Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the cholinesterase inhibitor pyridostigmine bromide in Chinese males

Pyridostigmine is a reversible inhibitor of acetylcholinesterase (AChE). The objective of the present analysis was to characterise the population pharmacokinetics / pharmacodynamics (PK/PD) of pyridostigmine given as pyridostigmine bromide. Fifty healthy Chinese males received 7 doses of 30 mg of pyridostigmine bromide each every 8 hours orally. Plasma concentrations of pyridostigmine and red blood cell (RBC) AChE activity were determined at various times within 8 hours after the first and the seventh doses. The resulting PK data were fit to a single compartment open model with first order absorption and elimination. The PD was modelled using an inhibitory E_max model. The potential influence of demographic and biological covariates on the model parameters was investigated. Modelling was performed using NONMEM VI. The apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 L/hr, 130 L and 0.68 1/hr respectively. The maximum RBC AChE activity decrease (E_max) 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 explained any additional variability in either PK or PD. Dosing simulations suggested that 30 mg repeated every 6 hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese male adults.