{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T18:30:14Z","timestamp":1777401014383,"version":"3.51.4"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009402","name":"Mekelle University","doi-asserted-by":"publisher","award":["CRPO\/CHS\/medium\/003\/09"],"award-info":[{"award-number":["CRPO\/CHS\/medium\/003\/09"]}],"id":[{"id":"10.13039\/501100009402","id-type":"DOI","asserted-by":"publisher"}]},{"name":"School of Pharmacy and Biomedical Sciences, Curtin University"},{"DOI":"10.13039\/501100009317","name":"Faculty of Health and Medical Sciences, University of Western Australia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009317","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Introduction<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>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\/m<jats:sup>2<\/jats:sup>, 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\u201366.3] l.70kg<jats:sup>-1<\/jats:sup>) whilst the absorption half-life (t<jats:sub>1\/2-abs2<\/jats:sub>) was longer (12.0 [8.75\u201317.7] 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\u201360) and 73% (58.5\u201399), respectively.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pntd.0009399","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T17:24:48Z","timestamp":1623432288000},"page":"e0009399","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6546-0591","authenticated-orcid":true,"given":"Ezra B.","family":"Ketema","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nigus Z.","family":"Gishen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abraha","family":"Hailu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abadi","family":"Leul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1006-7578","authenticated-orcid":true,"given":"Abera","family":"Hadgu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiflom","family":"Hagos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samual","family":"Berhane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8822-5498","authenticated-orcid":true,"given":"Temesgen","family":"Tsega","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhu","family":"Page-Sharp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0749-7411","authenticated-orcid":true,"given":"Timothy ME","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-7838","authenticated-orcid":true,"given":"Brioni","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3850-1778","authenticated-orcid":true,"given":"Kevin T.","family":"Batty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Carapetis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8276-6784","authenticated-orcid":true,"given":"Sam","family":"Salman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4334-5351","authenticated-orcid":true,"given":"Laurens","family":"Manning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"issue":"8","key":"pntd.0009399.ref001","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1056\/NEJMoa1603693","article-title":"Global, Regional, and National Burden of Rheumatic Heart Disease, 1990\u20132015.","volume":"377","author":"DA Watkins","year":"2017","journal-title":"New England Journal of Medicine."},{"key":"pntd.0009399.ref002","unstructured":"Rheumatic fever and rheumatic heart disease: report of a WHO Expert Consultation. 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