Pharmacokinetic-pharmacodynamic model for the anticholinergic effect of glycopyrrolate

The purpose of this study was to develop and test a pharmacokinetic-pharmacodynamic (PK-PD) model for the anticholinergic effect of glycopyrrolate in eight healthy male volunteers.

First, arterial drug concentration (Cp) data after a single intravenous (i.v.) bolus injection (5 micrograms/kg) were individually fitted to a three-compartment PK model. Second, the effect of a 2-h glycopyrrolate i.v. infusion (5 micrograms/kg/h) on the mean R-R interval (RRI) and the Hayano index of the high frequency variability of RRI (HF CCV) was modelled using an effect-compartment, inhibitory sigmoidal Emax model, with the individual PK parameters from the first part as constants. Third, the developed model was tested using a computer-driven infusion which aimed at two ascending steady-state effect-site concentrations (Ce) at 1-h intervals, corresponding to 20% and 80% of the maximal effect (Emax) observed in the second part.

Modeling of the HF CCV data yielded the following mean (+/- SD) estimates: concentration at 50% of Emax (EC50), 2.46 +/- 0.58 ng/ml, equilibration half-time (t1/2 ke0), 42.5 +/- 7.7 min, and sigmoidicity factor (gamma), 7.26 +/- 2.82. The corresponding values for RRI data were 2.79 +/- 0.52 ng/ml, 58.3 +/- 17.2 min, and 4.75 +/- 1.56. During the computer-controlled two-step infusion (performed using HF CCV as the effect variable), the measured Cp approached the targeted Ce in most of the subjects, while the observed effect appeared to surpass the targeted levels.

Although we were able to develop individual PK-PD models for glycopyrrolate, maintaining a stable anticholinergic effect in the computer-driven infusion appeared to be difficult. This is probably due to intra-individual variability in the PK-PD parameters and the extremely steep concentration-effect relationship of glycopyrrolate.