The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole.
OBJECTIVE
Fosfluconazole is a phosphate prodrug of fluconazole (FLCZ). This study was conducted to investigate the effect of renal impairment on the pharmacokinetics of fosfluconazole and FLCZ, and to assess the safety and toleration of fosfluconazole following a single intravenous bolus injection of fosfluconazole in subjects with normal and impaired renal function.


METHODS
In an open, parallel-group, two-centre study, subjects with normal and impaired renal function received a single 1000-mg bolus intravenous injection of fosfluconazole. Subjects were categorized as Normal (> 80 ml min(-1)), Mild (51-80 ml min(-1)), Moderate (30-50 ml min(-1)) or Severe (< 30 ml min(-1)) impairment group according to their Cockcroft and Gault creatinine clearance (CLcr) values. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 240 h and 48 h postdose, respectively.


RESULTS
Fosfluconazole plasma concentrations were very similar across the four groups, and there was no apparent relationship between any of the fosfluconazole pharmacokinetic parameters with increasing renal impairment. The conversion of fosfluconazole to FLCZ was unaffected by the degree of renal impairment. Only small amounts of fosfluconazole were excreted in the urine suggesting almost complete conversion to FLCZ. FLCZ concentrations were still detected in plasma after 240 h postdose and remained higher at the later sampling times in subjects in the Moderate and Severe groups. The area under the plasma concentration vs. time curve between time zero and infinity (AUC), the terminal elimination phase half-life (t(1/2)) and the mean residence time (MRT) of FLCZ all increased with the degree of renal impairment. The ratios (95% confidence interval) for AUC (Renal impairment group/Normal group) were 112.8% (89.5, 142.1), 240.6% (128.2, 451.4) and 355.1% (259.3, 486.3) for the Mild, Moderate and Severe impairment groups, respectively. There was a linear relationship between CLcr with AUC, t(1/2), MRT and the total plasma clearance of FLCZ (CL/F). Both the amount excreted over 48 h in the urine and the renal clearance of FLCZ decreased with an increase in renal impairment. The adverse events reported were mild to moderate in intensity, and there was no observed relationship with impairment group. There were no severe or serious adverse events, and in general fosfluconazole was well tolerated.


CONCLUSIONS
The pharmacokinetics of fosfluconazole, including its efficient conversion into FLCZ, were unaffected by renal impairment. For FLCZ, there was a significant linear relationship between CLcr and AUC, t(1/2), MRT and CL/F, with AUC, t(1/2) and MRT increasing and CL/F decreasing as renal impairment increased. The dose adjustment used for FLCZ (half normal dose for patients with CLcr at <or= 50 ml min(-1)) can be applied to fosfluconazole as well. There were no safety concerns for any subject in this study, and fosfluconazole and FLCZ were well tolerated by all the treatment groups.
Sobue
Satoshi
S
Clinical Pharmacology, Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan Inc., Tokyo, Japan. satoshi.sobue@japan.pfizer.com
Tan
Keith
K
Layton
Gary
G
Leclerc
Violette
V
Weil
Angelika
A
D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D015725:Fluconazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000150:complications*; D008297:Male; D010755:Organophosphates / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D010755:Organophosphates; C486878:fosfluconazole; D015725:Fluconazole