Abstract
BackgroundThis study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria.MethodsA total of 70 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrolment criteria were recruited in the pharmacokinetic study. Patients were treated with two different dosage regimens of fosmidomycin in combination with clindamycin as follows:Group I: fosmidomycin (900 mg) and clindamycin (300 mg) every 6 hours for 3 days (n = 25); and Group II: fosmidomycin (1,800 mg) and clindamycin (600 mg) every 12 hours for 3 days (n = 54).ResultsBoth regimens were well tolerated with no serious adverse events. The 28-day cure rates for Group I and Group II were 91.3 and 89.7%, respectively. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about 24 hr after the first dose. The pharmacokinetics of both fosmidomycin and clindamycin analysed by model-independent and model-dependent approaches were generally in broad agreement. There were marked differences in the pharmacokinetic profiles of fosmidomycin and clindamycin when given as two different combination regimens. In general, most of the dose-dependent pharmacokinetic parameters (model-independent Cmax: 3.74 vs 2.41 μg/ml; Cmax-ss: 2.80 vs 2.08 μg/ml; Cmax-min-ss: 2.03 vs 0.71 μg/ml; AUC: 23.31 vs 10.63 μg.hr/ml (median values) were significantly higher in patients who received the high dose regimen (Group II). However, Cmin-ss was lower in this group (0.80 vs 1.37 μg/ml), resulting in significantly higher fluctuations in the plasma concentrations of both fosmidomycin and clindamycin following multiple dosing (110.0 vs 41.9%). Other pharmacokinetic parameters, notably total clearance (CL/F), apparent volume of distribution (V/F, Vz/F) and elimination half-life (t1/2z, t1/2e) were also significantly different between the two dosage regimens. In addition, the dose-dependent pharmacokinetics of both fosmidomycin and clindamycin tended to be lower in patients with recrudescence responses in both groups.ConclusionThe findings may suggest that dosing frequency and duration have a significant impact on outcome. The combination of fosmidomycin (900 mg) and clindamycin (300–600 mg) administered every six hours for a minimum of five days would constitute the lowest dose regimen with the shortest duration of treatment and which could result in a cure rate greater than 95%.
Highlights
This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria
Fosmidomycin has been shown to be an effective blood schizonticide in addition to its wide spectrum of antibacterial activity. It possesses a novel mode of action through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the non-mevalonate pathway. This occurs in the organelles of the parasites, the apicoplasts, where it selectively blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P. falciparum [2,3,4,5]
Most patients had baseline laboratory parameters outside the normal ranges; most are common in patients with acute falciparum malaria and all were mild or moderate in severity
Summary
This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria. The Plasmodium falciparum parasite causing the disease is becoming highly resistant to a wide variety of anti-malarial drugs including chloroquine and the sulphadoxine/ pyrimethamine combination [1]. This underscores the urgent requirement for new effective and safe anti-malarial drugs with novel modes of action for the treatment of multidrug resistant P. falciparum malaria. Fosmidomycin has been shown to be an effective blood schizonticide in addition to its wide spectrum of antibacterial activity It possesses a novel mode of action through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the non-mevalonate pathway. The combination of fosmidomycin with clindamycin emerged as a potential antimalarial treatment on the basis of in vitro and in vivo synergistic activity [7,8] and the outcome of subsequent clinical studies in Gabonese children [9,10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
