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Extrapolation of pharmacokinetics and toxicity from pre-clinical data to humans

Jan Freijer, Bart Ploeger, Joost DeJongh & Meindert Danhof

LAP&P consultants BV & LACDR, division of pharmacology, Leiden, the Netherlands

Extrapolation of data from animal studies is required to predict pharmacokinetics and/or toxicity in humans during the development of new pharmaceutical products, as well as for risk assessment of unintentional exposure to toxic agents. In physiologically based pharmacokinetics (PB-PK), the process of animal-to-man extrapolation involves the construction of a relevant animal PB-PK model, followed by adjustment of anatomical, physiological, and/or biochemical parameters that are specific for humans.

Igari and co-workers published an instructive example of PB-PK model application in pharmacology in 1983, for diazepam. In this case, extrapolation involved the adjustment of parameters for tissue volume and perfusion, intrinsic clearance and plasma protein binding. For compounds with complex pharmacokinetics, mechanism-based extrapolation of pharmacokinetic species differences is required. This has been demonstrated recently for the food constituent glycyrrhizic acid and its metabolite glycyrrhetic acid. Successful rat-to-human extrapolation of the PK for this compound was achieved by taking into account in vitro data for pre-systemic metabolism, as well as by implementing the physiological mechanism for entero- hepatic circulation. The most relevant adjustments made to the human PB-PK model were: gall bladder release, a lower activity of the hepatic uptake protein (cMOAT), and a higher fraction bound to plasma protein. After validation of the extrapolated human PB-PK model, the population PK/PD for glycyrrhizic acidís effects on the renal cortisol metabolism could be modelled for risk analysis in populations with a high liquorice consumption (Ploeger et al 2000). It was observed that the high (77%) interindividual variability in gastro-intestinal transit rate in the study population was the major pharmacokinetic factor that determines the risk for adverse events due to liquorice intake.

For pharmaceutical products, clinical pharmacokinetics are usually well established from phase I studies. Quantitative estimates for long-term safety of these products during phase II/III trials can be obtained by combining clinical PK data with the results of pre-clinical PK and toxicity studies. The accuracy of the predicted safety profile will be high if species-specific differences in toxicity are mainly caused by pharmacokinetic differences. In this case, the physiological basis of the pharmacokinetic descriptions can be limited, since the PK in humans is known, and a clinical population PK model can be directly linked to a pre-clinical concentration-response relationship. This approach will be demonstrated for a new chemical entity (NCE) under clinical development. Preclinical study data for this NCE did demonstrate the occurrence of ocular toxicity in dogs exposed to doses of 20 mg/kg day or higher, whereas in rats and monkeys no toxicity was observed after doses up to 2000 mg/kg/day. Based on AUC, a 10-20 fold higher exposure was observed in dogs compared to rats. Additional in vitro and in vivo studies identified the parent compound as responsible for the toxicity. These findings were used to combine the clinical population pharmacokinetics with the PK/PD profile in dogs, in order to estimate the safety profile of the NCE in humans during phase II/III studies.

-Y. Igari, Y. Sugiyama, Y. Sawada, T. Iga, and M. Hanano. Prediction of diazepam disposition in the rat and man by a PB-PK model. J. Pharmacokin. Biopharm. 11 (6), 1983. 577-93.
-B. Ploeger, T. Mensinga, A. Sips, J. Meulenbelt, and J. DeJongh. A human PB-PK model for glycyrrhizic acid, a compound subject to presystemic metabolism and entero-hepatic cycling. Pharm. Res. 17 (12), 2000. 1516-23.