Jae Eun Ahn (1), Sridhar Duvvuri (1), Danny Chen (1), and David L. Gray (2)
(1) PTx Neuroscience Clinical Pharmacology, Pfizer, Cambridge, MA; (2) Neuroscience Research Unit, Pfizer, Cambridge, MA
Objectives: To simultaneously characterize multiple motor symptom measurements such as Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale Part 3 (UDPRS motor) scores, finger tapping speed (root mean square angular velocity) measured by Kinesia Technology, and patient’s reported diary (ON/OFF-state times) after L-Dopa administration in Parkinson’s Disease (PD) patients.
Methods: L-Dopa exposure-responses were obtained as a part of a phase 1B, randomized, subject and investigator-blind, sponsor-open, placebo controlled, cross-over efficacy, safety, and tolerability study of a novel compound in Parkinson’s patients. L-Dopa was administered in the form of Sinemet during the open label period 1. Analysis data consisted of 11 per protocol analysis subjects. Pharmacokinetic and pharmacodynamic data were simultaneously analyzed using NONMEM 7.3 [1].
Results: UPDRS motor score and finger tapping speed data were adequately described by an inhibitory Emax and linear model with effect compartments [2], respectively. Unlike motor scores, baseline dependency in response was not apparent in finger tapping speed. The equilibrium half-life for delay in effects was slightly shorter for motor scores than finger tapping speed (0.74 hr vs. 1.2 hr). Patient dairy records consisted of sleeping, off, on without dyskinesia, on with non-troublesome dyskinesia, and on with troublesome dyskinesia. Proportional odds model was initially applied with an assumption that such data are ordered categorical with respect to L-Dopa exposure but the description of such model to the data was inadequate. % off time (wake) appeared to be proportional to baseline motor scores.
Conclusions: Motor symptom measurements in PD patients were characterized with respect to L-Dopa exposures. Although motor responses such as UDPRS motor scores and finger tapping demonstrated exposure-related changes, patients’ report on when they feel “ON” or “OFF” was hard to correlate or quantify with PK exposure or other motor response in this small data set and study design.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. ICON Development Solutions, Ellicott City, Maryland, USA.
[2] Cotin M, Riva R, Martinelli P, Albani F, Avoni P, and Baruzzi A, Levodopa Therapy Monitoring in Patients With Parkinson Disease: a Kinetic-Dynamic Approach, Therapeutic Drug Monitoring 23: 621-629 (2001)
Reference: PAGE 24 (2015) Abstr 3410 [www.page-meeting.org/?abstract=3410]
Poster: Drug/Disease modeling - CNS