TY - JOUR T1 - Transient Lower Esophageal Sphincter Relaxation Pharmacokinetic-Pharmacodynamic Modeling: Count Model and Repeated Time-To-Event Model JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 878 LP - 885 DO - 10.1124/jpet.111.181636 VL - 339 IS - 3 AU - Elodie L. Plan AU - Guangli Ma AU - Mats Någård AU - Jörgen Jensen AU - Mats O. Karlsson Y1 - 2011/12/01 UR - http://jpet.aspetjournals.org/content/339/3/878.abstract N2 - Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism for gastroesophageal reflux. Characterizations of candidate compounds for reduction of TLESRs are traditionally done through summary exposure and response measures and would benefit from model-based analyses of exposure-TLESR events relationships. Pharmacokinetic (PK)-pharmacodynamic (PD) modeling approaches treating TLESRs either as count data or repeated time-to-event (RTTE) data were developed and compared in terms of their ability to characterize system and drug characteristics. Vehicle data comprising 294 TLESR events were collected from nine dogs. Compound [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55212-2)] data containing 66 TLESR events, as well as plasma concentrations, were obtained from four dogs. Each experiment lasted for 45 min and was initiated with a meal. Counts in equispaced 5- and 1-min intervals were modeled based on a Poisson probability distribution model. TLESR events were analyzed with the RTTE model. The PK was connected to the PD with a one-compartment model. Vehicle data were described by a baseline and a surge function; the surge peak was determined to be approximately 9.69 min by all approaches, and its width in time at half-maximal intensity was 5 min (1-min count and RTTE) or 10 min (5-min count). TLESR inhibition by WIN55212-2 was described by an Imax model, with an IC50 of on average 2.39 nmol · l−1. Modeling approaches using count or RTTE data linked to a dynamic PK-PD representation of exposure are superior to using summary PK and PD measures and are associated with a higher power for detecting a statistically significant drug effect. ER -