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Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children.
Clin Cancer Res. 2011 Nov 01; 17(21):6867-77.CC

Abstract

PURPOSE

To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM.

EXPERIMENTAL DESIGN

The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V.

RESULTS

CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation.

CONCLUSION

We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment.

Authors+Show Affiliations

Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Germany. tramemirjam@uni-muenster.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21918171

Citation

Trame, Mirjam N., et al. "Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 17, no. 21, 2011, pp. 6867-77.
Trame MN, Bergstrand M, Karlsson MO, et al. Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children. Clin Cancer Res. 2011;17(21):6867-77.
Trame, M. N., Bergstrand, M., Karlsson, M. O., Boos, J., & Hempel, G. (2011). Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 17(21), 6867-77. https://doi.org/10.1158/1078-0432.CCR-11-0074
Trame MN, et al. Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children. Clin Cancer Res. 2011 Nov 1;17(21):6867-77. PubMed PMID: 21918171.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children. AU - Trame,Mirjam N, AU - Bergstrand,Martin, AU - Karlsson,Mats O, AU - Boos,Joachim, AU - Hempel,Georg, Y1 - 2011/09/14/ PY - 2011/9/16/entrez PY - 2011/9/16/pubmed PY - 2012/1/21/medline SP - 6867 EP - 77 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 17 IS - 21 N2 - PURPOSE: To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM. EXPERIMENTAL DESIGN: The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V. RESULTS: CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation. CONCLUSION: We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/21918171/Population_pharmacokinetics_of_busulfan_in_children:_increased_evidence_for_body_surface_area_and_allometric_body_weight_dosing_of_busulfan_in_children_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=21918171 DB - PRIME DP - Unbound Medicine ER -