Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males

Abstract

AbstractObjectivesWe have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide.MethodsOver three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 times 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses. The resulting pharmacokinetic data were fitted to a single compartment open model with first-order absorption and elimination. The pharmacodynamics were modelled using an inhibitory Emax model. The potential influence of demographic and biological covariates on the model parameters was investigated. Nonlinear mixed effects modelling was performed using NONMEM.Key findingsThe apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 1/h, 130 1 and 0.68 1/h, respectively. The maximum red blood cell AChE activity decrease (Emax) and plasma pyridostigmine concentration producing 50% of this reduction (EC50) were estimated to be 9.32 AChE units per gram haemoglobin and 51.9 ng/ml, respectively. None of the tested covariates were found to be correlated with any of the model parameters. Dosing simulations suggested that 30 mg repeated every six hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese males.ConclusionsThe pharmacokinetics and the effects of pyridostigmine on red blood cell AChE activity were described using a mixed effects model. For Chinese males, the dosing interval may have been shorter than that recommended for the Caucasian population. Additional studies are needed to confirm these findings.