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Improved power for TB Phase IIa trials using a model-based pharmacokinetic-pharmacodynamic approach compared with commonly used analysis methods
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Univ St Andrews, Sch Med, St Andrews KY16 9TF, Fife, Scotland..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
2017 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 8, p. 2311-2319Article in journal (Refereed) Published
Abstract [en]

Background: The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process.

Objectives: To explore the power to find statistically significant drug effects using a model-based pharmacokinetic-pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials.

Methods: Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model. cfu data were simulated over 14 days for patients taking once-dailymonotherapy at four different doses per drug and a reference (10mg/kg rifampicin). The simulated data were analysed using t-test, ANOVA, mono-and bi-exponential models and a pharmacokinetic-pharmacodynamic model approach (MTP model) to establish their respective power to find a drug effect at the 5% significance level.

Results: For the pharmacokinetic-pharmacodynamic model approach, t-test, ANOVA, mono-exponential model and bi-exponential model, the sample sizes needed to achieve 90% power were: 10, 30, 75, 20 and 30 (drug A); 30, 75, 245, 75 and 105 (drug B); 70, > 1250, 315, > 1250 and >1250 (drug C); and 30, 110, 710, 170 and 185 (drug D), respectively.

Conclusions: A model-based design and analysis using a pharmacokinetic-pharmacodynamic approach can reduce the number of patients required to determine a drug effect at least 2-fold compared with current methodologies. This could significantly accelerate early-phase TB drug development.

Place, publisher, year, edition, pages
2017. Vol. 72, no 8, p. 2311-2319
National Category
Infectious Medicine Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-332928DOI: 10.1093/jac/dkx129ISI: 000406155400021PubMedID: 28520930OAI: oai:DiVA.org:uu-332928DiVA, id: diva2:1157651
Funder
Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme, FP7/2007-2013Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2018-01-13Bibliographically approved

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