Search

• Varied disposition imparts on the tolerance and safety of quinine, and thus constitutes a major limiting consideration for its dosing in uncomplicated malaria. Utilizing a population approach, the effect of body weight and infection status on disposition parameters of quinine were evaluated in Nigerian subjects. • A reversal of infection-induced changes in volume of distribution and clearance after 48 h of chronic quinine administration was noted. • It is hypothesized that a downward review of quinine regimen post-48 h of chronic administration, in the event of complete parasitaemia clearance, might be a useful approach in enhancing tolerance and safety. The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]