So Jin Lee (1), Soo Hyeon Bae (3), Sangil Jeon (2,3), Seounghoon Han (1,2), Dong-Seok Yim (1,2)
(1) Department of Clinical Pharmacology & Therapeutics, The Catholic University of Korea, South Korea, (2) Pharmacometrics Institute for Practical Education & Training (PIPET), College of Medicine, The Catholic University of Korea, South Korea, (3) Q-fitter, Inc., South Korea
Introduction: DWP16001 is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, an emerging class of agents for the treatment of type 2 diabetes mellitus by inhibiting the renal glucose reabsorption at the proximal tubule. In vivo pharmacokinetic (PK) data from four species and pharmacodynamic (PD) data, including blood glucose and cumulative urinary glucose excretion (cUGE) in normal rats and Zucker rats were available. Using these data, we aimed to develop PK-PD model. The PK parameters were estimated using the model and in silico methods, and PD parameters were estimated using the model and comparator drug’s reference. To address an interspecies difference in PD parameters between rat and human, we utilized a comparator drug, Dapagliflozin, published data. The goal of this study was to develop PK and PD model based on the nonclinical data to predict the efficacious doses of DWP16001 in healthy subjects.
Objectives:
- Develop PK model from the four species (mouse, rat, dog, and monkey) PK profiles and develop PD model from the normal rats and Zucker rats cUGE data
- Translate PK/PD relationship in in vivo to human
- Simulate cUGE in human and predict efficacious dose range of DWP16001
Methods: PK profiles from the mouse, rat, dog, and monkey given DWP16001 in oral or intravenous route were best described by the two-compartment model with first-order absorption and first-order elimination. PK parameters including absorption rate constant (Ka), clearance (CL), the volume of the central compartment (Vc), inter-compartment clearance (Q), the volume of the peripheral compartment (Vp), and absolute bioavailability (F) were estimated. Using simple allometry PK parameters in 70-kg human were predicted, such as CL, Vc, Vp and Q. To predict human Ka and F value, we used in silico methods based on the available in vitro Caco-2 permeability and in vitro metabolism data.
To develop PD model, cUGE data from a Zucker rat and normal rat were used. To described the DWP16001’s inhibitory effect of glucose reabsorption at the proximal tubule, (1-Emax) model was used. PD parameters were predicted, such as glucose reabsorption fraction (SCL), maximum fractional inhibition of glucose reabsorption (Imax) and concentration exhibiting half-maximal inhibitory effect (IC50). We also used in-house PD data of Dapagliflozin, and its published data on the in vivo (rat) to human IC50 ratios to adjust for the predicted interspecies difference between DWP16001’s in vivo IC50 and human IC50.
Based on the PK parameters and adjusted PD parameters acquired, human PD simulations were conducted when 1 – 20 mg of DWP16001 was administered orally. The target cUGE level was set to 46 g/day and the dose which achieves the target cUGE level was considered as an effective dose.
Results: Based on the PK model, simple allometry method, and in silico calculation, estimated CL, Vc, Q, Vp, Ka, and F in human was 13.4 L/h, 19.9 L, 9.70 L/h, 47.3 L, 0.53/h, and 0.76, respectively. The estimated IC50 value, which was adjusted for the interspecies difference based on the comparator drug information, in human was 0.43 ng/mL and 1.28 ng/mL from the Zucker rats and normal rats, respectively. Human Imax value was set to 0.35, which was from the comparator drugs published data. Simulations showed that the doses which achieve the target level of cUGE 46 g/day is predicted to be 1 mg and 5 mg for IC50 value of 0.43 ng/mL and 1.28 ng/mL, respectively.
Conclusion: Efficacious dose of DWP16001 predicted to reach the target level of cUGE is 1 mg and 5 mg based on the IC50 values from Zucker rats and normal rats, respectively.
References:
[1] Lennernäs H. Intestinal permeability and its relevance for absorption and elimination. Xenobiotica. 2007;37:1015-1051.
[2] Sun D, Lennernäs H, Welage LS et al. Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharm Res. 2002;19:1400–1416.
[3] Maurer TS, Ghosh A, Haddish-Berhane N et al. Pharmacodynamic model of sodium-glucose transporter 2 (SGLT2) inhibition: Implications for quantitative translational pharmacology. The AAPS Journal. 2011;13:576–584.
[4] Obermeier M, Yao M, Khanna A et al. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab Dispos. 2010;38:405–414.
Reference: PAGE () Abstr 9574 [www.page-meeting.org/?abstract=9574]
Poster: Drug/Disease Modelling - Endocrine