The Prediction of Human Pharmacokinetics at the Therapeutic Dose from Low Sub-Therapeutic Doses in Human.
C. L. Holliman, L. Buchholtz, J. McFadden, G. Pace, Pfizer Inc, Ann Arbor, MI, 48105
Background: Ultimately human pharmacokinetics can only be determined by human dosing. Low sub-therapeutic dosing is safe for the subject and can be used to predict human pharmacokinetics at the therapeutic dose. When the ionization efficiency of the compound is high, these studies can be supported with conventional LC/MS/MS.
Methods: Low sub-therapeutic studies are supported using API4000 LC/MS/MS with assays that achieve at least a 20-pg/mL limit of quantitation. The analytes are extracted from large plasma volumes by solid-phase extraction. Selectivity is a significant issue due to the relatively large concentrations of endogenous species co-extracted.
Results: Six case studies are presented. In three studies the strategy was tested in cynomolgus monkeys. In two studies the therapeutic pharmacokinetics are accurately predicted by the very low dose. The exposure was not dose-normalized in the third case. Two more case studies are presented where very low dose legs were added to human Phase I trials. In one case the low dose Cmax was not dose-normalized and all PK parameters were statistically different but in the other case the very low dose accurately predicted PK parameters and bi-phasic clearance. In the final case study three development candidates are separately dosed at very low levels to determine the candidate with a desirable half-life. The observed half-lives spanned a range of 10-64 hours. From this data an appropriate candidate was selected for development.
Conclusions: Very low dose studies can be viable strategy to predict or complement the prediction of pharmacokinetics at the therapeutic dose.