Pharmacokinetics of Oral Amoxicillin for the Treatment of Syphilis in Pregnancy

Background This open-label study compared single dose oral amoxicillin pharmacokinetics during pregnancy and post-partum relative to the established in vivo minimum inhibitory concentration (MIC) for Treponema pallidum (0.42 mcg/mL). Methods Pregnant women in good health at 24-34 weeks gestational age prescribed amoxicillin for preterm premature rupture of membranes were eligible. A 500 mg oral dose was administered at enrollment and six weeks postpartum. Blood was collected at time 0 (pre-dose) and 1, 2, 3, 4, 6, and 8-hours post-dose; venous cord blood was obtained at delivery. Amoxicillin concentrations were quantified with high-performance liquid chromatography with tandem mass spectrometry. Non-compartmental and population pharmacokinetic analyses were used to summarize parameters and estimate time above MIC (%T>MIC) and time of free drug concentrations >70% MIC (ƒT>70%MIC), for 500, 750, 875 and 1000 mg dosed every 8 or 12 hours. Results Participants (n=13) had a median age of 29 years and gestational age of 31 weeks. Three women (23%) returned for post-partum visits. Amoxicillin concentrations were reduced during pregnancy compared to post-partum: the median 8-hour area-under-the-curve was 14 vs. 22.2 mgxh/L (p=0.007), and oral clearance was 34 vs 22 L/h (p=0.03), respectively. The amoxicillin half-life was 1.3 hours. Simulated 12-hour dosing produced lower %ƒT>MIC results relative to the 8-hour dosing regimens. Conclusions Oral amoxicillin dosed every 8 hours during pregnancy is needed to maintain concentrations above the syphilis MIC threshold. Modeling suggests that 750 mg every 8 hours maintains adequate exposure during pregnancy and should be evaluated in future trials.