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Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug resistant tuberculosis
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
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2017 (Engelska)Ingår i: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 49, s. 212-217Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug–drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67–99%) and M2 clearance to 119% (92–156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17–35%) and M2 clearance to 59% (44–69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.

Ort, förlag, år, upplaga, sidor
2017. Vol. 49, s. 212-217
Nationell ämneskategori
Farmakologi och toxikologi
Forskningsämne
Farmaceutisk farmakologi
Identifikatorer
URN: urn:nbn:se:uu:diva-281726DOI: 10.1016/j.ijantimicag.2016.10.020ISI: 000397144300011PubMedID: 28038962OAI: oai:DiVA.org:uu-281726DiVA, id: diva2:915426
Forskningsfinansiär
Vetenskapsrådet, 521-20113442Tillgänglig från: 2016-03-30 Skapad: 2016-03-30 Senast uppdaterad: 2018-09-05Bibliografiskt granskad
Ingår i avhandling
1. Pharmacometric Models to Improve Treatment of Tuberculosis
Öppna denna publikation i ny flik eller fönster >>Pharmacometric Models to Improve Treatment of Tuberculosis
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Tuberculosis (TB) is the world’s most deadly infectious disease and causes enormous public health problems. The comorbidity with HIV and the rise of multidrug-resistant TB strains impede successful therapy through drug-drug interactions and the lack of efficient second-line treatments. The aim of this thesis was to support the improvement of anti-TB therapy through development of pharmacometric models, specifically focusing on the novel drug bedaquiline, pharmacokinetic interactions and methods for pooled population analyses.

A population pharmacokinetic model of bedaquiline and its metabolite M2, linked to semi-mechanistic models of body weight and albumin concentrations, was developed and used for exposure-response analysis. Treatment response was quantified by measurements of mycobacterial load and early bedaquiline exposure was found to significantly impact the half-life of bacterial clearance. The analysis represents the first successful characterization of a concentration-effect relationship for bedaquiline.

Single-dose Phase I studies investigating potential interactions between bedaquiline and efavirenz, nevirapine, ritonavir-boosted lopinavir, rifampicin and rifapentine were analyzed with a model-based approach. Substantial effects were detected in several cases and dose-adjustments mitigating the impact were suggested after simulations. The interaction effects of nevirapine and ritonavir-boosted lopinavir were also confirmed in patients with multidrug-resistant TB on long-term treatment combining the antiretrovirals and bedaquiline. Furthermore, the outcomes from model-based analysis were compared to results from conventional non-compartmental analysis in a simulation study. Non-compartmental analysis was found to consistently underpredict the interaction effect when most of the concentration-time profile was not observed, as commonly is the case for compounds with very long terminal half-life such as bedaquiline.

To facilitate pooled analyses of individual patient data from multiple sources a structured development procedure was outlined and a fast diagnostic tool for extensions of the stochastic model components was developed. Pooled analyses of nevirapine and rifabutin pharmacokinetics were performed; the latter generating comprehensive dosing recommendations for combined administration of rifabutin and antiretroviral protease inhibitors.

The work presented in this thesis demonstrates the usefulness of pharmacometric techniques to improve treatment of TB and especially contributes evidence to inform optimized dosing regimens of new and old anti-TB drugs in various clinical contexts.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 79
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 214
Nyckelord
pharmacokinetics, pharmacodynamics, population approach, nonlinear mixed-effects models, multidrug-resistant tuberculosis, bedaquiline, antiretroviral, drug-drug interactions, time-to-event, albumin
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Klinisk farmakologi
Identifikatorer
urn:nbn:se:uu:diva-282139 (URN)978-91-554-9539-8 (ISBN)
Disputation
2016-05-20, B21, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Forskningsfinansiär
Vetenskapsrådet, 521-2011-3442EU, FP7, Sjunde ramprogrammet, 115337EU, FP7, Sjunde ramprogrammet, 115156
Tillgänglig från: 2016-04-28 Skapad: 2016-04-03 Senast uppdaterad: 2016-05-12

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Brill, Margreke JESvensson, Elin MKarlsson, Mats O

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