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Tuesday 04 March 2008

Effect of Ketoconazole on the Pharmacokinetics of Maribavir in Healthy Adults.

By: Goldwater DR, Dougherty C, Schumacher M, Villano SA.

Antimicrob Agents Chemother 2008 Mar;(): [Epub ahead of print]

Maribavir, an oral antiviral drug with activity against cytomegalovirus, is currently undergoing studies to assess its efficacy and safety as cytomegalovirus prophylaxis following stem cell or solid organ transplantation. The main objective of this study was to assess the effects of oral ketoconazole, a potent inhibitor of the CYP3A4 isoenzyme, on the pharmacokinetics of maribavir. This was an open-label crossover study in 20 healthy adults. Subjects were administered a single dose of maribavir 400 mg. After a washout period, subjects received a single dose of ketoconazole 400 mg followed by a single dose of maribavir. Blood samples were collected in each sequence and pharmacokinetic parameters for maribavir and its principal metabolite, VP 44469, were determined. Safety was evaluated by physical examination, clinical laboratory testing, 12-lead electrocardiogram, and monitoring for adverse events. Ketoconazole moderately reduced the clearance of both maribavir and VP 44469; CL/F values were 35% and 13% lower, respectively, for maribavir plus ketoconazole treatment than for maribavir alone. Based on the assumption of complete inhibition of CYP3A4 activity, CYP3A4 is responsible for 35% of the overall clearance of maribavir. Treatment was generally well tolerated. The most common adverse event was dysgeusia (taste disturbance), reported by 9 (47%) and 7 (35%) subjects in the maribavir alone and maribavir plus ketoconazole groups, respectively. The pharmacokinetic findings, in combination with the acceptable tolerability within the maribavir and maribavir plus ketoconazole treatment groups, suggest that no dose adjustment of maribavir is necessary when coadministered with CYP3A4 inhibitors or substrates.

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