg 150/150 mg Mean ± SD (n=18 test, 10 ref.) ATV, EVG, COBI PK comparable with reference/historical data
7 Effect of on Rifabutin/metabolite PK Rifabutin Concentration (ng/ml) 0 Mean (%CV) AUC (ng.hr/ml) RIF 150 mg QOD + 150/150 mg QD RIF 300 mg QD Rifabutin + Mean ± SD (n=12) Rifabutin Exposures Rifabutin GMR O-desacetylrifabutin Exposures Rifabutin + Rifabutin GMR 8370 (13) 9320 (29) 92.4 (82.9, 103) 3010 (21) 518 (47) 625 (508, 769) C max (ng/ml) 566 (17) 529 (27) 109 (98.5, 120) 150 (22) 32 (39) 484 (409, 574) C tau (ng/ml) 74 (30) 80.1 (39) 93.9 (84.8, 104) 18.4 (39) 4.0 (61) 494 (404, 604) Similar Rifabutin exposures, 21% higher antimycobacterial activity with vs alone 25-O-desacetylrifabutin Concentration (ng/ml) 0 10 RIF 150 mg QOD + 150/150 mg RIF 300 mg QD Mean ± SD (n=12)
8 Effect of Rifabutin on EVG PK EVG Concentration (ng/ml) EVG C trough (ng/ml) /150 mg + RIF 150 mg QOD 150/150 mg 150/150 mg 150/150 mg + RIF 150 mg QOD + RIF Mean ± SD (n=12) EVG C trough lower with rifabutin Range ( ng/ml) in Ph 3 bottom quartile Conservatively, QUAD codosing not recommended Mean (%CV) AUC tau (ng.hr/ml) C max (ng/ml) C tau (ng/ml) + RIF (26) 2050 (25) 164 (61) EVG C trough (ng/ml) EVG Exposures (24) 2250 (26) 452 (46) GMR 79.4 (74.1, 85.1) 91.1 (83.6, 99.4) 32.9 (26.9, 40.1) QUAD Virologic Response vs EVG C trough Octile to < to < to < to < to < to < to < Virologic Response (%)
9 Effect of Rifabutin on COBI PK COBI Concentration (ng/ml) COBI Concentration (ng/ml) /150 mg + RIF 150 mg QOD 150/150 mg 150/150 mg + RIF 150 mg QOD 150/150 mg *BQL; assigned LLOQ/2 Mean ± SD (n=12) Mean ± SD (n=12) + RIF Mean (%CV) AUC tau (ng.hr/ml) C max (ng/ml) C tau (ng/ml) COBI Exposures + RIF (29) 1880 (29) (19) 1640 (19) 6.5 (72) 22.8 (61) COBI exposures lower with rifabutin
10 Historical data: Effect of Rifampin on ATV, RTV ATV ATV/r 300/ ATV 400 ATV/r 400/200 + RIF Δ ATV/r 300/200 + RIF ATV/r 300/ + RIF RTV ATV PK ATV/r 300/ ATV/r 400/200 + RIF Δ ATV/r 300/200 + RIF ATV/r 300/ + RIF RTV PK Dose (mg) ATV 400 ATV/r 300/ ATV/r 300/+RIF ATV/r 300/200+RIF ATV/r 400/200+RIF ATV Cmin (ng/ml) RTV AUC (ng.h/ml) ,900 11,300 EVG and COBI exposures lower with rifabutin Burger D M et al. Antimicrob. Agents Chemother. 2006;50: Figures shown with permission from Drs. Burger and Bertz
11 Conclusions COBI-boosted EVG and Rosuvastatin: no clinically relevant interactions No relevant effects based on inhibition of BCRP, OATP1B1 and OATP1B3 by EVG/COBI No dose adjustment of rosuvastatin necessary with QUAD No clinically relevant interactions with COBI-boosted EVG 85 mg + ATV Consistent with historical data on EVG/r EVG and COBI exposures lower with rifabutin Coadministration with QUAD not recommended presently Additional evaluation with antimycobacterial agents planned
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