Optimal design for a study of butadiene toxicokinetics in humans

The derivation of the optimal design for an upcoming toxicokinetic study of butadiene in humans is presented. The specific goal of the planned study i s to obtain a precise estimate of butadiene metabolic clearance for each st udy subject, together with a good characterization of its population varian ce. We used a two-compartment toxicokinetic model, imbedded in a hierarchic al population model of variability, in conjunction with a preliminary set o f butadiene kinetic data in humans, as a basis for design optimization. Opt imization was performed using Monte Carlo simulations. Candidate designs di ffered in the number and timing of exhaled air samples to be collected. Sim ulations indicated that only 10 air samples should be necessary to obtain a coefficient of variation of 15% for the estimated clearance rate, if the t iming of those samples is properly chosen. Optimal sampling times were foun d to closely bracket the end of exposure. This efficient design will allow the recruitment of more subjects in the study, in particular to match presc ribed levels of accuracy in the estimate of the population variance of the butadiene metabolic rate constant, The techniques presented here have gener al applicability to the design of human and animal toxicology studies.