High dose, subcutaneous injections of benzathine penicillin G (SCIP) to prevent rheumatic fever: A single arm, phase IIa trial of safety and pharmacokinetics

Abstract

Objectives: This Phase-IIa trial evaluates the safety and pharmacokinetics of high-dose, 10 weekly subcutaneous injections of penicillin (SCIP) in young people with a history of acute rheumatic fever (ARF). Methods: Participants received 7.2–10.8 MU (13.8–20.7 mL) of Bicillin-LA® via subcutaneous injection in Wellington, New Zealand. A subset underwent intensive safety monitoring and serial dried blood spot collection for penicillin assay. Penicillin concentrations informed a population pharmacokinetic model based on 169 data points from 31 participants. The proportion of time penicillin concentrations remained above a range of plausible pharmacological correlates of protection was estimated for SCIP and compared with estimates for intramuscular benzathine penicillin G (BPG). Results: Fifty-five participants received SCIP at least once, totalling 182 doses. No recurrent ARF or breakthrough streptococcal throat infections were reported. Model-based simulations indicated that SCIP outperformed intramuscular BPG in maintaining protective concentrations across nearly all plausible pharmacological target correlates of protection (10–20 ng/mL). SCIP performed even more favourably when considering modified weight-based dosing or missed BPG injections. Conclusions: SCIP is safe, well tolerated and demonstrates favourable penicillin exposure for most individuals. Future research should explore the effectiveness of SCIP over longer periods and in diverse populations and settings.