Translational Prediction of first-in-human Pharmacokinetics and Pharmacodynamics of janagliflozin, a selective SGLT2 inhibitor, using Allometric Scaling, Dedrick and PK/PD Modeling Methods
Abstract
AIM
Janagliflozin is an orally selective SGLT2 inhibitor. To predict human pharmacokinetics/pharmacodynamics (PK/PD) characteristics of janagliflozin. To design optimal starting dose and effective dose for janagliflozin first-in-human (FIH) study.
METHODS
Animal PK/PD properties of janagliflozin were obtained from preclinical in vivo and in vitro study. Pharmacologically effective level of same class SGLT2 inhibitors were assessed through preclinical and clinical efficacy data of dapagliflozin, empagliflozin and canagliflozin. Human PK parameters and profiles of janagliflozin were predicted by various methods such as allometric scaling (AS), dedrick and PK/PD modeling analysis. Mechanistic PK/PD model was developed to describe janagliflozin-mediated impact on urinary glucose excretion (UGE). Human IC50 was scaled from rat model-estimated IC50 by correcting interspecies difference of in vitro IC50 and plasma fu of rat and human. The quantitative PK/PD prediction of janagliflozin was evaluated via observed PK/PD profiles of healthy subjects. Predicted PK/PD characteristics of janagliflozin were applied in FIH dose design. Optimal starting dose was suggested by considering preclinical PD and toxicity data of janagliflozin. Effective dose was suggested by considering pharmacologically effective level of same class drugs.
RESULTS
PK/PD characteristics of janagliflozin in preclinical species were summarized. Pharmacologically effective level for SGLT2 inhibitors was defined as…
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