Donghwan Lee (1,2) , Bongsoo Cha (3), and Kyungsoo Park (1,2)
(1) Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. (2) Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Korea (3) Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Objectives: T2DM is a progressive disease. Decreasing β-cell function, increasing insulin resistance and increasing fasting plasma glucose levels are the natural sequels of T2DM. The purpose of this work is (i) to develop a disease progression model for Korean patients with T2DM and (ii) apply the developed model as a supportive tool to designing an optimal treatment regimen in this clinical population.
Methods: Data were obtained from medical records from 330 (121 new and 209 established) patients who were diagnosed of T2DM and visited outpatient clinics at Severance Hospital (Seoul, Korea) during the period from 2006 to 2012. The primary endpoints of disease progression were fasting plasma glucose (FPG, mmol/L) and glycated hemoglobin (HbA1c, %) observed for up to two years after the treatment began. Disease progression was modeled as the natural history of progress, denoted by the baseline and progress rate [1], and drug effect influencing the baseline (“offset”) or the progress rate (“slope”) or both [2]. A linear or Emax model was used for drug effect, which was related to the effect-site “dose rate” via a K-PD model [3] as no concentration information was available. All analyses were performed using NONMEM 7.2.
Results : Patients consisted of 69 men and 52 women, with the median age of 60 years. They were prescribed 1 to 3 classes of oral hypoglycemic agents(OHAs) at the first visit. When new patients’ FPG data were separately analyzed using an offset model for disease progression and a linear model for drug effect, parameter estimates were 7.71 mmol/L for the baseline, 0.311 mmol/L/year for the progress rate (individual variability 107%), and 11.6 days for the equilibrium half-life (individual variability 157%). The latter results indicated that inter-individual variation in our study population was similarly large as compared to previous results in western population [1], but disease progression rate was slower, with the effect-site equilibrium rate being faster. Analyses with other model types, influences of classes of OHAs and other covariates, characteristic differences between new and established patients as well as causal relationship between FPG and HbA1c are currently underway.
Conclusions: These preliminary results have demonstrated that Korean T2DM patients have the slower disease progression rate and the faster effect-site equilibrium rate as compared to western population. More work will be needed to complete the model and generalize the results.
References:
[1] Frey, N., et al., Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation. Br J Clin Pharmacol, 2003. 55(2): p. 147-57.
[2] Nicholas H.G. Holford at al. Disease Progression and Pharmacodynamics in Parkinson Disease – Evidence for Functional Protection with Levodopa and Other Treatments. J. Pharmacokinet. Pharmacodyn. 2006. 33(3): p. 281-311.
[3] Goonaseelan Pillai at al. A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis. Br J Clin Pharmacol 2004. 58(6): p. 618-631.
Reference: PAGE 22 () Abstr 2831 [www.page-meeting.org/?abstract=2831]
Poster: Other Drug/Disease Modelling