Application of a Semi-Mechanistic, Integrated Glucose-Insulin Model to Graded Glucose Infusion Placebo Data to translate Glucose Insulin dynamics between Healthy Humans and Non-Human Primates
Rolien Bosch 1*, Wei Gao 2, Ryan Vargo 2, Chandni Valiathan 2, Craig Fancourt 2, P.A. Kothare 2, Maria C. Kjellsson 3, Mats O. Karlsson 3, Teun Post 1*
1 PPDM: Quantitative Pharmacology & Pharmacometrics, MSD Oss B.V., Oss, The Netherlands, 2 PPDM: Quantitative Pharmacology & Pharmacometrics, Merck & Co, US, 3 Pharmetheus, Uppsala, Sweden, * Currently employed by LAP&P Consultants BV, Leiden, The Netherlands
Objectives: To develop a foundational framework for the extrapolation of novel drug effects observed in non-human primates (NNP) to healthy volunteers utilizing the Graded Glucose Infusion (GGI) study paradigm. The GGI is a simpler method than the hyperglycemic clamp (HGC) for measurement of glucose-dependent insulin secretion (GDIS).
Methods: Placebo glucose and insulin data from three healthy subject GGI studies (N=47) and one NHP GGI study (N=11) were included for an analysis using NONMEM.
The IGI model developed by Silber et al [1] was the starting point. The need for adjusting parameters to fit the GGI data was assessed [2]. Translation to NHP was done by allometric scaling of the human GGI model [3]. Subsequently the need for parameter adjustments was assessed. The model was evaluated using VPCs and was externally qualified on human GGI data from a separate study.
Results: All disposition parameters of glucose and insulin were kept identical as presented by Silber et al. [1]. The Insulin-dependent Glucose Clearance (CLGI) and the Insulin on Glucose production (IPRG) feedback were estimated in combination with glucose and insulin baseline values (GSS and ISS) and residual errors (RESG and RESI) for both NHP and human data. Species differences between NPH and humans were observed for CLGI, IPRG and GPRG estimates.
Conclusions: The IGI was optimized to human GGI placebo data and allometrically scaled and optimized to the NHP GGI placebo data. Based on the VPC and external validation the final IGI model for each species adequately described the observed GGI data. Glucose appears to have a larger effect on decreasing the Glucose production (GPRG) in NHP compared to human (-19.9 vs. -2.97, respectively). Insulin on Glucose production (IPRG) seems to be comparable in NHP and human, although insulin levels in NHP reach much higher levels after Glucose infusion. This foundational framework for interspecies translation of placebo GGI data can be used as a starting point in the drug discovery setting, to explore the effect of novel diabetes treatments on GDIS and ISR from animal to human.
References:
[1] Silber HE, Jauslin PM, Frey N, Gieschke R, Simonsson USH, Karlsson MO. An integrated model for glucose and insulin regulation in healthy volunteers and type 2 diabetic patients following intravenous glucose provocations. J Clin Pharmacol 2007;47:1159–71.
[2] Craig Fancourt, Wei Gao, Rolien Bosch, Chandni Valiathan, Ryan Vargo, P.A. Kothare, Teun Post , Application of the Integrated Glucose-Insulin Model to the Graded Glucose Infusion and Glucose Clamp Studies, ACOP 2014.
[3] Alskär et al. Using allometric scaling on an integrated glucose insulin model for humans to investigate anti-diabetics drug effects in rats, PAGE 21 (2012) Abstr 2540 [www.page-meeting.org/?abstract=2540]
