The effects of hepatic impairment on the pharmacokinetics of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole.
OBJECTIVE
Fosfluconazole is a phosphate pro-drug of fluconazole (FLCZ). This study was conducted to determine the pharmacokinetics of fosfluconazole and FLCZ following a single intravenous injection of fosfluconazole in subjects with hepatic impairment and to compare them with healthy subjects.


METHODS
Twenty-four subjects (12 with normal hepatic function and 12 with chronic stable mild to moderate impaired hepatic function) received a single 1000-mg bolus intravenous injection of fosfluconazole. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 192 h and 48 h postdose, respectively.


RESULTS
The total clearance of fosfluconazole was higher and the t(1/2,Z) and mean residence time were shorter in hepatically impaired subjects than in normal subjects. This may reflect more rapid conversion to FLCZ. The degree of protein binding of fosfluconazole (> 90%) and the amount of fosfluconazole excreted in the urine were similar in both groups. Slightly higher mean plasma concentrations of FLCZ were observed in the impaired group than in the normal group; however, hepatic impairment had no statistically significant effect on the FLCZ pharmacokinetic parameters apart from t(max). The t(max) values were 4.8 h and 3.1 h in the normal and impaired subjects, respectively. The shorter t(max) for FLCZ is also consistent with the more rapid conversion in the impaired subjects. The ratios (95% confidence intervals) for C(max) and AUC of FLCZ (impaired/normal) were 106.0% (92.8, 121.2) and 115.6% (86.4, 154.7), respectively. There were no serious adverse events, and no discontinuations due to adverse events or laboratory test abnormalities. The adverse events reported were mostly mild in severity and no trend could be discerned between the groups.


CONCLUSIONS
Fosfluconazole was more rapidly converted to FLCZ in the hepatically impaired subjects but the FLCZ pharmacokinetic parameters (except t(max)) were not statistically significantly affected by hepatic impairment. Fosfluconazole was well tolerated by both groups. These results suggest that there is no requirement to adjust the dose of fosfluconazole when administered to subjects with mild to moderate hepatic impairment.
Sobue
Satoshi
S
Clinical Pharmacology, Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan Inc., Tokyo, Japan. satoshi.sobue@japan.pfizer.com
Tan
Keith
K
Haug-Pihale
Gertraud
G
D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D010755:Organophosphates; D011355:Prodrugs; C486878:fosfluconazole; D015725:Fluconazole