Application of a Physiologically Based Pharmacokinetic Model to Predict Cefazolin and Cefuroxime Disposition in Obese Pregnant Women Undergoing Caesarean Section

Abstract

Intravenous (IV) cefuroxime and cefazolin are used prophylactically in caesarean sections (CS). Currently, there are concerns regarding sub-optimal dosing in obese pregnant women compared to lean pregnant women prior to CS. The current study used a physiologically based pharmacokinetic (PBPK) approach to predict cefazolin and cefuroxime pharmacokinetics in obese pregnant women at the time of CS as well as the duration that these drug concentrations remain above a target concentration (2, 4 or 8 µg/mL or µg/g) in plasma or adipose tissue. Cefazolin and cefuroxime PBPK models were first built using clinical data in lean and in obese non–pregnant populations. Models were then used to predict cefazolin and cefuroxime pharmacokinetics data in lean and obese pregnant populations. Both cefazolin and cefuroxime models sufficiently described their total and free levels in the plasma and in the adipose interstitial fluid (ISF) in non–pregnant and pregnant populations. The obese pregnant cefazolin model predicted adipose exposure adequately at different reference time points and indicated that an IV dose of 2000 mg can maintain unbound plasma and adipose ISF concentration above 8 µg/mL for 3.5 h post dose. Predictions indicated that an IV 1500 mg cefuroxime dose can achieve unbound plasma and unbound ISF cefuroxime concentration of ≥8 µg/mL up to 2 h post dose in obese pregnant women. Re-dosing should be considered if CS was not completed within 2 h post cefuroxime administration for both lean or obese pregnant if cefuroxime concentrations of ≥8 µg/mL is required. A clinical study to measure cefuroxime adipose concentration in pregnant and obese pregnant women is warranted.

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update

“…This is consistent with prior evidence that reported suboptimal ertapenem PTA at MICs ≥0.5 mcg/mL in obese patients 55,56 . Moreover, Chambers, et al found that one dose of ertapenem 1 g achieved PTA in bone of ≤45% when the MIC was ≥0.25 mg/L, suggesting obese patients with bone and joint infections are at greatest risk of suboptimal ertapenem dosing (median BMI 37.8 kg/m 2 ) 32–44,57 . This problem may be more pronounced in gram‐positive or mixed infections given differences in MIC breakpoints (CLSI breakpoint for Enterobacterales ≤0.5 mg/L, Streptococci ≤1 mg/L) 28…”

“…Additionally, the use of a simple weight cutoff for dose increase may be flawed as it does not account for differences in body size and composition 2 . Small, retrospective, and/or single‐center studies of a variety of surgical procedures continue to emerge and demonstrate conflicting results on adequacy of cefazolin adipose tissue or interstitial fluid concentrations in obesity, despite adequate plasma concentrations 1,14,40–44 …”

“…2 Small, retrospective, and/ or single-center studies of a variety of surgical procedures continue to emerge and demonstrate conflicting results on adequacy of cefazolin adipose tissue or interstitial fluid concentrations in obesity, despite adequate plasma concentrations. 1,14,[40][41][42][43][44] A recent systematic review of cefazolin dosing in obesity (15 pharmacokinetic studies and three clinical studies of caesarian section and elective surgeries) described conflicting results but ultimately concluded that increased preoperative cefazolin doses (3-4 g) are not needed in obese patients (BMI > 30 kg/m 2 ) undergoing surgeries lasting up to 4 h. 45 This conclusion was driven by three case-control studies and PK data derived from three randomized controlled trials (RCTs); eight cohort studies and four case series were evenly split in results. Authors caution readers that their conclusions draw upon PK studies in which there was large heterogeneity in study variables (e.g., MIC targets used, sample size, sampling, and simulation methodology).…”

“…55,56 Moreover, Chambers, et al found that one dose of ertapenem 1 g achieved PTA in bone of ≤45% when the MIC was ≥0.25 mg/L, suggesting obese patients with bone and joint infections are at greatest risk of suboptimal ertapenem dosing (median BMI 37.8 kg/m 2 ). [32][33][34][35][36][37][38][39][40][41][42][43][44]57 This problem may be more pronounced in gram-positive or mixed infections given differences in MIC breakpoints (CLSI breakpoint for Enterobacterales ≤0.5 mg/L, Streptococci ≤1 mg/L). 28 Despite these PK findings, retrospective and post hoc studies have demonstrated that ertapenem 1 g every 24 h yields similar clinical outcomes in obese and non-obese patients with moderate to severe diabetic foot infections, cIAI and pneumonia or when used for surgical prophylaxis.…”

An Application of a Physiologically Based Pharmacokinetic Approach to Predict Ceftazidime Pharmacokinetics in a Pregnant Population

“…This base model for non-pregnant subjects was then extended to predict ceftazidime kinetics in pregnant subjects at different gestational weeks (GWs) by selecting the built-in pregnancy population within the Simulator. The changes in predicted values for GFR ( GFR pred ), CO ( CO pred ), and RBF ( RBF pred ) are described in the PBPK model using the following functions based on a previously published analysis [ 2 ]: where are the baseline values in non-pregnant women [ 2 , 24 , 25 ]. Exposure in the fetus was simulated to occur via linking the maternal PBPK model to the multi-compartment feto-placental model ( Figure 1 ).…”