Confirmation of the Drug-drug Interaction Potential Between Cobicistat-boosted Antiretroviral Regimens and Hormonal Contraceptives

Transcription

1 Confirmation of the Drug-drug Interaction Potential Between Cobicistat-boosted Antiretroviral Regimens and Hormonal Contraceptives Sophia R. Majeed, Steve K. West, Shuping Jiang, Jessica Andrews, Savita O. Sinha, Kah Hiing J. Ling, Moupali Das, Huyen Cao, Brian P. Kearney, Joseph M. Custodio Gilead Sciences, Inc., Foster City, CA Oral # 5 IWCPAT 207, Chicago

2 Disclosures I am an employee of Gilead Sciences, Inc. 2

3 Background DHHS guidelines recommend offering effective and appropriate contraceptive methods to all HIV-infected women Drug-drug interactions (DDIs) between ARVs and hormonal ( oral ) contraceptives (OCs) are well documented 2-7 OCs are extensively metabolized by CYP enzymes (including CYP3A, CYP2C9/9), UGT and SULT. Antiretroviral Drugs in Pregnant HIV--Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Accessed 6/5/7; 2. STRIBILD [package insert]. Foster City, CA: Gilead Sciences Inc; 202; 3. German P et al. IWCPHT 20, Abstract O_7; 4. KALETRA (lopinavir/ritonavir) [package insert]. North Chicago, IL: AbbVie Inc; 2000; 5. Younis IR, et al. J Clin Pharm. 206;56(5):54-547; 6. REYATAZ [package insert]. Princeton, NJ: Briston-Myers Squibb Co; 2003; 7. PREZISTA [package insert]. Titusville, NJ: Janssen; 206.

4 Background Effect of COBI on OC (norgestimate/ethinyl estradiol []) evaluated previously with EVG/COBI/FTC/TDF in healthy subjects and confirmed in HIV-infected women,2 PK Parameter *Compared to historical data of levonorgestrel/ administered alone 4. Consistent with CYP3A inhibition by COBI EVG/COBI/FTC/TDF + norgestimate/ n=3 Norelgestromin AUCτ 30% C max 0% EVG/COBI/FTC/TDF + levonorgestrel/ 3 n=20 Norgestrel AUCτ 0% * C max 60% * AUCτ 25% 20% * C max 0% *. STRIBILD [package insert]. Foster City, CA: Gilead Sciences Inc; 2. German P et al. IWCPHT 20, Abstract O_7; 3. Squires K, et al. Asia Pacific AIDS & Co-Infections Conference 206, poster P68; 4. Olsson B, Landgren BM. Clin Ther 200;23 ():

5 Background For RTV-boosted protease inhibitors, DDIs between ATV and DRV and OCs have been evaluated,2 DDI with COBI-boosted ATV or DRV and OCs was not available Phase I DDI study conducted as a regulatory request to confirm the magnitude and direction of a potential interaction with OCs. PREZISTA [package insert]. Titusville, NJ: Janssen; 206; 2. REYATAZ [package insert]. Princeton, NJ: Briston-Myers Squibb Co; 2003.

6 Aim Yaz () is a combination oral contraceptive containing progestational and estrogenic compounds Drospirenone (DRSP): 3 mg Ethinyl Estradiol (): 20 µg Primary: to evaluate the effect of the PK enhancer COBI, plus ATV ( ATV + COBI) or DRV (DRV + COBI) on the pharmacokinetics (PK) of Secondary: safety and tolerability of administration of ATV + COBI or DRV + COBI when given alone or in combination with

7 Healthy Women Study Design and Methods Phase I open-label, two cohort, fixed sequence study in healthy women Cohort, DRSP/ Washout DRV + COBI mg DRSP/ Cohort 2, Day DRSP/ Intensive plasma PK over 96 h Washout ATV + COBI mg DRSP/ Intensive plasma PK over 96 h PK analysis: Plasma concentrations OCs (DRSP and ) and ATV, DRV and COBI determined using validated LC/MS-MS assays Primary PK parameters (mean [%CV]) include AUC /last (h ng/ml) and C max (ng/ml) Geometric least squares mean ratio (GMR; [Test Treatment vs Reference Treatment]) and 90% confidence intervals (CI) estimated using ANOVA; compared against lack of PK alteration bounds of 70 43% Safety assessed throughout the study AUC /last, area under plasma concentration-time curve from time 0 to /last measurable concentration; C max, maximal concentration; CV, coefficient of variation; LC/MS-MS, liquid chromatography tandem-mass spectrometry;

