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Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects.

Publication ,  Journal Article
Maharaj, AR; Gonzalez, D; Cohen-Wolkowiez, M; Hornik, CP; Edginton, AN
Published in: Clin Pharmacokinet
May 2018

BACKGROUND: Differences in plasma protein levels observed between children and adults can alter the extent of xenobiotic binding in plasma, resulting in divergent patterns of exposure. OBJECTIVE: This study aims to quantify the ontogeny of α1-acid glycoprotein in both healthy and infected subjects. METHODS: Data pertaining to α1-acid glycoprotein from healthy subjects were compiled over 26 different publications. For subjects diagnosed or suspected of infection, α1-acid glycoprotein levels were obtained from 214 individuals acquired over three clinical investigations. The analysis evaluated the use of linear, power, exponential, log-linear, and sigmoid E max models to describe the ontogeny of α1-acid glycoprotein. Utility of the derived ontogeny equation for estimation of pediatric fraction unbound was evaluated using average-fold error and absolute average-fold error as measures of bias and precision, respectively. A comparison to fraction unbound estimates derived using a previously proposed linear equation was also instituted. RESULTS: The sigmoid E max model provided the comparatively best depiction of α1-acid glycoprotein ontogeny in both healthy and infected subjects. Despite median α1-acid glycoprotein levels in infected subjects being more than two-fold greater than those observed in healthy subjects, a similar ontogeny pattern was observed when levels were normalized toward adult levels. For estimation of pediatric fraction unbound, the α1-acid glycoprotein ontogeny equation derived from this work (average fold error 0.99; absolute average fold error 1.24) provided a superior predictive performance in comparison to the previous equation (average fold error 0.74; absolute average fold error 1.45). CONCLUSION: The current investigation depicts a proficient modality for estimation of protein binding in pediatrics and will, therefore, aid in reducing uncertainty associated with pediatric pharmacokinetic predictions.

Duke Scholars

Published In

Clin Pharmacokinet

DOI

EISSN

1179-1926

Publication Date

May 2018

Volume

57

Issue

5

Start / End Page

577 / 589

Location

Switzerland

Related Subject Headings

  • Protein Binding
  • Pharmacology & Pharmacy
  • Pediatrics
  • Orosomucoid
  • Models, Biological
  • Infant, Newborn
  • Infant
  • Humans
  • Child, Preschool
  • Child
 

Citation

APA
Chicago
ICMJE
MLA
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Maharaj, A. R., Gonzalez, D., Cohen-Wolkowiez, M., Hornik, C. P., & Edginton, A. N. (2018). Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects. Clin Pharmacokinet, 57(5), 577–589. https://doi.org/10.1007/s40262-017-0576-7
Maharaj, Anil R., Daniel Gonzalez, Michael Cohen-Wolkowiez, Christoph P. Hornik, and Andrea N. Edginton. “Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects.Clin Pharmacokinet 57, no. 5 (May 2018): 577–89. https://doi.org/10.1007/s40262-017-0576-7.
Maharaj AR, Gonzalez D, Cohen-Wolkowiez M, Hornik CP, Edginton AN. Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects. Clin Pharmacokinet. 2018 May;57(5):577–89.
Maharaj, Anil R., et al. “Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects.Clin Pharmacokinet, vol. 57, no. 5, May 2018, pp. 577–89. Pubmed, doi:10.1007/s40262-017-0576-7.
Maharaj AR, Gonzalez D, Cohen-Wolkowiez M, Hornik CP, Edginton AN. Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects. Clin Pharmacokinet. 2018 May;57(5):577–589.
Journal cover image

Published In

Clin Pharmacokinet

DOI

EISSN

1179-1926

Publication Date

May 2018

Volume

57

Issue

5

Start / End Page

577 / 589

Location

Switzerland

Related Subject Headings

  • Protein Binding
  • Pharmacology & Pharmacy
  • Pediatrics
  • Orosomucoid
  • Models, Biological
  • Infant, Newborn
  • Infant
  • Humans
  • Child, Preschool
  • Child