Earvin Liang (1), Farkad Ezzet (2), Jonathan Wagg (2), Margaret Cooney (1), Susan Abushakra (1)
(1) Elan Pharmaceuticals, Inc. South San Francisco, CA, (2) Pharsight Corporation, St. Louis, MO
Introduction: One aspect of design optimization concerns finding an efficient pharmacokinetic (PK) sampling schedule to properly characterize PK of a given drug of interest in the target population. ELND005 (Scyllo-inositol) is being investigated as a potentially disease modifying oral treatment for Alzheimer's Disease (AD).
Objective: To identify an optimal PK sampling plan for a Phase 3 clinical trial in Mild AD patients receiving oral ELND005 250 mg or placebo BID over 78 weeks.
Methods: The method underling optimization approach involves the computation of "Fisher information matrix", whose determinant ("criterion") represents the degree of information inherent in the design using WinPOPT (http://www.winpopt.com/) sampling optimization based on a previously developed PK model of ELND005. PK samples are to be collected from 450 patients per arm receiving 250 mg ELND005 or placebo BID. A base PK sample collection study design occurs at baseline visit and weeks 6, 12, 24, 48 and 78, of which 1 sample collected at pre-dose and 2 post-dose collected with at least 1 hour apart from each other during baseline visit, and 2 blood samples drawn at approximately 5 to 9 hours post-dose with at least 1 hour apart from each other during follow-up clinical visits.
Results and Discussion: The base study design is likely to yield a criterion of 86 with %CV for clearance at ~51%. When the PK sampling schedule is modified to 2 post dose samples with one soon after dosing (0.5 hours) and the other at ~2 (Design A), 3 (Design B), or 4 (Design C) hours post-dose during baseline visit, and to 1 post dose sample during the rest of the visits, the criterion and %CV of clearance are likely to improve to 85 and ~34%, 94 and ~20%, and 111 and ~14%, respectively. Either Design is invariant in terms of efficiency to changes in sampling times anywhere between 5-9 hours post morning dose and there is no meaningful gain in efficiency if two samples instead of one are collected during PK visits at weeks 6 to 78. For Designs B and C, if sample size is maintained at 300 and 200 patients while other conditions remain the same, %CV of clearance is likely to increase slightly to ~24% and ~20%, respectively.
Conclusion: Taking into consideration patient compliance, comfort and safety, as well as data richness and consistency, Design B is considered an efficient and practical sampling plan and therefore proposed for the future Phase 3 trials.
Reference: PAGE 21 () Abstr 2309 [www.page-meeting.org/?abstract=2309]
Poster: Study Design