Quinine Pharmacokinetics and Pharmacodynamics in Children with Malaria Caused by Plasmodium falciparum

Abstract

The aim of the present study was to assess the pharmacokinetics and the efficacy of a shorter than usual 5-day quinine treatment given orally to children in Cameroon with malaria caused by Plasmodium falciparum. Quinine (8.3 mg of base per kg of body weight every 8 h) was administered as a 2% formiate salt syrup for 5 days to 30 children (age range, 0.55 to 6.7 years) with uncomplicated falciparum malaria (initial parasitemia, 1.4 ؋ 10 3 to 1.8 ؋ 10 5 /l). Quinine concentrations in plasma samples (five to nine per patient) were measured by liquid chromatography on days 1 to 3. Parasitemia was counted on days 0, 1, 2, 3, 4, 7, and 14. Pharmacokinetic and pharmacodynamic data were analyzed by population approaches by using NONMEM and WinBugs, respectively. The kinetics of quinine were best described by a one-compartment model with timevarying protein binding. Clearance and the volume of distribution were positively correlated with body weight and increased over time. Parasitemia was undetectable from day 3 to 14 in all children. The time to a 4-log reduction of the initial level of parasitemia (T er ) was related to the average quinine concentration from 0 to 72 h (C av ) as T er ‫؍‬ T min [1 ؉ (C 50 /C av ) s ], where sigmoidicity (s) is equal to 2, T min is the time to eradication at infinite C av , and C 50 is the value of C av for which T er is twice T min . The C 50 distribution was unimodal, and all C 50 values were less than 8 mg/liter, while C av ranged from 5.9 to 18.3 mg/liter. The median (10th to 90th percentile) T er was 47 h (range, 39 to 76 h). The efficacy of a 5-day treatment course should be evaluated in a larger clinical trial.

Taste-masked quinine pamoate tablets for treatment of children with uncomplicated Plasmodium falciparum malaria

“…Our results were comparable to those obtained in a previous study assessing the efficacy of quinine given orally for 7 days to children with uncomplicated malaria in Cameroun, when a dose of 8.3 mg of quinine base/kg was given every 8 h. The parasitaemia was undetectable from the third day in all children (n = 30), no rebound was observed at days 7 and 14 (Le Jouan et al, 2005). Comparable results have also been reported by Barennes et al (1996) after treating falciparum malaria in children using 12.8 mg quinine gluconate/kg administered via the intrarectal, intramuscular or intravenous route: parasitaemia after 48 h was 7.4 ± 16%, 4.1 ± 4.2% and 2.2 ± 3.8%, respectively; all children were aparasitemic on day 7 (Barennes et al, 1996).…”

“…The percentage of children without an episode of fever increased with the duration of treatment and is in accordance with other studies where quinine was used to treat uncomplicated P. falciparum malaria in children (at 72 h all children were apyretic) (Pussard et al, 2004;Le Jouan et al, 2005).…”

“…However, the specific design of the quinine pamoate tablets offers technological advantages as the entire dose range for children up to 20 kg is covered with a single dosage form, whereas body weight adapted dosing by means of the pellets required that the pellets were packed into capsules of different sizes (Kayumba et al, 2008). Following treatment of children with 8 mg/kg quinine three times a day for 7 days similar plasma concentrations were also reported by different authors (Pussard et al, 2004;Le Jouan et al, 2005).…”

Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Honduras

“…23 Drug susceptibility usually relies on various factors, such as the intensity of infection, immune status, plasma concentrations of the drug, and duration of drug application [24][25][26] ; however, the inherent capacity of the parasite to tolerate drugs is mostly based on its genotype. 27,28 We conducted this study to evaluate in vivo effectiveness of CQ against P. falciparum malaria infections and determine the pfcrt genotypes of the P. falciparum strains currently circulating in a highly endemic region of Honduras.…”

Changes in Individual Drug-Independent System Parameters during Virtual Paediatric Pharmacokinetic Trials: Introducing Time-Varying Physiology into a Paediatric PBPK Model

“…Over the last few years, there has been an increasing interest in understanding the covariate-parameter relationship with respect to time over the duration of study. Examples of where this approach has been adopted and applied in POPPK/PD analyses can be seen in the literature for paediatric (23) and adult (24)(25)(26) populations. However, whilst many paediatric PK/PD studies have given careful consideration to time-varying covariate effects and implemented it in the population model explicitly as the current age (27), or implicitly as the current weight, these covariates are usually fixed for each individual for the time course of the study (28).…”