Pharmacokinetics of mefloquine administered with artesunate in patients with uncomplicated falciparum malaria from the Brazilian Amazon basin.

BACKGROUND: A fixed-dose combination of mefloquine with artesunate was evaluated in cases of falciparum malaria in the Brazilian Amazon basin with acceptable efficacy, safety and tolerability. However, there are no data on the pharmacokinetics of mefloquine in this coformulation in Brazil, which is valuable to evaluate whether Plasmodium is exposed to an effective concentration of the drug. METHODS: A prospective, single-arm study was conducted in male patients with slide-confirmed infection by Plasmodium falciparum using two tablets of a fixed-dose combination of artesunate (100 mg) and mefloquine base (200 mg) once daily and over 3 consecutive days. Serial blood samples were collected at admission and throughout 672 h post-administration of the drugs. Mefloquine was measured in each blood sample by high-performance liquid chromatography. The pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: A total of 61 patients were enrolled in the study and 450 whole blood samples were collected for mefloquine measurement. The mefloquine half-life was 10.25 days, the maximum concentration (Cmax) was 2.53 µg/ml, the area-under-the-curve (AUC0-∞) was 359 µg/ml h, the observed clearance (Cl/f) was 0.045 l/kg/h and the volume of distribution (V/f) was 14.6 l/kg. Mefloquine concentrations above 0.5 µg/ml were sustained for a mean time of 9.2 days. CONCLUSION: The pharmacokinetic parameters of mefloquine determined in the study suggest an adequate exposure of parasite to mefloquine in the multiple oral dose regimen of the fixed dose combination of mefloquine and artesunate.

Primaquine in Plasma and Methemoglobinemia in Patients with Malaria Due to Plasmodium vivax in the Brazilian Amazon Basin.

AbstractPrimaquine is the only licensed drug available for the elimination of Plasmodium vivax hypnozoites. Methemoglobinemia is currently reported in the course of treatment. There is evidence that metabolites of primaquine formed by the cytochrome pathway are responsible for methemoglobin formation; a genetic polymorphism of cytochrome isoforms; and a potential influence of gender in the activities of these enzymes requiring the establishment of dose × response curves profiles in different population groups. Concentrations of primaquine in plasma and methemoglobin levels were investigated in 54 patients with malaria due to P. vivax during the course of the standard regimen of chloroquine with primaquine (0.25 mg/kg/day for 14 days). All study subjects lived in an endemic area of the Brazilian Amazon Basin. The blood samples were collected before initiation of treatment and 3 hours (range 2-4 hours) after the administration of antimalarial drugs on days 2, 7, and 14. Plasma primaquine concentrations were similar in both genders (males: range = 164-191 ng/mL, females: range = 193-212 ng/mL). Methemoglobin levels ranged from 3.3% to 5.9% in males and from 3.1% to 6.5% in females. There were no significant correlations between the plasma primaquine concentrations or total dose and methemoglobin levels, suggesting that unidentified metabolites rather than parent drug were likely responsible for changes in methemoglobin levels. There was no significant influence of gender on primaquine concentrations in plasma or methemoglobin levels.

Dapsone and body mass index in subjects with multibacillary leprosy.

BACKGROUND: The physiological changes in obese subjects can modify the pharmacokinetic profiles of drugs influencing the therapeutic efficacy. METHODS: In this study, the authors compare plasma dapsone trough levels of multibacillary leprosy subjects stratified by body mass index (BMI) to evaluate if obesity plays a significant role on drug levels. The relationship between drug levels and BMI was also determined. Dapsone was measured by high-performance liquid chromatography and BMI based on World Health Organization criteria. RESULTS: At steady state, the median plasma dapsone trough level was significantly lower in obesity class 2 group, when compared with other groups, but they were similar between normal weight and preobesity groups. A weak association between drug levels and BMI was observed. CONCLUSIONS: Obesity promotes a significant reduction in plasma dapsone trough levels of subjects with multibacillary leprosy with a weak association between drug levels and BMI.