DOSE SELECTION BY PREDICTION OF HUMAN ORAL CLEARANCE OF FTY 720 USING INTERSPECIES SCALING

Abstract

587 Interspecies scaling can be used to predict drug clearance (CI) in humans from animal data. This can be of particular value when selecting an initial dose for first in human studies. Prior to the first clinical trial of FTY 720, the clearance of this compound was predicted using two different interspecies scaling (or allometric) approaches. The "classic" approach describes the allometric relationship between CI and species body weight (bw), whereas the more conservative Maximum Lifespan Potential (MLP) method incorporates both species bw and brain weight (br. wt.). The latter approach has been used to improve predictions for drugs undergoing extensive hepatic metabolism. A comparison of the results of these approaches is now reported. Methods: With the classic method, CI from the rat, dog and monkey was regressed with bw (log-log scale) yielding the allometric relationship: Cl=0.5539*bw0.4771. Human clearance was determined (bw = 70kg) and divided by the bioavailability (F) observed in dogs to obtain a value for oral Cl (Cl/F). With the MLP approach, MLP was calculated (MLP=185.4*brain wt.0.636*bw−0.225) for each species and multiplied by the intrinsic clearance (Clu,i). MLP*Clu,i was regressed with bw (log-log scale) resulting in MLP*Clu,i=216213*bw0.8115. Based on an AUC that produced lymphopenia in animals, a predicted oral FTY 720 dose that would result in lymphopenia in humans was calculated. Predicted and observed clearance and lymphopenic FTY 720 dose data follow: (Table)TableConclusions: Although FTY 720 undergoes hepatic metabolism, it is apparent that the MLP method was not required. Rather, the classic allometric approach yielded a better prediction of human clearance and closely predicted the lymphopenic dose in humans. The ability to accurately predict drug pharmacokinetics and pharmacodynamics in humans from scaled animal data allowed a safe and efficient design of the first clinical trial of FTY 720.