Logotyp: till Uppsala universitets webbplats

uu.sePublikationer från Uppsala universitet
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients With Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
2016 (Engelska)Ingår i: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 5, nr 12, s. 682-691Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time. Bedaquiline and M2 disposition were well described by three and one-compartment models, respectively. Weight and albumin were correlated, typically increasing after the start of treatment, and significantly affected bedaquiline and M2 plasma disposition. Additionally, age and race were significant covariates, whereas concomitant human immunodeficiency virus (HIV) infection, sex, or having extensively drug-resistant TB was not. This is the first population model simultaneously characterizing bedaquiline and M2 PKs in its intended use population. The developed model will be used for efficacy and safety exposure-response analyses.

Ort, förlag, år, upplaga, sidor
2016. Vol. 5, nr 12, s. 682-691
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Farmaceutisk farmakologi
Identifikatorer
URN: urn:nbn:se:uu:diva-281724DOI: 10.1002/psp4.12147ISI: 000390923300005OAI: oai:DiVA.org:uu-281724DiVA, id: diva2:915422
Forskningsfinansiär
Vetenskapsrådet, 521-2011-3442EU, FP7, Sjunde ramprogrammet, FP7/2007-2013
Anmärkning

Title in Thesis list of papers: Population pharmacokinetics of bedaquiline and metabolite M2 in drug-resistant tuberculosis patients – the effect of time-varying weight and albumin

Tillgänglig från: 2016-03-30 Skapad: 2016-03-30 Senast uppdaterad: 2020-12-17Bibliografiskt 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

Open Access i DiVA

fulltext(701 kB)309 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 701 kBChecksumma SHA-512
fc220d7b057dd8dc891d83c7f8a4c137eadb5f54da296fa019a82d860444b8a629c15bc20af2fc6df0fef2dfffea25f9731821e374f3e52e46086b380fe93950
Typ fulltextMimetyp application/pdf

Övriga länkar

Förlagets fulltext

Person

Svensson, Elin MDosne, Anne-GaëlleKarlsson, Mats O

Sök vidare i DiVA

Av författaren/redaktören
Svensson, Elin MDosne, Anne-GaëlleKarlsson, Mats O
Av organisationen
Institutionen för farmaceutisk biovetenskap
I samma tidskrift
CPT: Pharmacometrics and Systems Pharmacology (PSP)
Medicin och hälsovetenskap

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 309 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 527 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf