A semi-mechanistic gastric emptying model for the population pharmacokinetic analysis of orally administered acetaminophen in critically ill patients.

PURPOSE: To develop a semi-mechanistic population pharmacokinetic model based on gastric emptying function for acetaminophen plasma concentration in critically ill patients tolerant and intolerant to enteral nutrition before and after prokinetic therapy.

METHODS

Acetaminophen plasma concentrations were available from a study with 10 tolerant and 20 intolerant patients before and after prokinetic therapy with either erythromycin or metoclopramide. Population pharmacokinetic modelling was carried out in a nonlinear mixed effects analysis software, NONMEM.

RESULTS

A four-compartment semi-mechanistic model for stomach, intestine, central and peripheral compartments was described. The rate of emptying of the stomach was described by a first-order rate parameter. The final model has two gastric emptying rate constant parameters: kg1 (1.30 h(-1), RSE=53.84%, T1/2=0.53 h) for the intolerant group before prokinetic therapy and kg2 (27.8 h(-1), RSE=59.35%, T1/2=0.025 h) for both the intolerant group after prokinetic therapy and the tolerant group. Other parameters and estimates (RSE) in the model were ka=5.12 h(-1) (28.13%), CL=13.0 L/h (19.62%), CLD=22.6 L/h (19.78%), V1=63.8 L (12.79%) and V2=69 L (38.70%).

CONCLUSIONS

The four-compartment semi-mechanistic population pharmacokinetic model adequately described the data. The gastric emptying half-time is improved by a factor of about 20 in the patients that are intolerant to enteral nutrition after treatment with prokinetic agents.