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Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers.
J Clin Pharm Ther. 2005 Jun; 30(3):285-90.JC

Abstract

BACKGROUND

Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine.

OBJECTIVE

To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers.

METHODS

In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection.

RESULTS

Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0-t, t(1/2), and Cmax when compared with mefloquine alone by 79% (P < 0.001), 39% (P < 0.05) and 64% (P < 0.001) respectively. The AUC0-t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0.05) and 31% (P < 0.05), respectively when compared with mefloquine alone.

CONCLUSIONS

Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug-drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.

Authors+Show Affiliations

Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Thailand. wibool.r@psu.ac.thNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15896247

Citation

Ridtitid, W, et al. "Ketoconazole Increases Plasma Concentrations of Antimalarial Mefloquine in Healthy Human Volunteers." Journal of Clinical Pharmacy and Therapeutics, vol. 30, no. 3, 2005, pp. 285-90.
Ridtitid W, Wongnawa M, Mahatthanatrakul W, et al. Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers. J Clin Pharm Ther. 2005;30(3):285-90.
Ridtitid, W., Wongnawa, M., Mahatthanatrakul, W., Raungsri, N., & Sunbhanich, M. (2005). Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers. Journal of Clinical Pharmacy and Therapeutics, 30(3), 285-90.
Ridtitid W, et al. Ketoconazole Increases Plasma Concentrations of Antimalarial Mefloquine in Healthy Human Volunteers. J Clin Pharm Ther. 2005;30(3):285-90. PubMed PMID: 15896247.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers. AU - Ridtitid,W, AU - Wongnawa,M, AU - Mahatthanatrakul,W, AU - Raungsri,N, AU - Sunbhanich,M, PY - 2005/5/18/pubmed PY - 2005/8/25/medline PY - 2005/5/18/entrez SP - 285 EP - 90 JF - Journal of clinical pharmacy and therapeutics JO - J Clin Pharm Ther VL - 30 IS - 3 N2 - BACKGROUND: Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. OBJECTIVE: To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. METHODS: In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. RESULTS: Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0-t, t(1/2), and Cmax when compared with mefloquine alone by 79% (P < 0.001), 39% (P < 0.05) and 64% (P < 0.001) respectively. The AUC0-t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0.05) and 31% (P < 0.05), respectively when compared with mefloquine alone. CONCLUSIONS: Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug-drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy. SN - 0269-4727 UR - https://www.unboundmedicine.com/medline/citation/15896247/full_citation L2 - https://doi.org/10.1111/j.1365-2710.2005.00651.x DB - PRIME DP - Unbound Medicine ER -