A NEW EXTRAPOLATION METHOD FROM ANIMALS TO MAN - APPLICATION TO A METABOLIZED COMPOUND, MOFAROTENE

Allometric scaling (a technique which uses data obtained in laboratory animals to predict human pharmacokinetics) works well for drugs that are cleared intact, but is less successful with extensively metabolise d compounds. This paper describes a new method to improve the accuracy of such projections, by integrating metabolic data obtained in vitro (e.g. with liver microsomes or hepatocytes) into these calculations. T he approach was used prospectively, to predict the clearance of mofaro tene (Ro 40-8757) in humans from in vivo kinetic data obtained in mous e, rat and dog. This compound was selected to illustrate this approach because it is exclusively eliminated through metabolism. Without the metabolic correction or using empirical correcting factors, the values predicted for man were 2.7 and 0.6 ml/min/kg. This fell outside the r ange subsequently obtained in healthy volunteers dosed orally with 300 mg of mofarotene (7.5 +/- 4.0 ml/min/kg, n=12). However, inclusion of the microsomal or hepatocyte data gave values of 5.1 and 4.2 ml/min/k g, respectively, illustrating that the integration of in vitro metabol ic data improves the accuracy of kinetic extrapolations. In contrast t o the existing empirical techniques, this approach offers a rational b asis to predict clearance of metabolized compounds in human.