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Pharmacokinetic modeling and placental transfer of gentamicin administered to peripartum women
Abstract Number: GM-04
Abstract Type: Original Research
Background: Gentamicin is a commonly used antibiotic in pregnant and peripartum women, however pharmacokinetic (PK) data to guide appropriate dosing in this population is lacking. The study aim was to characterize the maternal PK profile and placental transfer of gentamicin administered peripartum, and to compare findings to existing PK data derived from non-pregnant adults.
Methods: We conducted a prospective cohort trial of intravenous gentamicin administered during 3rd trimester. Dosing was per clinical recommendations: 160 mg once for preoperative prophylaxis or 5 mg/kg every 24h for chorioamnionitis. Maternal blood samples were collected before treatment, 5, 15, 30-min, 3h, 6h, 24h after dosing, and at delivery (MV). PK properties were evaluated with a population approach using non-linear mixed-effect modeling. Umbilical arterial (UA) and venous (UV) blood were sampled at delivery, and UA:MV and UA:UV ratios determined.
Results: PK profiles of 20 pregnant women were analyzed. A two-compartment model provided the best fit. Analysis revealed a central volume of distribution (V1) of 0.7 L, clearance (Cl) of 14 L/h, inter-compartmental CLRA of 0.05 L/h and peripheral volume of distribution (V2) of 13 L. Intraindividual portion of the variance was 0.1. A weight proportional model did not improve the model fit. Gentamicin concentrations over time are depicted in the Figure. The UV:MV(SD) and UA:UV(SD) ratios were 0.6(1.0) and 1.0(0.4) respectively. Our data show that current dosing paradigms may maintain the required minimum inhibitory concentration (MIC) for some obstetric pathogens (E. coli) but fall short for others, including Enterococcus faecalis (1)(Figure).
Conclusion: Our data demonstrate that gentamicin Cl is greater than published for non-pregnant women (14 L/h vs. 3.4 L/h)(2). These results are consistent with pregnancy physiology of greater renal clearance of hydrophilic drugs (3). However our two-compartment model did not find the V1 greater than in non-pregnant subjects using a one-compartment model (2), which would have been an expected in pregnancy. The results highlight the importance of studying drugs in the indicated population (pregnant vs. non-pregnant). Importantly, findings show that when pathogens with high MICs, such as Enterococcus faecalis are suspected, a shorter dosing interval may be indicated in pregnant women.
1. Clin Obstet Gynecol 2008;51:498–506
1. J Clin Pharm Ther 2007;32:595-602
2. PLoS One 2017;12:e0177324