Prediction of metabolic drug clearance in humans: In vitro–in vivo extrapolation vs allometric scaling

Abstract

Previously in vitro–in vivo extrapolation (IVIVE) with the Simcyp Clearance and Interaction Simulator® has been used to predict the clearance of 15 clinically used drugs in humans. The criteria for the selection of the drugs were that they are used as probes for the activity of specific cytochromes P450 (CYPs) or have a single CYP isoform as the major or sole contributor to their metabolism and that they do not exhibit non-linear kinetics in vivo. Where data were available for the clearance of the drugs in at least three animal species, the predictions from IVIVE have now been compared with those based on allometric scaling (AS). Adequate data were available for estimating oral clearance (CL_p.o.) in 9 cases (alprazolam, sildenafil, caffeine, clozapine, cyclosporine, dextromethorphan, midazolam, omeprazole and tolbutamide) and intravenous clearance in 6 cases (CL_i.v.) (cyclosporine, diclofenac, midazolam, omeprazole, theophylline and tolterodine). AS predictions were based on five different methods: (1) simple allometry (clearance versus body weight); (2) correction for maximum life-span potential (CL × MLP); (3) correction for brain weight (CL × BrW); (4) the use of body surface area; and (5) the rule of exponents. A prediction accuracy was indicated by mean-fold error and the Pearson product moment correlation coefficient. Predictions were considered successful if the mean-fold error was ≤2. IVIVE predictions were accurate in 14 of 15 cases (mean-fold error range: 1.02–4.00). All five AS methods were accurate in 13, 11, 10, 10 and 14 cases, respectively. However, in some cases the error of AS exceeded fivefold. On the basis of the current results, IVIVE is more reliable than AS in predicting human clearance values for drugs mainly metabolized by CYP450 enzymes. This suggests that the place of AS methods in pre-clinical drug development warrants further scrutiny.

Key words::

• Metabolic clearance
• allometric scaling
• in vitro–in vivo correlation
• pre-clinical drug development

Acknowledgement

The study was supported by a consortium of pharmaceutical companies. The Simcyp Simulator is available free of charge and after training to members of academic institutions and other non-profit organizations for research and teaching purposes. M. R. S. and N. J. P. were supported by The Dr Hadwen Trust for Humane Research.