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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; Swiss HIV Cohort Study (2019). Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting. Journal of Antimicrobial Chemotherapy, 74(9):2690-2697.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 September 2019
Deposited On:09 Aug 2019 08:12
Last Modified:20 Oct 2019 06:00
Publisher:Oxford University Press
ISSN:0305-7453
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/jac/dkz217
PubMed ID:31119275

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