8 Results: Demographics *All discontinuations were due to Grade maculopapular rash. DRV + COBI ATV + COBI Completed/enrolled, n 5/8 * 4/8 * Median age, y (range) 28 (8 43) 30 (22 44) Median body mass index, kg/m 2 (range) 26 (20 30) 26 (23 30) Mean creatinine clearance, ml/min (range) 29 (95 86) 22 (96 7) Race, % Black White Asian 0 6 Ethnicity, % Hispanic/Latino

9 Results: Safety AE by Preferred Term All treatments were generally well tolerated Cohort Cohort 2 DRV + COBI DRV + COBI + n=5 7 subjects discontinued due to Grade maculopapular rash, a known AE of boosted PIs AEs were consistent with the known safety profiles of the approved products,2,3 ATV + COBI Any TEAEs Ocular icterus Infrequent bowel movements Nausea Diarrhea Hyperbilirubinemia Headache Presyncope Oropharyngeal pain Rash maculo-popular ATV + COBI + n=4 Acne Yaz USPI 2. EVOTAZ [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; PREZCOBIX [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc;

10 Mean DRSP Concentration, ng/ml (± SD) Mean Concentration, pg/ml (± SD) Results: Effect of ATV + COBI on PK ATV + COBI DRSP/ DRSP PK Parameter Mean (%CV) ATV + COBI + [Test] n=4 PK Parameter Mean (%CV) ATV + COBI + [Test] n=4 AUC, h ng/ml 8 (38) 466 (2) 230 (200, 264) AUC, h pg/ml 296 (2) 396 (27) 78 (73, 85) C max, ng/ml 33 (23) 29 (20) 2 (05, 9) C max, pg/ml 27 (22) 34 (24) 82 (76, 89) ATV + COBI increased DRSP exposure Attributed to inhibition of CYP3A by COBI Similar increase in DRSP exposures observed with CYP3A inhibitor ketoconazole ATV + COBI did not impact PK (within no-effect boundary). Wiesinger, et al. Br J Clin Pharmacol. 205;80(6):

11 Mean DRSP Concentration, ng/ml (± SD) Mean Concentration, pg/ml (± SD) Results: Effect of DRV + COBI on PK DRV + COBI DRSP/ DRSP PK Parameter Mean (%CV) DRV + COBI + [Test] n=5 DRV + COBI increased DRSP exposure; attributed to inhibition of CYP3A by COBI DRV + COBI reduced exposure; decreases in exposures observed with DRV/ritonavir (RTV) May be attributed to induction (eg, P-gp, CYP2C9) PK Parameter Mean (%CV) DRV + COBI + [Test] n=5 AUC, h ng/ml 895 (24) 567 (24) 58 (47, 7) AUC, h pg/ml 308 (28) 439 (32) 70 (63, 77) C max, ng/ml 36 (2) 3 (20) 5 (05, 26) C max, pg/ml 29 (35) 33 (36) 86 (77, 95). PREZISTA [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2006.

12 Conclusions All treatments were generally well tolerated; no new safety findings DRSP DRSP exposure increased with ATV+COBI and DRV+COBI exposure was unchanged with ATV+COBI and modestly decreased with DRV+COBI Yaz prescribing information recommends clinical monitoring when used with strong CYP3A inhibitors due to potential for hyperkalemia,2 This recommendation remains when Yaz is administered with COBI-containing products. YAZ [package insert]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc; 200; 2.YASMIN [package insert]. NJ: Bayer Healthcare Pharmaceuticals Inc;

13 Acknowledgments We extend our thanks to the study participants and study teams. These studies were funded by Gilead Sciences, Inc. 3

14 Backup 4

15 Mean DRSP Concentration, ng/ml (± SD) Results: Effect of ATV+COBI on DRSP PK ATV + COBI DRSP PK Parameter Mean (%CV) ATV + COBI + [Test] n=4 AUC, h ng/ml 8 (38) 466 (2) 230 (200, 264) C max, ng/ml 33 (23) 29 (20) 2 (05, 9) ATV + COBI increased DRSP exposure Attributed to inhibition of CYP3A by COBI Similar increase in DRSP exposures observed with CYP3A inhibitor ketoconazole. Wiesinger, et al. Br J Clin Pharmacol. 205;80(6):

16 Mean Concentration, pg/ml (± SD) Results: Effect of DRV+COBI on PK ATV + COBI DRSP PK Parameter Mean (%CV) ATV + COBI + [Test] n=4 AUC, h pg/ml 296 (2) 396 (27) 78 (73, 85) C max, pg/ml 27 (22) 34 (24) 82 (76, 89) ATV + COBI did not impact PK (within no-effect boundary). Wiesinger, et al. Br J Clin Pharmacol. 205;80(6):

