Transient Lower Esophageal Sphincter Relaxation Pharmacokinetic-Pharmacodynamic Modeling: Count Model and Repeated Time-To-Event Model

Abstract

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.-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 I max model, with an IC 50 of on average 2.39 nmol ⅐ l Ϫ1. 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.

Evaluation of Estimation Methods and Power of Tests of Discrete Covariates in Repeated Time-to-Event Parametric Models: Application to Gaucher Patients Treated by Imiglucerase

“…First, the evaluation of a binary covariate that changes over time should be performed. Then, we should also study the impact of a continuous covariate changing or not over time (30).…”

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

“…Daily vomit frequencies over 8 days were evaluated using a Poisson model, as previously described (19,20). The suitability of the Poisson model was evaluated by plotting the individual mean frequency against variance to evaluate for equidispersion.…”

Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene‐based FVIIa prophylaxis

“…Compared with traditional plasma based assays, 7 these whole blood based assays provide a more detailed description of the global haemostasis function which includes the cellular components of haemostasis. 13 These are important components that may affect clinical efficacy and need to be accounted for. Previous in vitro 8 and ex vivo 9 studies have reported that TEG allowed for individualization of treatment regimens of rhFVIIa and pd-aPCC in haemophilia patients with inhibitors.…”