R W Force1, M C Nahata. 1. College of Pharmacy, Ohio State University, Columbus 43210.
Abstract
OBJECTIVE: To determine whether salivary concentrations of ketoconazole and fluconazole may explain the apparent disparity between in vitro activity and clinical efficacy observed with these drugs. DESIGN:Healthy subjects received a single oral dose of ketoconazole 400 mg or fluconazole 100 mg in a randomized, crossover fashion. Saliva was collected at 0, 1, 2, 3, 6, 12, and 24 hours. Blood samples were obtained at 2 and 24 hours. Salivary concentrations and plasma concentrations for each drug were determined by HPLC. Minimum inhibitory concentration (MIC) testing was determined in triplicate on 6 clinical isolates of Candida albicans, and times over the median MIC values were calculated. PARTICIPANTS: Eight subjects completed the study. RESULTS: The mean (+/- SD) peak salivary concentration for ketoconazole was 0.119 +/- 0.050 microgram/mL at 3 hours; no subject had a detectable ketoconazole salivary concentration at 24 hours. At 2 and 24 hours, mean ketoconazole plasma concentrations were 7.64 +/- 3.87 and 0.11 +/- 0.05 microgram/mL, respectively. The saliva to plasma concentration ratio at 2 hours was 0.01. The mean peak salivary concentration of fluconazole was 2.56 +/- 0.34 microgram/mL at 3 hours. At 24 hours, the mean salivary concentration was 1.44 +/- 0.33 microgram/mL. At 2 and 24 hours, mean fluconazole plasma concentrations were 4.39 +/- 3.33 and 3.72 +/- 2.83 micrograms/mL, respectively. The saliva to plasma concentration ratio at 2 hours was 0.55. Median MIC values were 0.0625 microgram/mL (range 0.0313-0.125) for ketoconazole and 0.25 microgram/mL (range 0.125-0.5) for fluconazole. Calculated times over which ketoconazole and fluconazole exceeded the median MICs in saliva were approximately 13 and greater than 24 hours, respectively. CONCLUSIONS: After a single oral dose, fluconazole achieved higher salivary concentrations than did ketoconazole. This may explain the increased clinical efficacy of fluconazole in the treatment of oropharyngeal-esophageal candidiasis when compared with ketoconazole.
RCT Entities:
OBJECTIVE: To determine whether salivary concentrations of ketoconazole and fluconazole may explain the apparent disparity between in vitro activity and clinical efficacy observed with these drugs. DESIGN: Healthy subjects received a single oral dose of ketoconazole 400 mg or fluconazole 100 mg in a randomized, crossover fashion. Saliva was collected at 0, 1, 2, 3, 6, 12, and 24 hours. Blood samples were obtained at 2 and 24 hours. Salivary concentrations and plasma concentrations for each drug were determined by HPLC. Minimum inhibitory concentration (MIC) testing was determined in triplicate on 6 clinical isolates of Candida albicans, and times over the median MIC values were calculated. PARTICIPANTS: Eight subjects completed the study. RESULTS: The mean (+/- SD) peak salivary concentration for ketoconazole was 0.119 +/- 0.050 microgram/mL at 3 hours; no subject had a detectable ketoconazole salivary concentration at 24 hours. At 2 and 24 hours, mean ketoconazole plasma concentrations were 7.64 +/- 3.87 and 0.11 +/- 0.05 microgram/mL, respectively. The saliva to plasma concentration ratio at 2 hours was 0.01. The mean peak salivary concentration of fluconazole was 2.56 +/- 0.34 microgram/mL at 3 hours. At 24 hours, the mean salivary concentration was 1.44 +/- 0.33 microgram/mL. At 2 and 24 hours, mean fluconazole plasma concentrations were 4.39 +/- 3.33 and 3.72 +/- 2.83 micrograms/mL, respectively. The saliva to plasma concentration ratio at 2 hours was 0.55. Median MIC values were 0.0625 microgram/mL (range 0.0313-0.125) for ketoconazole and 0.25 microgram/mL (range 0.125-0.5) for fluconazole. Calculated times over which ketoconazole and fluconazole exceeded the median MICs in saliva were approximately 13 and greater than 24 hours, respectively. CONCLUSIONS: After a single oral dose, fluconazole achieved higher salivary concentrations than did ketoconazole. This may explain the increased clinical efficacy of fluconazole in the treatment of oropharyngeal-esophageal candidiasis when compared with ketoconazole.
Authors: Kim C M van der Elst; Manouche van Alst; Marjolijn N Lub-de Hooge; Kai van Hateren; Jos G W Kosterink; Jan-Willem C Alffenaar; Elisabeth H Schölvinck Journal: Antimicrob Agents Chemother Date: 2014-09-02 Impact factor: 5.191