EC Pharmacology And Toxicology

Gentamicin is a critical antibiotic used to treat neonatal infections, but its narrow therapeutic index presents significant challenges in optimizing dosing, especially in neonates with immature organ systems. The pharmacokinetics (PK) of gentamicin in neonates differs markedly from that in older children and adults due to developmental variations in body composition, renal function, and hepatic maturation. This review explores the application of Physiologically Based Pharmacokinetic (PBPK) and Pharmacokinetic/Pharmacodynamic (PK/PD) modeling to optimize gentamicin dosing in neonates, with a focus on improving therapeutic efficacy while minimizing the risk of toxicity, including nephrotoxicity and ototoxicity. PBPK modeling provides a detailed framework for simulating drug behavior by incorporating neonatal-specific physiological parameters such as total body water (TBW), extracellular fluid (ECF) volume, and organ function. These models can predict the volume of distribution (Vd), renal clearance, and half-life of gentamicin, facilitating the development of personalized dosing regimens. Neonates, particularly preterm infants, exhibit a high proportion of body water and reduced renal clearance, which alters the pharmacokinetics of hydrophilic drugs like gentamicin, potentially increasing the risk of toxicity. Furthermore, the maturation of renal and hepatic function over the neonatal period influences drug elimination and metabolism, further complicating dosing decisions.PK/PD modeling, which integrates drug concentration-time profiles with therapeutic response, can inform dosing schedules to optimize drug efficacy while minimizing adverse effects. This review highlights the importance of PBPK and PK/PD models in neonatal pharmacotherapy and underscores their role in enhancing the safety and efficacy of gentamicin therapy in this vulnerable population.

 Keywords: Gentamicin; Neonates; PBPK Modeling; PKPD Modeling; Dosing Optimization; Pharmacokinetics; Pharmacodynamics; Nephrotoxicity; Ototoxicity; Therapeutic Drug Monitoring

1. Duffull SB., et al. “Physiologically based pharmacokinetic models”. Clinical Pharmacology and Therapeutics 3 (2007): 412-423.
2. Farkas A., et al. “Application of PBPK modeling in neonatal pharmacotherapy: case study of gentamicin”. British Journal of Clinical Pharmacology 4 (2015): 570-580.
3. Gagnadoux F., et al. “Pharmacokinetics of gentamicin in neonates: Review of current evidence and role of pharmacometric modeling”. Pediatric Infectious Disease Journal 1 (2016): 87-94.
4. Allegaert K., et al. “Neonatal pharmacokinetics and modeling of gentamicin”. Journal of Pediatrics 6 (2014): 1285-1292.
5. Zuppa AF., et al. “A pharmacokinetic model of gentamicin in preterm neonates”. Journal of Pediatrics 2 (2012): 306-311.
6. Vengurlekar S., et al. “Pharmacokinetic studies of gentamicin in neonates: A model-based approach”. Journal of Clinical Pharmacy and Therapeutics 5 (2017): 639-645.
7. Murray KT. “Gentamicin and ototoxicity: A clinical perspective”. Clinical Pharmacology and Therapeutics 4 (2008): 506-514.
8. Li L., et al. “Population pharmacokinetics of gentamicin in neonates”. Therapeutic Drug Monitoring 3 (2015): 324-329.
9. Kharasch ED., et al. “The role of physiologically-based pharmacokinetic (PBPK) models in personalized neonatal dosing”. Journal of Clinical Pharmacology 5 (2018): 607-618.
10. Thoma R., et al. “Impact of renal immaturity on gentamicin pharmacokinetics in neonates”. Pediatric Nephrology 2 (2019): 205-211.
11. Tong R., et al. “Clinical application of PK/PD modeling in neonatal gentamicin therapy”. Antimicrobial Agents and Chemotherapy 10 (2019): e01085-19.
12. Tsuchida K and Shime N. “Gentamicin pharmacokinetics in neonates: Evaluation and model-based analysis”. Clinical Therapeutics 3 (2017): 546-554.
13. Kazi S., et al. “Challenges in gentamicin dosing for neonates and the role of PK/PD modeling”. Pediatric Drugs 2 (2017): 113-121.
14. Lipsky MS and Goodman S. “Pharmacokinetic modeling in pediatrics: A review of current techniques and their application in clinical practice”. Journal of Clinical Pharmacology 1 (2017): 16-25.
15. Karon BS and Swartz RS. “Pharmacometric modeling: Applications in pediatric drug development”. Clinical Pharmacology and Therapeutics 1 (2019): 23-34.
16. Shankar R., et al. “Neonatal pharmacokinetics: The role of age in drug clearance”. Pediatric Drugs 1 (2015): 1-10.
17. Wajima T and Matsumoto Y. “Renal function and pharmacokinetics of gentamicin in neonates”. Clinical Pharmacokinetics 10 (2016): 1203-1213.
18. Liu J., et al. “Neonatal pharmacology and the development of PK/PD models”. Journal of Clinical Pharmacology 9 (2019): 1213-1225.
19. Choonara I., et al. “Pharmacokinetics of gentamicin in neonates”. Pharmacology and Therapeutics3 (2002): 263-271.
20. Bressler J., et al. “The role of body composition in pharmacokinetics of drugs in neonates and infants”. Clinical Pharmacokinetics1 (2005): 13-28.
21. Mistry R., et al. “The impact of electrolytes in hard and soft water on drug pharmacokinetics”. Journal of Pediatric Pharmacology and Therapeutics4 (2011): 273-278.
22. Rakhmanina NY., et al. “Pharmacokinetics and pharmacodynamics of gentamicin in neonates: implications for drug monitoring and clinical practice”. Pediatric Infectious Disease Journal3 (2010): 228-233.
23. Andrade S., et al. “Modelling the pharmacokinetics of gentamicin in premature neonates”. European Journal of Clinical Pharmacology4 (2012): 331-338.
24. McFadden S., et al. “The role of pharmacokinetic models in optimizing gentamicin dosing in premature neonates”. Pediatric Drugs4 (2009): 257-269.
25. Countdown to ACOP Encore Lecture with Stephen Dufful 9/18/2024, sheiner Lecture Series. ISoP.