Quinine Pharmacokinetic-Pharmacodynamic Relationships in Uncomplicated Falciparum Malaria

Abstract

The relationships between the pharmacokinetic properties of quinine during a 7-day treatment course and the therapeutic response were studied in 30 adult patients with uncomplicated falciparum malaria monitored for >28 days. All patients received a 7-day oral quinine regimen either alone (n ‫؍‬ 22) or in combination with rifampin (n ‫؍‬ 8). The median fever clearance time was 58.5 h, and the mean ؎ standard deviation parasite clearance time was 73 ؎ 24 h. After recovery, six patients had recrudescences of Plasmodium falciparum malaria and seven had delayed appearances of P. vivax infection between days 16 and 23. Between the patients with and without recrudescences, there were no significant differences either in fever clearance time or parasite clearance time or in the overall pharmacokinetics of quinine and 3-hydroxyquinine. Patients for whom the area under the concentration-time curve from 3 to 7 days for quinine in plasma was <20 g ⅐ day/ml had a relative risk of 5.3 (95% confidence interval ‫؍‬ 1.6 to 17.7) of having a subsequent recrudescence of infection (P ‫؍‬ 0.016). Modeling of these data suggested an average minimum parasiticidal concentration of quinine in plasma of 3.4 g/ml and an MIC of 0.7 g/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days).The cinchona alkaloids have been important antimalarial drugs for more than 350 years. The principal alkaloid, quinine, still remains effective against chloroquine-resistant falciparum malaria, and it is widely used. Development of quinine resistance in Plasmodium falciparum has been relatively slow and incomplete by comparison with those of the other principal antimalarial drugs, e.g., chloroquine, mefloquine, and sufadoxine-pyrimethamine. In areas with multidrug-resistant strains, 7-day regimens of quinine and tetracycline still provide cure rates well over 90% in patients with uncomplicated falciparum malaria (4, 5). To date there is no convincing evidence of high-grade quinine resistance in the treatment of severe malaria (9). The pharmacokinetic properties of and therapeutic responses to quinine vary with age, pregnancy, immunity, and disease severity (2,8,14). As patients recover from malaria, the total apparent volume of distribution of quinine expands and systemic clearance increases (13). As a result, concentrations in plasma fall. In areas with resistant strains of P. falciparum in order to achieve good therapeutic responses in children, the dose of quinine must be increased after the 3rd day of treatment to compensate for this decline in the concentration in plasma which occurs with recovery (2). These observations suggest that quinine concentrations must remain above levels which inhibit parasite multiplication throughout the course of treatment to eradicate the infection from the body (14). Knowledge of the in vivo minimum parasiticidal concentrations and MICs (14) of quinine in patients with malaria are necessary for optimization of d...

Comparison of quinine-doxycycline and quinine-clindamycin for falciparum malaria in children

“…Because clindamycin is a slowly acting drug, clindamycin is a candidate for combination treatment with fast-acting drugs, such as quinine. [12][13][14][15][16][17] Clindamycin, usually combined with quinine, has been used extensively in South America and also proved effective in adults and children with acute malaria. The efficacy of clindamycin plus quinine for children has not been evaluated in the South east Asian region, where the most drug resistant Plasmodium falciparum strains are found.…”

Relationship between plasma and red blood cell concentrations of quinine in Brazilian children with uncomplicated Plasmodium falciparummalaria on oral therapy

“…This is essential for the success of the treatment once a marked interpersonal and interracial difference in quinine disposition have been demonstrated 3,4,5 . Therefore, this work was done to elucidate this relationship in an endemic area of Amazon region, in a prospective clinical treatment trial.…”

“…This result demonstrated that quinine do not concentrate in red blood cell of Brazilian children and demonstrates an absence of interracial differences in agreement with previous studies that show the ratio between the plasma and red blood cell quinine concentrations varied from 0.2 to 2.3. The variability in this relation could be of therapeutic relevance, once the concentration of quinine in plasma and red blood cell must remain above levels which inhibit parasite multiplication throughout the course of treatment to eradicate the infection because there is a higher probability that a resistant strain will emerge if the drug is present at a sub therapeutic concentration 3,4,7,8 .…”

“…The response of the developing malaria parasite to antimalarials is largely determined by the concentration of drug accessible to the parasite within the red cell and its sensitivity to that drug 4 . The level of antimalarial drug in the plasma is proportional to the concentration within the parasitized red cell and it is determined by several independent variables as the drug formulation, age, race, immunity, the fraction of drug absorbed, the apparent volume of distribution and the clearance 5,6,7 .…”

“…In the last decade there has been an effort at monitoring the blood levels of antimalarials in patients with falciparum malaria, an important tool in the evaluation of efficacy and effectiveness of antimalarial drugs 4,5 . The response of the developing malaria parasite to antimalarials is largely determined by the concentration of drug accessible to the parasite within the red cell and its sensitivity to that drug 4 .…”