Phase I Trial of Pirfenidone in Children with Neurofibromatosis 1 and Plexiform Neurofibromas

Dusica Babovic-Vuksanovic; Brigitte C. Widemann; Eva Dombi; Andrea Gillespie; Pamela L. Wolters; Mary Anne Toledo-Tamula; Brian P. O'Neill; Elizabeth Fox; Tobey MacDonald; Heather Beck; Roger J. Packer

doi:10.1016/j.pediatrneurol.2007.01.009

Phase I Trial of Pirfenidone in Children with Neurofibromatosis 1 and Plexiform Neurofibromas

Dusica Babovic-Vuksanovic, Brigitte C. Widemann, Eva Dombi, Andrea Gillespie, Pamela L. Wolters, Mary Anne Toledo-Tamula, Brian P. O'Neill, Elizabeth Fox, Tobey MacDonald, Heather Beck, Roger J. Packer

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	293-300
Number of pages	8
Journal	Pediatric Neurology
Volume	36
Issue number	5
DOIs	https://doi.org/10.1016/j.pediatrneurol.2007.01.009
State	Published - May 2007
Externally published	Yes

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Neurology
Developmental Neuroscience
Clinical Neurology

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10.1016/j.pediatrneurol.2007.01.009

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@article{0fb67e1cb6b34c7a919a5e94098a3c31,

title = "Phase I Trial of Pirfenidone in Children with Neurofibromatosis 1 and Plexiform Neurofibromas",

abstract = "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.",

author = "Dusica Babovic-Vuksanovic and Widemann, {Brigitte C.} and Eva Dombi and Andrea Gillespie and Wolters, {Pamela L.} and Toledo-Tamula, {Mary Anne} and O'Neill, {Brian P.} and Elizabeth Fox and Tobey MacDonald and Heather Beck and Packer, {Roger J.}",

note = "Funding Information: This trial was sponsored under an investigator IND (investigational new drug application) held by D.B.-V., Mayo Clinic, coordinated by the Pediatric Oncology Branch of the National Cancer Institute (NCI), and included three participating sites: NCI Pediatric Oncology Branch, Bethesda, MD; Children{\textquoteright}s National Medical Center, Washington, DC, and Mayo Clinic, Rochester, MN. Drug was supplied by Solanan, Inc. (Dallas, TX). This trial received funding through a Clinical Trial Award by the U.S. Army Department of Defense. Funding Information: This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (contracts N01-SC-07006 and HHSN26120047704C) and in part by a clinical trial award provided by the U.S. Army (grant no. DAMD17-2-1-0641). The drug pirfenidone was provided by Solanan, Inc. (Dallas, TX), who also supported pharmacokinetic studies for this trial, as well as analysis of plasma samples obtained for pharmacokinetic analysis of pirfenidone.",

year = "2007",

month = may,

doi = "10.1016/j.pediatrneurol.2007.01.009",

language = "English (US)",

volume = "36",

pages = "293--300",

journal = "Pediatric Neurology",

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T1 - Phase I Trial of Pirfenidone in Children with Neurofibromatosis 1 and Plexiform Neurofibromas

AU - Babovic-Vuksanovic, Dusica

AU - Widemann, Brigitte C.

AU - Dombi, Eva

AU - Gillespie, Andrea

AU - Wolters, Pamela L.

AU - Toledo-Tamula, Mary Anne

AU - O'Neill, Brian P.

AU - Fox, Elizabeth

AU - MacDonald, Tobey

AU - Beck, Heather

AU - Packer, Roger J.

N1 - Funding Information: This trial was sponsored under an investigator IND (investigational new drug application) held by D.B.-V., Mayo Clinic, coordinated by the Pediatric Oncology Branch of the National Cancer Institute (NCI), and included three participating sites: NCI Pediatric Oncology Branch, Bethesda, MD; Children’s National Medical Center, Washington, DC, and Mayo Clinic, Rochester, MN. Drug was supplied by Solanan, Inc. (Dallas, TX). This trial received funding through a Clinical Trial Award by the U.S. Army Department of Defense. Funding Information: This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (contracts N01-SC-07006 and HHSN26120047704C) and in part by a clinical trial award provided by the U.S. Army (grant no. DAMD17-2-1-0641). The drug pirfenidone was provided by Solanan, Inc. (Dallas, TX), who also supported pharmacokinetic studies for this trial, as well as analysis of plasma samples obtained for pharmacokinetic analysis of pirfenidone.

PY - 2007/5

Y1 - 2007/5

N2 - 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.

AB - 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.

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Phase I Trial of Pirfenidone in Children with Neurofibromatosis 1 and Plexiform Neurofibromas

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