1. High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.
- Author
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Ketema EB, Gishen NZ, Hailu A, Leul A, Hadgu A, Hagos K, Berhane S, Tsega T, Page-Sharp M, Davis TM, Moore B, Batty KT, Carapetis J, Salman S, and Manning L
- Subjects
- Adolescent, Adult, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Cohort Studies, Ethiopia, Humans, Injections, Intramuscular, Penicillins pharmacokinetics, Prospective Studies, Rheumatic Heart Disease etiology, Young Adult, Penicillin G Benzathine administration & dosage, Penicillin G Benzathine pharmacokinetics, Penicillins blood, Rheumatic Fever complications, Rheumatic Heart Disease prevention & control
- Abstract
Introduction: Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control., Methods: To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM., Results: A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg-1) whilst the absorption half-life (t1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively., Conclusions: The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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