Abstract
BackgroundCharacterization of anti-malarial drug concentration profiles is necessary to optimize dosing, and thereby optimize cure rates and reduce both toxicity and the emergence of resistance. Population pharmacokinetic studies determine the drug concentration time profiles in the target patient populations, including children who have limited sampling options. Currently, population pharmacokinetic studies of anti-malarial drugs are designed based on logistical, financial and ethical constraints, and prior knowledge of the drug concentration time profile. Although these factors are important, the proposed design may be unable to determine the desired pharmacokinetic profile because there was no formal consideration of the complex statistical models used to analyse the drug concentration data.MethodsOptimal design methods incorporate prior knowledge of the pharmacokinetic profile of the drug, the statistical methods used to analyse data from population pharmacokinetic studies, and also the practical constraints of sampling the patient population. The methods determine the statistical efficiency of the design by evaluating the information of the candidate study design prior to the pharmacokinetic study being conducted.ResultsIn a hypothetical population pharmacokinetic study of intravenous artesunate, where the number of patients and blood samples to be assayed was constrained to be 50 and 200 respectively, an evaluation of varying elementary designs using optimal design methods found that the designs with more patients and less samples per patient improved the precision of the pharmacokinetic parameters and inter-patient variability, and the overall statistical efficiency by at least 50%.ConclusionOptimal design methods ensure that the proposed study designs for population pharmacokinetic studies are robust and efficient. It is unethical to continue conducting population pharmacokinetic studies when the sampling schedule may be insufficient to estimate precisely the pharmacokinetic profile.
Highlights
Characterization of anti-malarial drug concentration profiles is necessary to optimize dosing, and thereby optimize cure rates and reduce both toxicity and the emergence of resistance
Most recommended dosage regimens are based on studies in nonpregnant adult patients, yet young children and pregnant women are at the greatest risk of treatment failure and often bear the brunt of the malaria burden[2]
The design of a population PK study is very different to a sample size calculation for the number of participants required for a randomized controlled trial which can be performed using a hand calculator
Summary
Julie A Simpson*1,2, Kris M Jamsen, Ric N Price, Nicholas J White, Niklas Lindegardh, Joel Tarning and Stephen B Duffull. Address: 1Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Victoria, Australia, 2Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, 3International Health Program, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia, 4Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK and 5School of Pharmacy, University of Otago, Dunedin, New Zealand. Published: 6 August 2009 Malaria Journal 2009, 8:189 doi:10.1186/1475-2875-8-189
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