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Population Pharmacokinetics and Dosing Recommendations of Vancomycin in Neonates Using Modeling and Simulation Approach

Bhongsatiern, Jiraganya (JJ)
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689427

Abstract Details

2015, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics.
Sources of variability in drug exposure play an important role in evidence-based drug dosing strategies. Body size representing growth and age representing developmental changes are primary factors for dosing information that describes functional differences between children and adults and those among children at different ages such as neonates, infants, and adolescents. Unfortunately, pediatric drug doses are often extrapolated from adult doses, partly due to inadequate evidence of these factors on drug pharmacokinetics and pharmacodynamics. In neonates, changes in body composition and organ function in drug elimination such as the kidney occur rapidly during the first week of life, affecting clearance of renally-excreted drugs such as vancomycin. As an antimicrobial agent to treat neonatal infections with coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus (MRSA), vancomycin is widely used in the neonatal intensive care unit. However, clinical guidelines with respect to vancomycin pharmacokinetics and pharmacodynamics in neonate are mostly extrapolated based on review of in vitro studies, animal studies, and limited adult data. This is an urgent need to determine influences of developmental changes in an integrated manner that would allow better predictions of vancomycin clearance and further optimize an improved dosing strategy in neonates. The objective of the current dissertation research was to identify factors that significantly describe variability of vancomycin clearance, including serum creatinine (SCr)-based renal function descriptors reflecting function and maturational changes of the neonatal kidney using a population pharmacokinetic approach. Weight, postmenstrual age, and creatinine clearance were the most significant factors and influences of the renal function descriptors such as the modified Schwartz and Léger formulas significantly outperformed those of neonatal age and weight combined. Furthermore, evaluation of vancomycin use in late-onset neonatal sepsis using the vancomycin pharmacodynamic target, a ratio of the 24-hour area under the concentration time curve to the minimum inhibitory concentration (AUC24⁄MIC) ≥400, was performed and suggested that although higher doses may be considered, the current vancomycin doses are acceptable at MICs ≤1 µg⁄mL, as 54% of neonates were likely to achieve the pharmacodynamic target. Additionally, an optimal dosing strategy of vancomycin in the neonatal population with respect to probability of target attainment was developed. Evaluation of the published dosings was performed using the population pharmacokinetic model, which was successfully validated against external datasets. Using a simulated hypothetical population, information obtained from the dosing evaluations and the overall dosing regimens facilitated the optimization of the age-appropriate dosing strategy based on assessment of the target clinical indices, trough vancomycin concentrations at 15 mg⁄L and the target AUC24⁄MIC ≥400. The optimal dosing strategy features the modified SCr-based dosing with incorporation of gestational age at 37 weeks and postnatal age at 7 days, which is considered practical in clinics. Neonates are classified as preterm and term, and the cutoff of 7 days is usually applied in neonatal sepsis upon hospital admission. This research study proposed an optimized dosing strategy with weight, age, and serum creatinine or creatinine clearance as significant factors that improved probability of target attainment and vancomycin treatment success in the neonatal population.
Pankaj Desai, Ph.D. (Committee Chair)
Alfred Balch, Ph.D. (Committee Member)
Catherine H. Sherwin, Ph.D (Committee Member)
Daniel Healy, Pharm.D. (Committee Member)
Gerald Kasting, Ph.D. (Committee Member)
216 p.
Pharmaceuticals
population pharmacokinetics; infectious diseases; special populations; neonates; vancomycin; dosing strategy

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Citations

  • Bhongsatiern, J. (2015). Population Pharmacokinetics and Dosing Recommendations of Vancomycin in Neonates Using Modeling and Simulation Approach [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689427

    APA Style (7th edition)

  • Bhongsatiern, Jiraganya (JJ). Population Pharmacokinetics and Dosing Recommendations of Vancomycin in Neonates Using Modeling and Simulation Approach. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689427.

    MLA Style (8th edition)

  • Bhongsatiern, Jiraganya (JJ). "Population Pharmacokinetics and Dosing Recommendations of Vancomycin in Neonates Using Modeling and Simulation Approach." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689427

    Chicago Manual of Style (17th edition)

ucin1447689427
850
© 2015, some rights reserved.Creative Commons License Population Pharmacokinetics and Dosing Recommendations of Vancomycin in Neonates Using Modeling and Simulation Approach by Jiraganya (JJ) Bhongsatiern is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.