uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug resistant tuberculosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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.
Show others and affiliations
2017 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 49, p. 212-217Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2017. Vol. 49, p. 212-217
National Category
Pharmacology and Toxicology
Research subject
Pharmaceutical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-281726DOI: 10.1016/j.ijantimicag.2016.10.020ISI: 000397144300011PubMedID: 28038962OAI: oai:DiVA.org:uu-281726DiVA, id: diva2:915426
Funder
Swedish Research Council, 521-20113442Available from: 2016-03-30 Created: 2016-03-30 Last updated: 2018-09-05Bibliographically approved
In thesis
1. Pharmacometric Models to Improve Treatment of Tuberculosis
Open this publication in new window or tab >>Pharmacometric Models to Improve Treatment of Tuberculosis
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 79
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 214
Keywords
pharmacokinetics, pharmacodynamics, population approach, nonlinear mixed-effects models, multidrug-resistant tuberculosis, bedaquiline, antiretroviral, drug-drug interactions, time-to-event, albumin
National Category
Medical and Health Sciences
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-282139 (URN)978-91-554-9539-8 (ISBN)
Public defence
2016-05-20, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme, 115337EU, FP7, Seventh Framework Programme, 115156
Available from: 2016-04-28 Created: 2016-04-03 Last updated: 2016-05-12

Open Access in DiVA

fulltext(419 kB)2 downloads
File information
File name FULLTEXT01.pdfFile size 419 kBChecksum SHA-512
0e28c6eed0cc00883110739314a060b3be29627f7e225eae93bb87b859272c381e9f03bf5bbeaff55fdaf0971186d729f2900ea4ee430d7c4e36c9091c23cd90
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Brill, Margreke JESvensson, Elin MKarlsson, Mats O

Search in DiVA

By author/editor
Brill, Margreke JESvensson, Elin MKarlsson, Mats O
By organisation
Department of Pharmaceutical Biosciences
In the same journal
International Journal of Antimicrobial Agents
Pharmacology and Toxicology

Search outside of DiVA

GoogleGoogle Scholar
Total: 2 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 220 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf