Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting

Barcelo, Catalina
Aouri, Manel
Courlet, Perrine
Guidi, Monia
Braun, Dominique L
Günthard, Huldrych F
Piso, Rein J
Cavassini, Matthias
Buclin, Thierry
Decosterd, Laurent A
Csajka, Chantal
Anagnostopoulos, A
Battegay, M
Bernasconi, E
Böni, J
Braun, D L
Bucher, H C
Calmy, A
Cavassini, M
Ciuffi, A
Dollenmaier, G
Egger, M
Elzi, L
Fehr, J
Fellay, J
Furrer, H
Fux, C A
Günthard, H F
Haerry, D
Hasse, B
Hirsch, H H
Hoffmann, M
Hösli, I
Huber, M
Kahlert, C R
Kaiser, L
Keiser, O
Klimkait, T
Kouyos, R D
Kovari, H
Ledergerber, B
Martinetti, G
de Tejada, Martinez B
Marzolini, C
Metzner, K J
Müller, N
Nicca, D
Paioni, P
Pantaleo, G
Perreau, M
Rauch, A
Rudin, C
Scherrer, A U
Schmid, P
Speck, R
Stöckle, M
Tarr, P
Trkola, A
Vernazza, P
Wandeler, G
Weber, R
Yerly, S

^1-10Service of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Bugnon 17, Lausanne, Switzerland
²Service of Clinical Chemistry, University Hospital Centre and University of Lausanne, Bugnon 46, Lausanne, Switzerland
³School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Michel-Servet 1, Geneva, Switzerland
⁴Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Rämistrasse 100, Zurich, Switzerland
⁵Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland
⁶Division of Infectious Diseases, Department of Medicine, Cantonal Hospital of Olten, Baslerstrasse 150, Olten, Switzerland
⁷Service of Infectious Diseases, University Hospital Centre and University of Lausanne, Bugnon 46, Lausanne, Switzerland

Corresponding author. Service of Clinical Pharmacology, University Hospital Centre (CHUV), Bugnon 17, Lausanne 1011, Switzerland. Tel: +41 21 314 42 60; Fax: +41 21 314 42 66; E-mail: [email protected]; orcid.org/0000-0002-0660-082X

^†Equal contribution to the work.

^‡Members are listed in the Acknowledgements section.

Received 15 November 2018; returned 07 February 2019; revised 4 April 2019; accepted 23 April 2019

Journal of Antimicrobial Chemotherapy 74(9):p 2690-2697, September 2019. | DOI: 10.1093/jac/dkz217

Objectives:

Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition.

Methods:

A population pharmacokinetic model was developed using NONMEM^®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions.

Results:

A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h⁻¹. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively.

Conclusions:

Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.