Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults.

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 cytochrome P450 3A4 (CYP3A4) isoenzyme, on the pharmacokinetics of maribavir. This was an open-label crossover study with 20 healthy adults. Subjects were administered a single dose of maribavir at 400 mg. After a washout period, subjects received a single dose of ketoconazole at 400 mg followed by a single dose of maribavir. Blood samples were collected for each drug 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; oral clearance 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 nine (47%) and seven (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.

RCT Entities:   Population Interventions Outcomes