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Model based design and analysis of phase II HIV-1 trials

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Abstract

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 ≤ 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 ≥20 % 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.

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Disclosure

Daniel Röshammar is a current employee of AstraZeneca. However, this work is not funded by AstraZeneca or any other pharmaceutical company.

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Authors and Affiliations

  1. Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, PO Box 431, 405 30, Gothenburg, Sweden

    Dinko Rekić

  2. AstraZeneca R&D, Mölndal, Sweden

    Daniel Röshammar

  3. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

    Ulrika S. H. Simonsson

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  1. Dinko Rekić
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  2. Daniel Röshammar
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  3. Ulrika S. H. Simonsson
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Correspondence to Dinko Rekić.

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Rekić, D., Röshammar, D. & Simonsson, U.S.H. Model based design and analysis of phase II HIV-1 trials. J Pharmacokinet Pharmacodyn 40, 487–496 (2013). https://doi.org/10.1007/s10928-013-9324-2

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  • DOI: https://doi.org/10.1007/s10928-013-9324-2

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