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Infectious Diseases

Poster Session 1

(198) Impact of Pregnancy on Ceftriaxone Pharmacokinetics and Treatment of Syphilis: Physiologic-Based Population PK Modeling Approach

Tuesday, February 13, 2024
10:30 AM – 12:00 PM  
Location: Prince George's Exhibit Hall CDE, Lower Atrium Level
Objective: Cases of congenital syphilis are rapidly rising. For pregnant women, penicillin G benzathine is the only endorsed treatment option; however, global shortages of penicillin are restricting supply to critical populations. Ceftriaxone (CTX) is a WHO alternative treatment, with limited data on pharmacokinetics (PK) and optimal dosing in pregnancy. Our objective was to characterize expected CTX PK changes during pregnancy using a physiologic-based population PK (PopPK) model to optimize CTX dosing for syphilis treatment.

Study Design:

A PopPK CTX model was developed for simulations from existing literature (Pollack 1982, Garot 2011). These limited CTX PK data in pregnancy were leveraged (Bourget 1993, Poavic 2007) with established PopPK pregnancy models that utilize a large repository of anatomic, physiologic, and biologic parameters that change with gestational age, e.g., plasma volume, GFR (Dallmann 2018). Steady-state CTX exposures were predicted in pregnant and non-pregnant persons with different dosing strategies (1g vs 2g IV/IM; q24h, q48h, vs q72h).


Results: With all dosing strategies, concentrations were highly variable with lower CTX concentrations in the 3rd trimester compared to non-pregnant persons. Following a 1g IM q24h regimen, as gestation increased, the CTX trough decreased by 58% to 11.7 mcg/mL, 5.9-21.5 (median, IQR) at 40 wks gestation (Figure). The predicted concentration of unbound CTX trough also decreased quicker than in non-pregnancy to < 1% of non-pregnant adult levels due to non-linear binding. Cord blood troughs were predicted to be only 22% of non-pregnant plasma trough levels. Increasing the CTX dose to 2g did not compensate for the changes between pregnant and nonpregnant states nor allow for infrequent dosing.

Conclusion:

There is a significant decrease in CTX exposure to the mother and fetus in the 3rd trimester regardless of dosing strategy. Currently, effective CTX dosing in vivo is unknown against T. pallidum in pregnancy, however late pregnancy may require different dosing approaches than non-pregnant persons to maintain adequate concentration in the mother and fetus.