title: Pharmacokinetics of sequential and simultaneous treatment with the combination chloroquine and sulfadoxine-pyrimethamine in acute uncomplicated Plasmodium falciparum malaria in the Philippines.
abstract: The efficacy and kinetics of the combination chloroquine plus sulfadoxine-pyrimethamine (CQ + SP), given sequentially and simultaneously, were investigated in 32 patients with acute uncomplicated Plasmodium falciparum malaria in Palawan Island, the Philippines. Group 1 with 11 patients received oral CQ 25 mg/kg bw over 3 days followed by a single dose of SP (three tablets 250 mg S + 25 mg P) on Day 4 (CQ0 + SP4). Group 2 with 21 patients received a loading dose of CQ 10 mg/kg plus a single dose of SP three tablets on Day 0, and doses of CQ on Days 1 and 2 (CQ0 + SP0). Patients were followed-up for 28 days until after the clinical and parasitological remission of the disease. Serum samples for CQ, des-ethylchloroquine (DCQ), S and P levels were assayed by high-pressure liquid chromatography with UV and spectrofluorometric detection (HPLC-SF) to determine effective therapeutic concentrations achieved. Parasite and fever clearance times (PCT and FCT) in Group 1 were 48 and 33.5 h, respectively, and 39 and 24 h in Group 2. The parasite elimination half-life (pt1/2) in the CQ + SP0 group was 2.5 h, significantly shorter than the CQ + SP4 group of 5.7 h (P=0.006). Late-treatment failures (R I) were observed in 2/11 patients in Group 1 and in 2/21 patients in Group 2. Serum CQ and DCQ concentrations were effectively adequate. Group 1 pharmacokinetic parameters showed a median maximum concentration (Cmax), area under the curve (AUC) and elimination half-life (t1/2) of 285 ng/ml, 2299 day ng/ml and 5.7 days for CQ, and 89 ng/ml 1845 day ng/ml and 7.3 days for DCQ, respectively. SP was not assayed in Group 1 because of very limited time points. In Group 2, the median Cmax, AUC and t1/2 for CQ and DCQ were at 283 ng/ml 1980 day ng/ml and 5.9 days for CQ and 220 ng/ml, 2680 day ng/ml and 8.5 days for DCQ, respectively. For S and P, the median Cmax, AUC and t1/2 were at 169 microg/ml, 2758 day ng/ml and 10.9 days for sulfadoxine, and 591 ng/ml, 3029 day ng/ml and 2.9 days for pyrimethamine, respectively. Both regimens were well tolerated with a minimum of side-effects, mainly nausea and vomiting. The combination CQ + SP administered simultaneously on Day 0 is more efficacious than when administered sequentially. In the absence of an alternative treatment for acute uncomplicated malaria, this combination is well tolerated, and has an advantage over CQ or SP monotherapy, especially in countries where one drug is still highly effective.
authors.affiliation: Research Institute for Tropical Medicine, Department of Health, Alabang, Muntinlupa City, Philippines. dbustos@ritm.gov.ph
authors.forename: Dorina G
authors.initials: DG
authors.lastname: Bustos
authors.forename: Jose Enrico
authors.initials: JE
authors.lastname: Lazaro
authors.forename: Frederick
authors.initials: F
authors.lastname: Gay
authors.forename: Anne
authors.initials: A
authors.lastname: Pottier
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Laracas
authors.forename: Boubacar
authors.initials: B
authors.lastname: Traore
authors.forename: Bertrand
authors.initials: B
authors.lastname: Diquet
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002738:Chloroquine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D010679:Philippines; D011739:Pyrimethamine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012008:Recurrence; D013413:Sulfadoxine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D002738:Chloroquine; D011739:Pyrimethamine