Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants

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Abstract

This study describes the maturation of sirolimus clearance in a cohort of very young pediatric patients with vascular anomalies. The relationship between allometrically scaled in vivo clearance and age was described by the E _max model in patients aged 1 month to 2 years. Consistent with the observed increase, in vitro intrinsic clearance of sirolimus using pediatric liver microsomes showed a similar age-dependent increase. In children older than 2 years, allometrically scaled sirolimus clearance did not show further maturation. Simulated clearance estimates with a sirolimus physiologically based pharmacokinetic model that included CYP3A4/5/7 and CYP2C8 maturation profiles were in close agreement with observed in vivo clearance values. In addition, physiologically based pharmacokinetic model-simulated sirolimus pharmacokinetic profiles predicted the actual observations well. These results demonstrate the utility of a physiologically based pharmacokinetic modeling approach for the prediction of the developmental trajectory of sirolimus metabolic activity and its effects on total body clearance in neonates and infants.

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Most cited references 35

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Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics.

J Mulliken, J Glowacki (1982)

Forty-nine specimens from a variety of vascular lesions were analyzed for cellular characteristics. Two major categories of lesions emerged from this investigation: hemangiomas and vascular malformations. This classification and its implications are justified by several considerations. Hemangiomas in the proliferating phase (n = 14) were distinguished by (1) endothelial hyperplasia with incorporation of [3H]thymidine, (2) multilaminated basement membrane formation beneath the endothelium, and (3) clinical history of rapid growth during early infancy. Hemangiomas in the involuting phase (n = 12) exhibited (1) histologic fibrosis and fat deposition, (2) low to absent [3H]thymidine labeling of endothelial cells, and (3) rapid growth and subsequent regression. The endothelium in hemangiomas had many characteristics of differentiation: Weibel-Palade bodies, alkaline phosphatase, and factor VIII production. Vascular malformations (n = 23) demonstrated no tritiated thymidine incorporation and normal ultrastructural characteristics. These lesions were usually noted at birth, grew proportionately with the child, and consisted of abnormal, often combined, capillary, arterial, venous, and lymphatic vascular elements. This cell-oriented analysis provides a simple yet comprehensive classification of vascular lesions of infancy and childhood and serves as a guide for diagnosis, management, and further research.

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Sirolimus for the treatment of complicated vascular anomalies in children.

Adrienne M Hammill, MarySue Wentzel, Anita Gupta … (2011)

Vascular anomalies comprise a diverse group of diagnoses. While infantile hemangiomas are common, the majority of these conditions are quite rare and have not been widely studied. Some of these lesions, though benign, can impair vital structures, be deforming, or even become life-threatening. Vascular tumors such as kaposiform hemangioendotheliomas (KHE) and complicated vascular malformations have proven particularly difficult to treat.

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Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.

Jennifer C Tudor, G Chuck, Cynthia Tudor … (2006)

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in multiple organs. Five to 15% of affected individuals display subependymal giant cell astrocytomas, which can lead to substantial neurological and postoperative morbidity due to the production of hydrocephalus, mass effect, and their typical location adjacent to the foramen of Monro. We sought to see whether therapy with oral rapamycin could affect growth or induce regression in astrocytomas associated with TSC. Five subjects with clinically definite TSC and either subependymal giant cell astrocytomas (n = 4) or a pilocytic astrocytoma (n = 1) were treated with oral rapamycin at standard immunosuppressive doses (serum levels 5-15 ng/ml) from 2.5 to 20 months. All lesions demonstrated growth on serial neuroimaging studies. Magnetic resonance imaging scans were performed before and at regular intervals following initiation of therapy. All lesions exhibited regression and, in one case, necrosis. Interruption of therapy resulted in regrowth of subependymal giant cell astrocytomas in one patient. Resumption of therapy resulted in further regression. Treatment was well tolerated. Oral rapamycin therapy can induce regression of astrocytomas associated with TSC and may offer an alternative to operative therapy of these lesions.

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Author and article information

Journal

Journal ID (nlm-ta): CPT Pharmacometrics Syst Pharmacol

Journal ID (iso-abbrev): CPT Pharmacometrics Syst Pharmacol

Journal ID (publisher-id): psp4

Title: CPT: Pharmacometrics & Systems Pharmacology

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 2163-8306

ISSN (Electronic): 2163-8306

Publication date (Print): February 2015

Publication date (Electronic): 04 February 2015

Volume: 4

Issue: 2

Electronic Location Identifier: e17

Affiliations

[1 ]Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, USA

[2 ]Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, Ohio, USA

[3 ]Simcyp Limited, Blades Enterprise Centre John Street, Sheffield, UK

[4 ]Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, USA

Author notes

* Correspondence: AA Vinks ( sander.vinks@ 123456cchmc.org )

Article

DOI: 10.1002/psp4.17

PMC ID: 4360665

PubMed ID: 26225230

SO-VID: d66d1e4d-d94d-4d5c-9359-c7efdfbee078

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants

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Most cited references 35

Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics.

Sirolimus for the treatment of complicated vascular anomalies in children.

Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.

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