17 Mean DRSP Concentration, ng/ml (± SD) Results: Effect of DRV+COBI on DRSP PK DRV + COBI DRSP PK Parameter Mean (%CV) DRV + COBI + [Test] n=5 AUC, h ng/ml 895 (24) 567 (24) 58 (47, 7) C max, ng/ml 36 (2) 3 (20) 5 (05, 26) DRV + COBI increased DRSP exposure; attributed to inhibition of CYP3A by COBI. Wiesinger, et al. Br J Clin Pharmacol. 205;80(6):

18 Mean Concentration, pg/ml (± SD) Results: Effect of DRV+COBI on PK DRV + COBI PK Parameter Mean (%CV) DRV + COBI + [Test] n=5 AUC, h pg/ml 308 (28) 439 (32) 70 (63, 77) C max, pg/ml 29 (35) 33 (36) 86 (77, 95) DRV + COBI reduced exposure; decreases in exposures observed with DRV/ritonavir (RTV) May be attributed to induction (eg, P-gp, CYP2C9). Wiesinger, et al. Br J Clin Pharmacol. 205;80(6):

19 Study Design and Methods Study 2 A PK substudy was done in the WAVES open label extension phase to evaluate the effect of EVG/COBI/FTC/TDF on the PK of commonly used OCs,2 OC Regimen* HIV-infected, treatmentnaive women N=25 Day EVG/COBI/FTC/TDF (50/50/200/300 mg) po qd *levonorgestrel/; n=20, norgestimate/; n=, drospirenone/; n=4 Plasma concentrations determined using validated LC/MS/MS assays Primary PK parameters (mean [%CV]) include AUCτ /last (h ng/ml) and C max (ng/ml) Norgestrel (NG) and exposures compared to historical data Intensive Plasma PK over 96 h. STRIBILD [package insert]. Foster City, CA: Gilead Sciences Inc; Squires K, et al. Asia Pacific AIDS & Co-Infections Conference 206, poster P68. 9

20 Mean DRSP Concentration, ng/ml (± SD) Results: Effect of DRV+COBI and ATV+COBI on DRSP PK DRV+COBI ARV+COBI DRSP PK Parameter Mean (%CV) DRV + COBI + [Test] n=5 ATV + COBI + [Test] n=4 AUC, h ng/ml 895 (24) 567 (24) 58 (47, 7) 8 (38) 466 (2) 230 (200, 264) C max, ng/ml 36 (2) 3 (20) 5 (05, 26) 33 (23) 29 (20) 2 (05, 9) DRV + COBI increased DRSP exposure; attributed to inhibition of CYP3A by COBI ATV + COBI increased DRSP exposure Attributed to inhibition of CYP3A by COBI Similar increase in DRSP exposures observed with CYP3A inhibitor ketoconazole. Wiesinger, et al. Br J Clin Pharmacol. 205;80(6):

21 Mean Concentration, pg/ml (± SD) Results: Effect of DRV+COBI and ATV+COBI on PK DRV+COBI ARV+COBI PK Parameter Mean (%CV) DRV + COBI + [Test] n=5 ATV + COBI + [Test] n=4 AUC, h pg/ml 308 (28) 439 (32) 70 (63, 77) 296 (2) 396 (27) 78 (73, 85) C max, pg/ml 29 (35) 33 (36) 86 (77, 95) 27 (22) 34 (24) 82 (76, 89) DRV + COBI reduced exposure; decreases in exposures observed with DRV/ritonavir (RTV) May be attributed to induction (eg, P-gp, CYP2C9) ATV + COBI did not impact PK (within no-effect boundary). PREZISTA [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc;

22 Results: Effect of DRV + COBI and ATV + COBI on PK DRV + COBI DRSP/ ATV + COBI DRSP/ AUC AUC last C max D R S P E E 0 D R S P E E DRV + COBI increased DRSP exposure; attributed to inhibition of CYP3A by COBI DRV + COBI reduced exposure; decreases in exposures observed with DRV/ritonavir (RTV) May be attributed to induction of non-cyp3a pathways (ie, P-gp, CYP2C9) ATV + COBI increased DRSP exposure Attributed to inhibition of CYP3A by COBI Similar increase in DRSP exposures observed with CYP3A inhibitor ketoconazole ATV + COBI did not impact PK (within no-effect boundary). PREZISTA [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc;