Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1

Chie Emoto, Tsuyoshi Fukuda, Tomoyuki Mizuno, Shareen Cox, Björn Schniedewind, Uwe Christians, Brigitte C. Widemann, Michael J. Fisher, Brian Weiss, John Perentesis, Alexander A. Vinks

Research output: Contribution to journalArticle

Abstract

Background: Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism. Methods: Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC-UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation. Results: Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults. Conclusions: This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of age-appropriate dosing algorithms for sirolimus in infants and children. ©

Original languageEnglish (US)
Pages (from-to)395-399
Number of pages5
JournalTherapeutic Drug Monitoring
Volume37
Issue number3
DOIs
StatePublished - Jun 26 2015
Externally publishedYes

Fingerprint

Neurofibromatosis 1
Sirolimus
Cytochrome P-450 CYP3A
Pharmacokinetics
Phase II Clinical Trials
Growth
High Pressure Liquid Chromatography
Pediatrics
Liver

Keywords

  • body size
  • metabolite
  • neurofibromatosis
  • pediatric
  • pharmacokinetics
  • sirolimus

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Emoto, C., Fukuda, T., Mizuno, T., Cox, S., Schniedewind, B., Christians, U., ... Vinks, A. A. (2015). Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1. Therapeutic Drug Monitoring, 37(3), 395-399. https://doi.org/10.1097/FTD.0000000000000130

Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1. / Emoto, Chie; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Cox, Shareen; Schniedewind, Björn; Christians, Uwe; Widemann, Brigitte C.; Fisher, Michael J.; Weiss, Brian; Perentesis, John; Vinks, Alexander A.

In: Therapeutic Drug Monitoring, Vol. 37, No. 3, 26.06.2015, p. 395-399.

Research output: Contribution to journalArticle

Emoto, C, Fukuda, T, Mizuno, T, Cox, S, Schniedewind, B, Christians, U, Widemann, BC, Fisher, MJ, Weiss, B, Perentesis, J & Vinks, AA 2015, 'Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1', Therapeutic Drug Monitoring, vol. 37, no. 3, pp. 395-399. https://doi.org/10.1097/FTD.0000000000000130
Emoto, Chie ; Fukuda, Tsuyoshi ; Mizuno, Tomoyuki ; Cox, Shareen ; Schniedewind, Björn ; Christians, Uwe ; Widemann, Brigitte C. ; Fisher, Michael J. ; Weiss, Brian ; Perentesis, John ; Vinks, Alexander A. / Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1. In: Therapeutic Drug Monitoring. 2015 ; Vol. 37, No. 3. pp. 395-399.
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AU - Fukuda, Tsuyoshi

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AU - Cox, Shareen

AU - Schniedewind, Björn

AU - Christians, Uwe

AU - Widemann, Brigitte C.

AU - Fisher, Michael J.

AU - Weiss, Brian

AU - Perentesis, John

AU - Vinks, Alexander A.

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N2 - Background: Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism. Methods: Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC-UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation. Results: Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults. Conclusions: This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of age-appropriate dosing algorithms for sirolimus in infants and children. ©

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