And Etravirine (ETR) Alone and Coadministered in HIV-Infected Patients

Pharmacokinetics of darunavir/cobicistat (DRV/c) and etravirine (ETR) alone and coadministered in HIV-infected patients

José Moltó1,2, Adriá Curran2,3, Marta Valle2,4, Cristina Miranda1, Laura Else5, Esteban Ribera2,3, José Ramón Santos1, Saye Khoo5, Bonaventura Clotet1,2,7,8.

1Fundació Lluita contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 2Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 3Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain. 4PKPD Modeling and Simulation, Institut de Recerca HSCSP-IIB St Pau, Barcelona, Spain. 5Department of Molecular and Clinical Pharmacology, University of Liverpool, UK. 7Fundació IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 8Universitat de Vic-Universitat Central de Catalunya (UVIC-UCC). Spain.

18th International Workshop on Clinical Pharmacology of Antiviral Therapy Chicago, IL. 14th June 2017 Background

- Interest in NRTI-sparing ARV regimens has grown in recent years.

Encouraging data with darunavir/ritonavir + ETR dual therapy.

- A FDC of DRV/c (Rezolsta®) has been developed, and interest in its combination with ETR has emerged.

- Results with darunavir/ritonavir might not be applicable to DRV/c

DDIs between ETR and DRV/c need to be assessed before recommending this combination in clinical practice.

1 Pasquau J. AIDS Rev 2015;17:220-31. 2 DeJesus E. Antivir Ther 2010;15:711-20 3 Ruane PJ. HIV Med 2015;16:288-96. 4 Bernardino JI. J Int AIDS Soc 2014;17: 19787 Objectives

• To assess the safety and tolerability of DRV/c plus ETR in HIV- infected patients.

• To determine the effect of DRV/c on the pharmacokinetics of ETR and vice versa. Study design

PK PK DRV cohort DRV/c 800/150 mg QD n=15 ETR 400 mg QD

PK PK ETR cohort ETR 400 mg QD n=15 DRV/c QD

Day -14 0 7 14 +14 Methods

• Individual PK parameters were calculated in each occasion using a non- compartmental approach (Winnonlin. Phoenix, version 7.0). – DRV and COBI PK parameters were compared between days 0 and 14 in the DRV cohort. – ETR PK parameters were compared between days 0 and 7 in the ETR cohort. – LSM ratios and 90% CIs were derived from the log transformed

AUC0-24, Cmax and C24 using linear mixed-effects models.

• Adverse events (AEs) and HIV-1 RNA load in plasma were monitored throughout the study. Demographics DRV cohort ETR cohort (n=15) (n=15) Age (years), median (range) 45.1 (21.6 – 62.2) 50.0 (25.2 – 67.9) Gender (male), n (%) 14 (93.3) 12 (80.0) BMI (kg/m2), median (range) 23.9 (20.2 – 35.8) 24.2 (18.6 – 34.4) NRTIs in the cART regimen TDF/FTC, n (%) - 5 (33.3) ABC/3TC, n (%) - 8 (53.3) CD4+ T cell count, median 746 (474 – 1584) 638 (295 – 1331) (range) HCV coinfection, n (%) 1 (6.7) 4 (26.7) Safety

G 1 G 2 G 3 G 4 Headache 1 1 Fatigue 2 Upper respiratory tract 1 1 infection Nausea 2 1 Abdominal pain 2 Diarrhea 1 1 2a Dizzines 2 aAcute episode of self-limited diarrea. Lumbalgia 1 Not drug-related

HIV-1 RNA in plasma remained undetectable in all participants. Etravirine pharmacokinetics

Day 0 Day 14 LSM ratio (n=15) (n=15) (90% CI)

Cmax 783.0 ± 909.8 ± 1.06 (ng/mL) 277.6 459.6 (0.91 – 1.23)

AUC0-24 10481.5 ± 12747.6 ± 1.11 (ng.h/mL) 4163.5 6603.2 (0.96 – 1.28)

C24 280.5 ± 348.7 ± 1.11 (ng/mL) 116.8 180.0 (0.95 – 1.29) Cobicistat pharmacokinetics

Day 0 Day 14 LSM ratio (n=15) (n=15) (90% CI)

Cmax 825.5 ± 693.7 ± 0.86 (ng/mL) 279.0 176.0 (0.75 – 0.98)

AUC0-24 7776.3 ± 5472.0 ± 0.70 (ng.h/mL) 3005.8 1762.9 (0.56 – 0.87)

C24 65.6 ± 17.5 ± 0.34 (ng/mL) 85.6 11.0 (0.23 -0.50)

t1/2 5.4 ± 3.6 ± - (h) 3.3 0.6 Darunavir pharmacokinetics

Day 0 Day 14 LSM ratio (n=15) (n=15) (90% CI)

Cmax 4885.3 ± 5329.3 ± 1.11 (ng/mL) 1420.2 1158.2 (0.99 – 1.24)

AUC0-24 57173.6 ± 54848.0 ± 0.99 (ng.h/mL) 18925.6 9953.7 (0.86 – 1.13)

C24 1145.9 ± 539.3 ± 0.44 (ng/mL) 567.7 380.0 (0.33 – 0.58)

t1/2 16.8 ± 7.6 ± - (h) 12.0 7.3 Summary

• DRV/c + ETR was safe and well tolerated in HIV-infected patients.

• DRV/c had no effect in ETR PK.

• ETR caused a decrease in COBI exposure that resulted in a marked decline in DRV concentrations, specially at the end of the dosing interval.

• Based on our results, boosting DRV with ritonavir instead of with COBI should be preferred if DRV and ETR are to be combined in clinical practice. Aknowledgments

Saye Khoo Laura Else Marta Valle Cristina Miranda Alieu Amara Adrián Curran José Ramón Santos Esteban Ribera Beatriz Mothe Joaquin Burgos Aroa Nieto Jordi Navarro Miriam López Miriam Soler Eugenia Vispo To the patients and their families Carmen González-Ortega Eva García Aguilar