In vitro to in vivo pharmacokinetic translation guidance

ABSTRACT Background Pharmacokinetics (PK), exposure profiles and doses of candidate drugs in man are commonly predicted using data produced using various in vitro methods, such as hepatocytes (for intrinsic metabolic clearance (CL int )), plasma (for unbound fraction (f u )), Caco-2 (measuring apparent permeability (P app ) for prediction of in vivo fraction absorbed (f a )) and plasma water and buffers (measuring solubility (S) for prediction of in vivo fraction dissolved (f diss )). For best possible predictions it is required that the clinical relevance of in vitro data is understood ( in vitro-in vivo relationships) and that uncertainties have been investigated and considered. Methods The aim was to investigate in vitro-in vivo relationships for CL int , P app vs f a and S vs f diss and interlaboratory variability for f u , describe the clinical significance and uncertainties at certain levels of in vitro CL int , f u , P app and S, and (based on the findings) develop a general in vitro-in vivo translation guide. Results and Conclusion It was possible to finf data for describing how in vivo CL int , f a and f diss distribute and varies at different levels of in vitro CL int , P app and S and how f u varies between laboratories and methods at different f u -levels. It is apparent that there are considerable interlaboratory variabilities for CL int , f u and P app : corresponding to up to 2500-, 700- and 35-fold variability for CL int , f u and f a , respectively. Apparently, S is a poor predictor of f diss . Proposed S-thresholds do not seem clinically useful (overestimated). It does not seem appropriate to define in vitro CL int of 0.5-2 µL/min/10 6 cells as good metabolic stability (rather moderate to moderately high). Results shown for CL int , P app and f u are applicable as general guidelines when internal standard values for reference compounds are unavailable.