Dose projection and prediction of PK/PD response - a bench to bedside example for LY drug.
Sophie Callies, Elizabeth Smith LaBell, Enaksha Wickremsinhe, Vijay Reddy, Ji Lin, Gregory Donoho, Volker Wacheck, Johan Wallin
Eli Lilly and Company
Background: Small molecule (LY) is an inhibitor leading to a decrease in biomarker X levels in preclinical model. We hypothesize LY could lead in human to disease control (DC) as observed in non-clinical disease model.
Objectives: to predict human efficacious dose range through modeling analysis of non-clinical data, to design the first in human dose (FHD).
Material Methods: Data available were: in mice, pharmacokinetic (PK, intravenous IV and oral PO administration), biomarker inhibition (BI) and disease control (DC) data; in dog PK data (n=45, n=11 IV/PO, n=34 PO); in rat PK data (n=21 PO); in human PK, BI data (n=38). Allometric scaling was used to predict human PK based on non-clinical PK data. Mice PK, BI and DC data were modelled to determine the biologically relevant LY exposure range. Based on this information, the relevant dose range to be investigated in FHD study was determined with support of the toxicology studies. NONMEM (version VII) was used for the analysis. Text regarding methods.
Results: Allometric scaling predicted an IV and PO LY clearance (CL, CL/F) of 41.9 (34.0-51.7) and 55.9 (45.3-68.9) L/h in human (mean (90% CI), assuming bioavailability (F) 0.75 and body weight 70 kg). The non-clinical DC versus exposure relationship was modelled using an Emax model. This model indicated an IC50 of 95.1 ng/mL (CV 40 %), corresponding to daily exposure of 2280 ng*h/mL following a 3 mg/kg BID dose, which was considered a minimally efficacious dose in mice. Efficacious dose range in mice was determined to be 6 -10 mg/kg BID leading to daily exposure of 5380-9110 ng*h/mL. To reach 2280 and 5380-9110 ng*h/mL in human, the model predicted that LY dose range of 100-150 and 250-600 mg daily would be needed, respectively. The proposed dose range for FHD was 20 mg (starting dose) to possibly 600 mg maximum daily dose. Observed human CL/F was 64 L/h (CV 45.6%, 90%CI 60-70, n=38) after repeated doses in the 20 to 325 mg dose range. A two compartmental model, with first order absorption, adequately fit LY clinical exposure. A sigmoidal Emax model adequately fit the BI versus LY exposure relationship with mean AUCdaily50 and Caverage50 (leading to 50 % of maximal inhibition) of 1090 ng.h/mL and 45.4 ng/mL, respectively (CV=44%, n=19).
Conclusions: The integration of the non-clinical data, using modelling, enabled the prediction of the relevant biological dose range to be investigated in human.
