Integrated Modeling & Simulation of Clinical Response and Drop-out of D2 receptor agonists in Patients with Early Parkinsonís Disease.
E.H. Cox (1)(3), N.H. Prins (1), G. DíSouza (2) & L. McFadyen (2)
(1) Pharsight, Strategic Consulting Services, Lent, The Netherlands, (2) Pfizer, Clinical Research and Development, Sandwich, UK, (3) Current: J & J Pharmaceuticals, Beerse, Belgium
Objectives: This Modeling & Simulation (M&S) project aimed to establish a simulation framework for efficacy of the D2 receptor agonist sumanirole and its comparator ropinirole in the treatment of early Parkinson's disease (PD) to address drug development questions.
Methodology & Results: Available data consisted of longitudinal Unified Parkinson's Disease Rating Scale (UPDRS) II/III measurements from a total of 994 patients with early PD participating in two studies. The first was a 12-week placebo controlled fixed dose study (0, 2, 8, 24 & 48 mg) of sumanirole (7-week titration, 4-week maintenance and 1 week taper phases). The second study was a flexible-dose comparator study of placebo, sumanirole (≤ 16 mg) and ropinirole (≤ 24 mg) conducted over 40 weeks (13-week titration, 26 week maintenance, 1 week taper phases).
Using NONMEM, UPDRS response was modeled as a function of baseline UPDRS score, time and drug dose. A sizeable dropout due to tolerability issues or lack of efficacy was found in both studies. This was not consistently dose related or related to reported adverse events but correlated best with low response. Therefore response-related dropout was integrated into the UPDRS model. The dose-response relationship for sumanirole and ropinirole was best described by a power model which was validated and qualified through partial residual plots and posterior predictive checking. In the flexible dose study, no clear relationship was found between dose adjustment and lack of efficacy or adverse events. Without knowing the specifics for dose adjustment (or not) such flexible dose designs could not be simulated. Simulations under a fixed dose design indicated that in the expected patient population there is a reasonable probability that high doses of sumanirole (from 24 mg and upward) may be non-inferior on efficacy to ropinirole.
Conclusion: An integrated efficacy/dropout model for D2 receptor agonist treatment of early PD was established, constituting a suitable framework for simulation of drug response in patients with PD. Simulation of flexible dosing designs requires more specific information than protocol guidance on reasons for dosing decisions. The characterization of the sumanirole dose response was helpful in decision making.