Pharmacokinetics of a three-dose regimen of intramuscular benzathine penicillin G in pregnant women with syphilis

BACKGROUND: Syphilis remains a global public health concern, particularly in pregnancy due to the risk of congenital syphilis. The WHO recommends benzathine penicillin G (BPG) as the standard treatment in pregnant women, whilst the optimal dosing strategy has not been established, particularly in relation to the impact of gestational age. This study sought to characterize the pharmacokinetics (PK) of a three-dose regimen of intramuscular BPG, given at weekly intervals, in pregnant women with syphilis. METHODS: A prospective PK study was undertaken in 30 pregnant Ethiopian women (second (n = 15) and third (n = 15) trimester) with syphilis (late or of unknown duration) who received three, once-weekly doses of intramuscular BPG (2.4 million units per dose). Dried blood spot samples were collected for up to 8 weeks after the first dose and benzylpenicillin concentrations quantified by liquid chromatography-mass spectrometry. Population PK analysis was performed using nonlinear, mixed-effects modelling. RESULTS: The PK model demonstrated biphasic absorption with a second-phase absorption half-life of 18 days. Gestational age did not impact apparent clearance or volume of distribution. Benzylpenicillin concentrations remained above the target threshold (18 ng/mL) for at least 28 days after the second dose in all women (median total cumulative time >18 ng/mL was 46 days [interquartile range 41-52 days)]. However, six participants (21%) exhibited subtherapeutic concentrations before the scheduled second injection (Day 7). CONCLUSION: A three-dose, once-weekly intramuscular BPG regimen maintained therapeutic concentrations for at least 4 weeks, suggesting potentially simpler, single- or two-dose BPG regimens in pregnant women with syphilis should be evaluated for both PK exposure and clinical outcomes.