Sohail Aziz, Siti Maisharah Sheikh Ghadzi, Shalini C Sree Dharan, Sabariah Noor Harun
School of pharmaceutical sciences, Universiti Sains Malaysia
Objectives:
Time-to-event (TTE) pharmacometric analysis has an important role in the parametric quantification of the occurrence of diabetic nephropathy. Incorporating censoring event and time components in the TTE analysis allow unbiased and better estimates of survival function than the traditional regression methods. The present study focused on the development of TTE model of diabetic nephropathy among patients with type 2 diabetes mellitus (T2DM). Furthermore, the study evaluated the influence of covariates (discrete and continuous) on the progression of diabetes to diabetic nephropathy.
Methods:
The data was collected from a tertiary care hospital comprising of 200 T2DM patients. The maximum follow up period was about 6.5 years. Parametric TTE analysis was performed using NONMEM software. The event was defined by the development of diabetic nephropathy (persistent proteinuria for three visits). Three TTE models; exponential, Gompertz and Weibull hazard models were tested for base model. The effect of covariates on the overall hazard of developing diabetic nephropathy was investigated using stepwise approach. Univariate analysis was performed, followed by multivariate analysis. Multivariate analysis included the significant covariates from the univariate analysis. The likelihood ratio test (LRT) with a significance level (a) of 5% was used to discriminate between nested models. A drop of 3.84 with one degree freedom by the addition of covariate with the base model is considered statistically significant (p>0.05). The selection of final model was based on the lowest OFV, Kaplan Meier visual predictive check (KM-VPC) with 100 simulations, relative standard error (RSE) as well as the scientific plausibility.
Results:
Out of 200 patients, 82 (41%) patients developed diabetic nephropathy. The best base model was exponential hazard model (h(t) = λ0 . e0) with the baseline hazard of 1.5068 /year (RSE=31%). The hazard of developing diabetic nephropathy decreases with the use of angiotensin receptor blockers (ARBs) (HR, 0.454; 95% CI [0.628-0.328], with 1-year increment in age (HR, 0.965; 95% CI [0.980-0.950] as well as having the eGFR of > 90ml/min (HR, 0.278; 95% CI [0.580-0.118]. Having eGFR of 60-89 ml/min and
H(t) = λ0 . exp (θEGFR . EGFRstatus +θARB . ARBstatus + θAGE . AGEstatus)
Conclusions:
The use of pharmacometrics approach in this study will help to generate new knowledge on the underlying mechanism of the progression of diabetic nephropathy in patients with T2DM by exploring patients and disease data over time and developing thereon so called pharmacometric models. These approaches may not only improve the medical practitioners understanding about disease progression but will also be helpful in improving treatment strategies. Present study found that ARBs can be helpful in minimizing the risk of developing diabetic nephropathy while eGFR trend can be useful indicator for diabetic nephropathy
References:
[1] Beal, S. L., Sheiner, L. B. & Boeckman, A. J. NONMEM Users Guides. (1989–2006) (Icon Development Solutions, Ellicott City, MD, 2008).
[2] Barrett, J. S., Fossler, M. J., Cadieu, K. D. & Gastonguay, M. R. 2008. Pharmacometrics: A multidisciplinary field to facilitate critical thinking in drug development and translational research settings. J. Clin. Pharmacol. 48, pp. 632–649.
[3] Holford N. 2013. A time to event tutorial for pharmacometricians. CPT: Pharmacometrics and System Pharmacology, 2 (e43), pp.1-8.
[4] Adler, A.I., Stevens, R.J., Manley, S.E., Bilous, R.W., Cull, C.A., Holman, R.R. and UKPDS Group, 2003. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney international, 63(1), pp.225-232.
Reference: PAGE () Abstr 9274 [www.page-meeting.org/?abstract=9274]
Poster: Drug/Disease Modelling - Endocrine