Pharmacokinetics of Oral Amoxicillin for the Treatment of Syphilis in Pregnancy

Abstract Background This open-label study compared single-dose oral amoxicillin pharmacokinetics during pregnancy and postpartum 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 6 weeks postpartum. Blood was collected at time 0 (predose) and at 1, 2, 3, 4, 6, and 8 hours postdose; venous cord blood was obtained at delivery. Amoxicillin concentrations were quantified with high-performance liquid chromatography with tandem mass spectrometry. Noncompartmental 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 postpartum visits. Amoxicillin concentrations were reduced during pregnancy compared with postpartum: the median 8-hour area under the curve was 14 vs 22.2 mgxh/L (P = .007), and oral clearance was 34 vs 22 L/h (P = .03). 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.