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J Antimicrob Chemother. 2019 May 22. pii: dkz217. doi: 10.1093/jac/dkz217. [Epub ahead of print]

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

Author information

1
Service of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Bugnon 17, Lausanne 1011, Switzerland.
2
Service of Clinical Chemistry, University Hospital Centre and University of Lausanne, Bugnon 46, Lausanne 1011, Switzerland.
3
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Michel-Servet 1, Geneva 1211, Switzerland.
4
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland.
5
Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.
6
Division of Infectious Diseases, Department of Medicine, Cantonal Hospital of Olten, Baslerstrasse 150, Olten 4600, Switzerland.
7
Service of Infectious Diseases, University Hospital Centre and University of Lausanne, Bugnon 46, Lausanne 1011, Switzerland.

Abstract

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/12 h with rifampicin compared with a standard dosage of 50 mg/24 h without rifampicin. Average trough concentrations after 100 mg/24 h and 100 mg/12 h 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.

PMID:
31119275
DOI:
10.1093/jac/dkz217

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