Application of a PBPK Model to Predict the Required Ceftazidime Concentration and Duration in Maternal and Umbilical Plasma Prior to Caesarean Section in Virtual Pregnant Women with Different Renal Function
Khaled Abduljalil, Iain Gardner, Masoud Jamei
Certara UK, Simcyp Division, Sheffield, UK
Objectives: Ceftazidime injection has been used as prophylaxis for emergency caesarean section. The drug is given just before the surgery that takes about 40-50 minutes. Ceftazidime is mainly eliminated via renal filtration. The objective of this work is to assess the duration of ceftazidime maternal and umbilical plasma concentrations that remains above a target concentration in pregnant women at term with varying degree of renal function using the physiologically Based Pharmacokinetic (PBPK) model approach.
Methods: A previously developed ceftazidime PBPK model [1] was used in the Simcyp Simulator V22. Ceftazidime was modelled using a full PBPK distribution model using the Rodgers & Rowland’s method [2] and passive renal clearance. The PBPK model was verified in non-pregnant populations after intravenous (i.v.) administration of 0.5 g and 2 g ceftazidime [3]. The model was then extended to predict maternal and umbilical ceftazidime PK in pregnant women with normal renal function at different gestational weeks after i.v. administration of 1 g ceftazidime. The fetal PBPK model was coupled to the maternal PBPK model via a multi-compartment placenta model. The transplacental passive permeability clearance (CLPD) was predicted using the compound polar surface area and hydrogen bond donor count [4]. Predictions were compared to observations in pregnant women at term after 1 and 2g doses [5-7]. The developed feto-maternal PBPK model was then used to predict the duration of plasma drug concentration remains above the reported pseudomonas aeruginosa MIC90 (16 mg/L) for [8] in pregnant women at term with normal, mild, and moderate renal function.
Results: The developed PBPK model showed good agreement with non-pregnant population. The calculated placenta CLPD= 0.002 L/h/mL of placenta volume together with physiological changes in PBPK parameters resulted in good prediction of both maternal plasma and umbilical concentration profiles after 1g iv doses (observations fall within 95 predictive intervals). The average predicted cord-to-maternal ratio was 0.85±0.05 (range 0.70 -1.0). The predicted Cmax in umbilical cord after 1 and 2 g maternal doses were 19.2±3.9 and 36.4±7.9 mg/L, respectively and both were achieved at 0.87±3.9 h (range 0.10 -2.0 h). Executed simulations for the 2 g dose, indicated that ceftazidime maternal plasma concentration remains above the MIC90 of 16 mg/L for P. aeruginosa in 90% of subjects for about 1.6 h, 2.3 h, and 3.5 h in pregnant women with normal renal function and mild, and moderate renal impairment, respectively. While the umbilical plasma remained 0.5 h longer than maternal level above the MIC50 level for 2 g ceftazidime bolus dose. For the 1 g dose, maternal concentration was above the 16 mg/L for 1.2h, 2.0 h, and 2.5 h in pregnant women with normal renal function and mild and moderate renal impairment, however umbilical cord level was only higher than 16 mg/L in the moderate renal function.
Conclusions: The pregnancy PBPK model predicted that the 1 g maternal dose in pregnant women at term with normal renal function can provide a protection against P.aeruginosa infection to 90% of the mothers, but not their fetuses. In pregnant women with moderate renal function the 1g dose is expected to be sufficient for the mother (and the fetus) against P. aeruginosa when the caesarean section carried out within the first 1-2h of maternal drug intake. Sufficient protection was predicted for the 2 g dose when the procedure was carried out within the first 1.5 h for pregnant women with normal renal function. These results suggested that PBPK models developed using prior drugs physicochemical properties and systems parameters can be used for investigating the drug exposure in different scenarios and to inform dose adjustment.
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