Transient Lower Esophageal Sphincter Relaxations PKPD Modeling : Count Model and Repeated Time-To-Event Model

• Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism for gastro-esophageal reflux. Characterization 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. PKPD modeling approaches treating TLESR either as count data or as repeated time-to-event (RTTE) data were developed and compared in terms of ability to characterize system and drug characteristics. Vehicle data comprising 294 TLESR events were collected from 9 dogs. Compound (WIN55251-2) data containing 66 TLESR events, as well as plasma concentrations, were obtained from 4 dogs. Each experiment lasted for 45min and was initiated with a meal. Counts in equispaced 5-min intervals and 1-min intervals were modeled based on a Poisson probability distribution model. TLESR events were analyzed with the RTTE model. PK was connected to PD models with a 1-compartment model. Vehicle data were described by a baseline and a surge function; the surge peak was determined around 9.69min by all approaches and its width of 5min (1-min count and RTTE) or 10min (5-min count). TLESRs inhibition by WIN55251-2 was described by an Imax model, with an IC50 of on average 2.39nmol.L-1. Modeling approaches utilizing count or RTTE data linked to a dynamic PKPD representation of exposure is superior to using summary PK and PD measures. Differences in terms of predictions and power to detect a significant drug effect are illustrated with a simulation-based investigation, and a range of diagnostics for such modeling approaches is presented.  

Nyckelord

PKPD

pharmacokinetic-pharmacodynamic

TLESR

Transient lower esophageal sphincter relaxation

RTTE

repeated time-to-event

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)