Population pharmacokinetics of bevacizumab in children with osteosarcoma: Implications for dosing

David C. Turner, Fariba Navid, Najat C. Daw, Shenghua Mao, Jianrong Wu, Victor M. Santana, Michael Neel, Bhaskar Rao, Jennifer Reikes Willert, David M. Loeb, K. Elaine Harstead, Stacy L. Throm, Burgess B. Freeman, Clinton F. Stewart

Research output: Contribution to journalArticle

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Abstract

Purpose: To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. Apopulation pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results: Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P 0.05). Conclusion: A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. Clin Cancer Res.

Original languageEnglish (US)
Pages (from-to)2783-2792
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number10
DOIs
StatePublished - May 15 2014
Externally publishedYes

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Osteosarcoma
Pharmacokinetics
Population
Wound Healing
Body Composition
Bevacizumab
Ideal Body Weight
Neoplasms
Clinical Chemistry
Blood Vessels
Half-Life
Body Mass Index
Research Design
Logistic Models
Body Weight
Demography
Pediatrics
Weights and Measures

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Turner, D. C., Navid, F., Daw, N. C., Mao, S., Wu, J., Santana, V. M., ... Stewart, C. F. (2014). Population pharmacokinetics of bevacizumab in children with osteosarcoma: Implications for dosing. Clinical Cancer Research, 20(10), 2783-2792. https://doi.org/10.1158/1078-0432.CCR-13-2364

Population pharmacokinetics of bevacizumab in children with osteosarcoma : Implications for dosing. / Turner, David C.; Navid, Fariba; Daw, Najat C.; Mao, Shenghua; Wu, Jianrong; Santana, Victor M.; Neel, Michael; Rao, Bhaskar; Willert, Jennifer Reikes; Loeb, David M.; Harstead, K. Elaine; Throm, Stacy L.; Freeman, Burgess B.; Stewart, Clinton F.

In: Clinical Cancer Research, Vol. 20, No. 10, 15.05.2014, p. 2783-2792.

Research output: Contribution to journalArticle

Turner, DC, Navid, F, Daw, NC, Mao, S, Wu, J, Santana, VM, Neel, M, Rao, B, Willert, JR, Loeb, DM, Harstead, KE, Throm, SL, Freeman, BB & Stewart, CF 2014, 'Population pharmacokinetics of bevacizumab in children with osteosarcoma: Implications for dosing', Clinical Cancer Research, vol. 20, no. 10, pp. 2783-2792. https://doi.org/10.1158/1078-0432.CCR-13-2364
Turner, David C. ; Navid, Fariba ; Daw, Najat C. ; Mao, Shenghua ; Wu, Jianrong ; Santana, Victor M. ; Neel, Michael ; Rao, Bhaskar ; Willert, Jennifer Reikes ; Loeb, David M. ; Harstead, K. Elaine ; Throm, Stacy L. ; Freeman, Burgess B. ; Stewart, Clinton F. / Population pharmacokinetics of bevacizumab in children with osteosarcoma : Implications for dosing. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 10. pp. 2783-2792.
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T1 - Population pharmacokinetics of bevacizumab in children with osteosarcoma

T2 - Implications for dosing

AU - Turner, David C.

AU - Navid, Fariba

AU - Daw, Najat C.

AU - Mao, Shenghua

AU - Wu, Jianrong

AU - Santana, Victor M.

AU - Neel, Michael

AU - Rao, Bhaskar

AU - Willert, Jennifer Reikes

AU - Loeb, David M.

AU - Harstead, K. Elaine

AU - Throm, Stacy L.

AU - Freeman, Burgess B.

AU - Stewart, Clinton F.

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N2 - Purpose: To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. Apopulation pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results: Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P 0.05). Conclusion: A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. Clin Cancer Res.

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