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Model based design and analysis of phase II HIV-1 trials
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2013 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 40, no 4, 487-496 p.Article in journal (Refereed) Published
Abstract [en]

This work explores the advantages of a model based drug development (MBDD) approach for the design and analysis of antiretroviral phase II trials. Two different study settings were investigated: (1) a 5-arm placebo-controlled parallel group dose-finding/proof of concept (POC) study and (2) a comparison of investigational drug and competitor. Studies were simulated using a HIV-1 dynamics model in NONMEM. The Monte-Carlo Mapped Power method determined the sample size required for detecting a dose-response relationship and a significant difference in effect compared to the competitor using a MBDD approach. Stochastic simulation and re-estimation were used for evaluation of model parameter precision and bias given different sample sizes. Results were compared to those from an unpaired, two-sided t test and ANOVA (p a parts per thousand currency sign 0.05). In all scenarios, the MBDD approach resulted in smaller study sizes and more precisely estimated treatment effect than conventional statistical analysis. Using a MBDD approach, a sample size of 15 patients could be used to show POC and estimate ED50 with a good precision (relative standard error, 25.7 %). A sample size of 10 patients per arm was needed using the MBDD approach for detecting a difference in treatment effect of a parts per thousand yen20 % at 80 % power, a 3.4-fold reduction in sample size compared to a t test. The MBDD approach can be used to achieve more precise dose-response characterization facilitating decision making and dose selection. If necessitated, the sample size needed to reach a desired power can potentially be reduced compared to traditional statistical analyses. This may allow for comparison against competitors already in early clinical studies.

Place, publisher, year, edition, pages
2013. Vol. 40, no 4, 487-496 p.
Keyword [en]
Monte-Carlo Mapped Power, Power, Model based drug development, Phase II, HIV
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-206574DOI: 10.1007/s10928-013-9324-2ISI: 000322244900006OAI: oai:DiVA.org:uu-206574DiVA: diva2:644883
Available from: 2013-09-02 Created: 2013-09-02 Last updated: 2013-09-02Bibliographically approved

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Simonsson, Ulrika S. H.
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