Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas.

We aimed to define the dose of pirfenidone in children and adolescents with neurofibromatosis 1 and plexiform neurofibromas that is pharmacokinetically comparable to the active adult dose. Pirfenidone was administered orally on a continuous dosing schedule. The starting dose level was 250 mg/m2/dose. The second dose level (500 mg/m2/dose) corresponded to the adult dose that previously showed activity in sclerosing conditions. A dose was considered pharmacokinetically comparable if the drug exposure in children was <1 standard deviation below the drug exposure in adults treated with 800 mg three times a day. Pharmacokinetic sampling was performed for 24 hours after the first dose. Response to treatment was evaluated using automated volumetric magnetic resonance imaging analysis; quality of life was evaluated using the Impact of Pediatric Illness Scale. Sixteen patients were entered and evaluated for toxicity. Dose-limiting toxicities were observed in 2 of 12 patients receiving 500 mg/m2 three times a day. The plasma pharmacokinetics of pirfenidone were highly variable, but not age dependent. The second dose level was the pharmacokinetically comparable dose and is being used in an ongoing phase II trial of pirfenidone for children with neurofibromatosis 1 and progressive plexiform neurofibroma.