دورية أكاديمية
أعرض في EDS

Pharmacokinetics of chlorproguanil, dapsone, artesunate and their major metabolites in patients during treatment of acute uncomplicated Plasmodium falciparum malaria.

التفاصيل البيبلوغرافية
العنوان: Pharmacokinetics of chlorproguanil, dapsone, artesunate and their major metabolites in patients during treatment of acute uncomplicated Plasmodium falciparum malaria.
المؤلفون: Miller AK; Clinical PK Modelling & Simulation, Quantitative Sciences, GlaxoSmithKline, Mailcode UW2350, King of Prussia, PA, 19406, USA. ann.k.miller@gsk.com, Bandyopadhyay N, Wootton DG, Duparc S, Kirby PL, Winstanley PA, Ward SA
المصدر: European journal of clinical pharmacology [Eur J Clin Pharmacol] 2009 Oct; Vol. 65 (10), pp. 977-87. Date of Electronic Publication: 2009 Jun 11.
نوع المنشور: Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer Country of Publication: Germany NLM ID: 1256165 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1041 (Electronic) Linking ISSN: 00316970 NLM ISO Abbreviation: Eur J Clin Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Berlin, New York, Springer.
مواضيع طبية MeSH: Antimalarials/*pharmacokinetics , Artemisinins/*pharmacokinetics , Dapsone/*pharmacokinetics , Malaria, Falciparum/*metabolism , Proguanil/*analogs & derivatives, Adult ; Antimalarials/administration & dosage ; Antimalarials/blood ; Area Under Curve ; Artemisinins/administration & dosage ; Artemisinins/blood ; Artesunate ; Dapsone/administration & dosage ; Dapsone/blood ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Synergism ; Drug Therapy, Combination ; Female ; Gambia ; Humans ; Malaria, Falciparum/drug therapy ; Malawi ; Male ; Middle Aged ; Parasitic Sensitivity Tests ; Proguanil/administration & dosage ; Proguanil/blood ; Proguanil/pharmacokinetics ; Time Factors
مستخلص: Objective: Chlorproguanil (CPG)-dapsone (DDS)-artesunate was in development for the treatment of uncomplicated Plasmodium falciparum malaria. The pharmacokinetics of CPG, DDS, artesunate and their metabolites chlorcycloguanil (CCG), monoacetyl dapsone (MADDS) and dihydroartemisinin (DHA) were investigated in patients with P. falciparum given CPG-DDS alone or plus artesunate.
Methods: Adult patients from Malawi and The Gambia taking part in a phase II clinical trial were randomised to receive a 3-day treatment of CPG-DDS alone (2/2.5 mg/kg/day) or plus 1, 2 or 4 mg/kg/day artesunate. Blood samples for pharmacokinetic analysis were collected up to 24 h post-first dose.
Results: The pharmacokinetic analysis included 115 patients. For CPG, there was no significant effect of artesunate on C(max) or AUC(0-24), except the 90% confidence interval (CI) for AUC(0-24) for the 4 mg/kg artesunate dose was slightly below that for the standard bioequivalence range (90% CI 0.78, 1.11); this was not considered clinically relevant. Artesunate increased the CCG AUC(0-24) by 6-17% and C(max) by 0-16%. Artesunate had no significant effect on the rate or extent of absorption of DDS. For MADDS, artesunate increased the AUC(0-24) by 13-47% and C(max) by 8-45%. For 1, 2 and 4 mg/kg artesunate dosing, artesunate AUC(0-infinity) was 64.6, 151 and 400 ng.h/ml and C(max) 48.9, 106 and 224 ng/ml respectively; DHA AUC(0-infinity) was 538, 1,445 and 3,837 ng.h/ml and C(max) 228, 581 and 1,414 ng/ml respectively. Using a power model, the point estimates of slope were greater than 1 for artesunate AUC(0-t) by 16% and C(max) by 5% and for DHA by 39 and 21% respectively.
Conclusion: Artesunate did not significantly affect CPG or DDS pharmacokinetics. For CCG and MADDS, small to moderate increases in exposure with artesunate dosing were observed. There was a greater than proportional increase in artesunate and DHA exposure with increasing artesunate dose. These effects are not considered to be clinically relevant. It should be noted that the CPG-DDS-artesunate programme has now been stopped following unacceptable haematological toxicity in patients with glucose-6-phosphate dehydrogenase deficiency during a phase III trial. In addition, the CPG-DDS combination has been withdrawn from clinical use.
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سلسلة جزيئية: ClinicalTrials.gov NCT00519467
المشرفين على المادة: 0 (Antimalarials)
0 (Artemisinins)
0 (Drug Combinations)
0 (chloroguanil, dapsone drug combination)
60W3249T9M (Artesunate)
6A9O50735X (artenimol)
8O3249M729 (chlorproguanil)
8W5C518302 (Dapsone)
S61K3P7B2V (Proguanil)
تواريخ الأحداث: Date Created: 20090612 Date Completed: 20091102 Latest Revision: 20211020
رمز التحديث: 20231215
DOI: 10.1007/s00228-009-0672-1
PMID: 19517101
قاعدة البيانات: MEDLINE
الوصف
تدمد:1432-1041
DOI:10.1007/s00228-009-0672-1