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Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria

BACKGROUND: This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria. METHODS: A total of 70 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the...

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Autores principales: Ruangweerayut, Ronnatrai, Looareesuwan, Sornchai, Hutchinson, David, Chauemung, Anurak, Banmairuroi, Vick, Na-Bangchang, Kesara
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600645/
https://www.ncbi.nlm.nih.gov/pubmed/18973702
http://dx.doi.org/10.1186/1475-2875-7-225
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author Ruangweerayut, Ronnatrai
Looareesuwan, Sornchai
Hutchinson, David
Chauemung, Anurak
Banmairuroi, Vick
Na-Bangchang, Kesara
author_facet Ruangweerayut, Ronnatrai
Looareesuwan, Sornchai
Hutchinson, David
Chauemung, Anurak
Banmairuroi, Vick
Na-Bangchang, Kesara
author_sort Ruangweerayut, Ronnatrai
collection PubMed
description BACKGROUND: This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria. METHODS: A 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). RESULTS: Both 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 C(max): 3.74 vs 2.41 μg/ml; C(max-ss): 2.80 vs 2.08 μg/ml; C(max-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, C(min-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, V(z)/F) and elimination half-life (t(1/2z), t(1/2e)) 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. CONCLUSION: The 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%.
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spelling pubmed-26006452008-12-15 Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria Ruangweerayut, Ronnatrai Looareesuwan, Sornchai Hutchinson, David Chauemung, Anurak Banmairuroi, Vick Na-Bangchang, Kesara Malar J Research BACKGROUND: This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria. METHODS: A 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). RESULTS: Both 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 C(max): 3.74 vs 2.41 μg/ml; C(max-ss): 2.80 vs 2.08 μg/ml; C(max-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, C(min-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, V(z)/F) and elimination half-life (t(1/2z), t(1/2e)) 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. CONCLUSION: The 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%. BioMed Central 2008-10-31 /pmc/articles/PMC2600645/ /pubmed/18973702 http://dx.doi.org/10.1186/1475-2875-7-225 Text en Copyright © 2008 Ruangweerayut et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Ruangweerayut, Ronnatrai
Looareesuwan, Sornchai
Hutchinson, David
Chauemung, Anurak
Banmairuroi, Vick
Na-Bangchang, Kesara
Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria
title Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria
title_full Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria
title_fullStr Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria
title_full_unstemmed Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria
title_short Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria
title_sort assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600645/
https://www.ncbi.nlm.nih.gov/pubmed/18973702
http://dx.doi.org/10.1186/1475-2875-7-225
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