Fran Stringer(1), Joost DeJongh(2,3), Kumi Matsuno(1), Masashi Hirayama(1) and Meindert Danhof(3)
(1) Clinical Pharmacology Dept, Takeda Pharmaceutical Company, Osaka, Japan; (2) LAP&P Consultants BV, Leiden, The Netherlands; (3) Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden, The Netherlands
Objectives: Type 2 diabetes mellitus (T2DM) is a slowly progressing disease, making changes in disease trajectory difficult to assess in short term trials. However, the prediction of long term drug effects is often relevant early in clinical development. Disease system analysis can describe and explain changes in disease status as a function of time and drug therapy, separating symptomatic from protective effects on the disease1. This approach has been utilised in Caucasian T2DM patients to discriminate between standard of care (SoC) and new therapy2. Long term analysis in the UKPDS demonstrated symptomatic effects for both lifestyle and classical anti-diabetic agents3. Short term benefits were demonstrated but no effect on disease modification was found with all agents failing to alter the long-term rate of disease progression. Up until now, no disease progression analysis in Japanese subjects has been undertaken on mid to long-term data.
Methods: A study in Japanese T2DM patients (n=587) was conducted over 4 years comparing pioglitazone to SoC treatment4. Patients received pioglitazone with other oral glucose-lowering drugs (excluding another TZD) or oral glucose-lowering drugs excluding TZD. The aims were firstly to determine disease progression rates in Japanese subjects and secondly to evaluate the relative drug effect of pioglitazone vs. SoC on HbA1c levels and underlying disease progression. The disease progression model was implemented to distinguish symptomatic drug effects on disease status from effects on disease progress.
Results: The disease process was modeled using an indirect response model for HbA1c, with a proportional time-dependent increase in the HbA1c level relative to the baseline at study start. Pioglitazone showed a superior decrease in HbA1c resulting from stronger symptomatic inhibition of HbA1c, in addition to modification of the disease rate relative to SoC treated patients. The disease progression rates estimated in the Japanese population were found to be comparable to those in the Caucasian population.
Conclusion: The work presented here describes the first comprehensive disease progression model in Japanese patients comparing pioglitazone with SoC to enhance the understanding of drug action on disease status and long-term disease progression. This disease systems analysis result can be utilized to create a framework to enable more accurate long term prediction of drug effects when only short term trial data is available.
References:
[1] Post TM et al. Disease System Analysis: Basic Disease Progression Modelling in Degenerative Disease. Pharm Res 2005 22:1038-1049.
[2] de Winter WA et al. Mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying type 2 diabetes mellitus. J. Pharmacokinet Pharmacodyn. 2006;33:313-343.
[3] UKPDS33. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 1998 352:837-853.
[4] Kaku K et al. Long-term effects of pioglitazone in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity. Curr Med Res Opin 2009; 25:2925-2932
Reference: PAGE 21 (2012) Abstr 2339 [www.page-meeting.org/?abstract=2339]
Poster: Other Drug/Disease Modelling