In vitro to in vivo pharmacokinetic translation guidance

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/10⁶ 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.