Pharmacometric Approaches to Personalize Use of Primarily Renally Eliminated Antibiotics in Preterm and Term Neonates

Abstract

Sepsis remains a major cause of mortality and morbidity in neonates, and, as a consequence, antibiotics are the most frequently prescribed drugs in this vulnerable patient population. Growth and dynamic maturation processes during the first weeks of life result in large inter- and intrasubject variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics. In this review we (1) summarize the available population PK data and models for primarily renally eliminated antibiotics, (2) discuss quantitative approaches to account for effects of growth and maturation processes on drug exposure and response, (3) evaluate current dose recommendations, and (4) identify opportunities to further optimize and personalize dosing strategies of these antibiotics in preterm and term neonates. Although population PK models have been developed for several of these drugs, exposure-response relationships of primarily renally eliminated antibiotics in these fragile infants are not well understood, monitoring strategies remain inconsistent, and consensus on optimal, personalized dosing of these drugs in these patients is absent. Tailored PK/PD studies and models are useful to better understand relationships between drug exposures and microbiological or clinical outcomes. Pharmacometric modeling and simulation approaches facilitate quantitative evaluation and optimization of treatment strategies. National and international collaborations and platforms are essential to standardize and harmonize not only studies and models but also monitoring and dosing strategies. Simple bedside decision tools assist clinical pharmacologists and neonatologists in their efforts to fine-tune and personalize the use of primarily renally eliminated antibiotics in term and preterm neonates.

Developmental Changes in Pharmacokinetics and Pharmacodynamics

“…This has resulted in the development of a semiphysiological modeling function to describe GFR maturation on the basis of simultaneous population PK modeling of gentamicin, tobramycin, and vancomycin, drugs that are almost entirely eliminated through GFR . A very recent review has elegantly summarized the currently available pharmacometric approaches to personalize the use of primarily renally excreted antibiotics in preterm and term neonates …”

Population Pharmacokinetic Modeling of Gentamicin in Pediatrics

“…Glomerular filtration is primarily responsible for the renal elimination of gentamicin. The glomerular filtration rate (GFR) is often used to quantitate renal function and depends on postmenstrual age (PMA), with a size‐adjusted GFR in full‐term neonates only 35% of the adult value . Full‐term neonates show a rapid increase in GFR during the first 2 weeks of life and reach adult values by the end of the first year .…”

Antibiotic PK/PD Research in Critically Ill Neonates and Children: How do we Proceed?

“…Wilbaux et al recently systematically reviewed available neonatal PK models for antibiotics. Although for vancomycin 17 models were published, a prospective validation of these models was absent [19]. This, in part, explains why there is still no consensus on optimal vancomycin dosing recommendations.…”

“…In these models, the PK is linked to the microbiological response over time from in vitro or animal infection experiments [20]. Reports on models describing clinical PK/PD relationships in critically ill neonates and young infants are currently limited [19]. Ultimately, the impact of new dosing regimens on morbidity (i.e., short and long-term effects) and mortality should be investigated.…”