Sophie Glatt, Pinky Dua, Emma McEntee, Zahid Ali
Pfizer
Objectives: The objective of this work was to assess the safety, tolerability and pharmacokinetics of an oral sodium channel blocker in healthy subjects and also to explore the relationship between the predicted exposure and adverse events of interest.
Methods: Two Phase I studies were conducted in healthy subjects. The first study was a double-blind, randomized, placebo-controlled dose escalation study. The sodium channel blocker was administered as two different oral formulations. The primary formulation was a spray-dried dispersion (SDD) formulation of the free base. An alternative tosylate salt (TS) suspension formulation was also investigated. 12 single oral doses were investigated from 10 to 2400 mg. The effect of food and of another formulation on the pharmacokinetics of the compound was also investigated. The second study was a double-blind, randomized, placebo-controlled, parallel-group study. Dose regimens of 100 mg, 300 mg and 600 mg twice daily (BID) for 14 days were investigated. The pharmacokinetics were characterized with the use of a population modelling approach and were described by a two-compartment model with first order absorption and first order elimination. The relationship between the adverse events of interest (severity of paraesthesia/hypoesthesia episodes) and predicted exposure was characterized by logistic regression analysis.
Results: Pharmacokinetic analysis showed a dose dependent effect of the food and of the formulation on the PK of the compound. Logistic regression analysis showed that at exposures that exceeded approximately 21000 ng/mL, the severity of paraesthesia/hypoesthesia events increased and also the percentage of subjects with these events increased
Conclusions: Our preliminary results show that the incidence model described the data well. Further work is ongoing to assess the influence of covariates on adverse events of interest in patients.
References:
Mould D. Chapelsky M. Aluri J. Swagzdis J. Samuels R. Granett J. A population pharmacokinetic-pharmacodynamic and logistic regression analysis of lotrafiban in patients. Clinical Pharmacology & Therapeutics. 69(4):210-22, 2001 Apr.
Reference: PAGE 21 (2012) Abstr 2522 [www.page-meeting.org/?abstract=2522]
Poster: CNS