Simulation of the impact of rifampicin on once-daily darunavir/ritonavir pharmacokinetics and dose adjustment strategies: A population pharmacokinetic approach

Dickinson, L ORCID: 0000-0001-5557-9396, Winston, A, Boffito, M, Khoo, S ORCID: 0000-0002-2769-0967, Back, D and Siccardi, M ORCID: 0000-0002-3539-7867 (2016) Simulation of the impact of rifampicin on once-daily darunavir/ritonavir pharmacokinetics and dose adjustment strategies: A population pharmacokinetic approach Journal of Antimicrobial Chemotherapy, 71 (4). pp. 1041-1045. ISSN 0305-7453, 1460-2091

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Abstract

Objectives: Treatment of HIV/TB coinfection is challenging due to potent drug-drug interactions between antiretrovirals and rifampicin. The effect of rifampicin on darunavir/ritonavir has not been studied. Population pharmacokinetic modelling was applied to investigate the interaction and generate alternative doses to inform clinical trial design. Patients and methods: Darunavir/ritonavir concentrations were modelled simultaneously, including data from three studies in HIV patients (n = 51, 7 female). The darunavir/ritonavir-rifampicin interaction was assumed to mimic that previously observed with lopinavir/ritonavir. Daily darunavir/ritonavir 800/100 mg was simulated as a reference (n = 1000; -rifampicin). Simulations with apparent oral clearance increased by 71% and 36% and relative bioavailability decreased by 20% and 45% for darunavir and ritonavir, respectively, were performed for +rifampicin, 600 mg once daily (n = 1000). Darunavir/ritonavir 1200/200 mg once daily, 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily +rifampicin were simulated. Darunavir parameters for each dose +rifampicin were compared with -rifampicin by geometric mean ratio (90% CI). Results: A maximum effect model, with ritonavir inhibiting darunavir clearance, best described the relationship between the drugs. Compared with -rifampicin, simulated darunavir AUC<inf>0-24</inf> was 57%, 26%, 1% and 16% lower for 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily and 800/100 mg twice daily +rifampicin, respectively; but 39% higher with 1200/150 mg twice daily +rifampicin. Conclusions: Darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. In the absence of clinical data, modelling and simulation may be useful to predict drug-drug interactions and aid optimal dose selection.

Item Type:	Article
Uncontrolled Keywords:	Humans, Ritonavir, Rifampin, Drug Administration Schedule, Area Under Curve, Drug Interactions, Models, Theoretical, Computer Simulation, Adult, Middle Aged, Female, Male, Young Adult, Darunavir
Depositing User:	Symplectic Admin
Date Deposited:	13 Jul 2018 15:04
Last Modified:	24 Jan 2026 00:12
DOI:	10.1093/jac/dkv439
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3002216
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