The extrapolation of nonclinical pharmacokinetics (PK) to prediction of human pharmacokinetics is a critical step in drug development. Several strategies have been employed for such extrapolations, often based on the pharmacokinetics of one or more nonclinical animal species. The success of these strategies has been limited, often by the lack of similarity between the physiology of the selected nonclinical species and that of humans. For biotherapeutics, whose pharmacokinetics often depend on target binding, this dissimilarity is often more apparent.

Trastuzumab-MCC-DM1 is an antibody drug conjugate (ADC) currently in development for the treatment of metastatic breast cancer. This conjugate is binds to HER2, an antigen expressed only in humans and primates.

In this work, we utilized multiple methods for predicting the pharmacokinetics of an antibody drug conjugate in humans. Using PK data from mice, rats, and cynomolgus monkeys, we used simple allometry, simple allometry with corrections (eg. brain weight, maximum lifespan), and species invariant time methods. Because the ADC exhibited dose dependent pharmacokinetics in monkeys, and was expected to behave similarly in humans, it was difficult to employ simple allometry methods. Species invariant time methods, however, were capable of incorporating this pharmacokinetic behavior and appropriately propagating it to predictions of human pharmacokinetics. For the species invariant scaling of the ADC to humans, it was assumed that ADC pharmacokinetics in monkeys scaled to humans as a function of metabolic rate. Concentration-time curves for the ADC were transformed using kallynochron times for a 70 kg human. This provided predicted concentration-time curves for humans, from which pharmacokinetic parameters could be determined. The resulting predicted mean ± SD population PK estimates of human total clearance (CLt, L/day) and terminal half-lives (t1/2β, days) at 0.3, 3, and 30 mg/kg were 1.51 ± 0.48, 0.772 ± 355, and 0.336 ± 0.0471 L/day; and 2.80, 5.28, and 9.89 days, respectively. The mean population estimate for volume of distribution was 2.92 L. Trastuzumab-MCC-DM1 is currently being studied in a Phase I trial for the treatment of metastatic breast cancer; a trial that will provide PK data for comparison to the allometric predictions shown above.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA