Factors influencing lithium pharmacokinetics in patients with acute mania: A population pharmacokinetic analysis

Abstract

Objective: The objective of this study was to conduct a population pharmacokinetic model of lithium in Thai patients with acute mania.

Methods: Lithium concentrations from 222 acute manic patients were included in this study. The population pharmacokinetic model was developed using NONMEM 7.3 software. Influences of potential covariates including body size, age, renal function, and gender were evaluated through a stepwise approach. Bootstrap analysis and an external validation approach were used to evaluate the robustness and predictability of the final model.

Results: A one-compartment model adequately described lithium pharmacokinetics. Body weight and age were significant predictors for lithium clearance, with the following relationship: CL/F (L/hr) = 1.43 * (WT/65)^0.425 * (age/38)^-0.242 . The population estimates of lithium clearance, volume of distribution, and absorption rate constant of the final model were 1.43 L/hr, 54 L (fixed), and 0.426 hr^-1 (fixed), respectively. Model evaluation showed that the final model was predictive and robust.

Conclusions: A population pharmacokinetic model of lithium with good performance was developed in Thai patients with acute mania. This model can be used to assist clinicians in individualized lithium therapy.

Keywords: NONMEM; lithium; nonlinear mixed effect modeling; population pharmacokinetics.