Application of physiologically based pharmacokinetic models for assessing drug disposition in space

Exposure to weightlessness induces physiologic changes that may lead to pharmacokinetic and pharmacodynamic alterations of drugs administered to crew members in flight. Preliminary data from flight and ground-based studies indicate that pharmacologically significant changes occur in the kinetics of medications given in weightlessness and in simulated microgravity (head-down bed rest). Conducting flight studies on all available medications to identify the changes in their pharmacokinetic behavior in weightlessness is not feasible. An alternative approach for obtaining such information is to use computer simulations employing physiologically based pharmacokinetic (PBPK) models. Information thus obtained would be helpful in predicting the therapeutic effectiveness of medications in space, and also in developing plans for flight studies. This paper presents a brief review of relevant physiologic factors and pharmacokinetic implications of space flight, and includes a preliminary PBPK model for estimating plasma concentration-time profiles of acetaminophen under different experimental conditions.