Pharmacokinetic Parameters of Quinine in Healthy Subjects and in Patients with Uncomplicated Malaria in Nigeria: Analysis of Data using a Population Approach

Abstract

Background: The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans.

Objective: Using a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes.

Methods: Concentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm.

Results: All datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h^-1, 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients.

Conclusions: The study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients.

Keywords: Nigerians; malaria; population pharmacokinetics; quinine; tolerance; toxicity.

Figure 1

Plots of residuals against predicted plasma concentrations of quinine in a population of Nigerians comprising 24 healthy subjects and 6 malaria-infected patients. (a) A plot of population-weighted residuals (PWRES) versus predicted plasma concentration of quinine in the final model. (b) A plot of individual-weighted residuals (IWRES) versus predicted plasma concentration of quinine in the final model.

Figure 2

Plots of observed versus predicted concentration of quinine and a visual predictive plot in Nigerians: 24 healthy subjects and 6 malaria-infected patients. (A) Observed concentration versus individual-predicted concentration for the final model. (B) Observed concentration versus population-predicted concentration of quinine for the final model. (C) A visual predictive check (corrected) for the final model showing observed data points in the first 48 hours of quinine administration after a single oral dose. The continuous green lines represent the 10th, 50th, and the 90th percentiles, whereas the shaded blue and pink regions are the 90% prediction intervals for corresponding percentiles.