Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects
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.
This study aims to quantify the ontogeny of α1-acid glycoprotein in both healthy and infected subjects.
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.
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).
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.
The AAG data taken from subjects with diagnosed or suspected infections were collected through the Pediatric Trials Network, which is sponsored by the National Institute of Child Health and Human Development (NICHD) contract HHSN275201000003I (PI: Benjamin). The data were collected through three separate trials: HHSN27500013 (PI: Benjamin) for the Pharmacokinetics of Antistaphylococcal Antibiotics in Infants study (Staph Trio; protocol NICHD-2012-STA01); HHSN27500006 (PI: Melloni, Cohen-Wolkowiez) for the Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care Study (PTN POPS; protocol NICHD-2011-POP01); and HHSN27500018 (PI: Watt) for the Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin in Pediatric Subjects with BMI ≥85th Percentile study (CLIN01; protocol NICHD-2012-CLN01).
Compliance with Ethical Standards
No sources of funding were received for the preparation of this study.
Conflict of interest
A.R.M. is supported by the Natural Sciences and Engineering Research Council of Canada. A.N.E receives support for research from the National Institutes of Health [NIH] (1R01-HD076676-01A1, PI: M.C.W.). D.G. is funded by K23HD083465 from the National Institute for Child Health and Human Development and by the nonprofit Thrasher Research Fund (http://www.thrasherresearch.org). C.P.H receives salary support for research from the National Center for Advancing Translational Sciences of the NIH (UL1TR001117). M.C.W. receives support for research from the NIH (1R01-HD076676-01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the National Institute for Child Health and Human Development of the NIH (HHSN275201000003I), the Food and Drug Administration (1U01FD004858-01), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), the nonprofit organization Thrasher Research Fund (http://www.thrasherresearch.org), and from industry for drug development in adults and children (http://www.dcri.duke.edu/research/coi.jsp).
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