High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.

<h4>Introduction</h4>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...

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Autores principales:	Ezra B Ketema, Nigus Z Gishen, Abraha Hailu, Abadi Leul, Abera Hadgu, Kiflom Hagos, Samual Berhane, Temesgen Tsega, Madhu Page-Sharp, Timothy Me Davis, Brioni Moore, Kevin T Batty, Jonathan Carapetis, Sam Salman, Laurens Manning
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/a8be4e16c1974b01be6d3c664dcb0d1a
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spelling	oai:doaj.org-article:a8be4e16c1974b01be6d3c664dcb0d1a2021-11-25T06:31:47ZHigh risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.1935-27271935-273510.1371/journal.pntd.0009399https://doaj.org/article/a8be4e16c1974b01be6d3c664dcb0d1a2021-06-01T00:00:00Zhttps://doi.org/10.1371/journal.pntd.0009399https://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Ezra B KetemaNigus Z GishenAbraha HailuAbadi LeulAbera HadguKiflom HagosSamual BerhaneTemesgen TsegaMadhu Page-SharpTimothy Me DavisBrioni MooreKevin T BattyJonathan CarapetisSam SalmanLaurens ManningPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 15, Iss 6, p e0009399 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Ezra B Ketema Nigus Z Gishen Abraha Hailu Abadi Leul Abera Hadgu Kiflom Hagos Samual Berhane Temesgen Tsega Madhu Page-Sharp Timothy Me Davis Brioni Moore Kevin T Batty Jonathan Carapetis Sam Salman Laurens Manning High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.
description	<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
format	article
author	Ezra B Ketema Nigus Z Gishen Abraha Hailu Abadi Leul Abera Hadgu Kiflom Hagos Samual Berhane Temesgen Tsega Madhu Page-Sharp Timothy Me Davis Brioni Moore Kevin T Batty Jonathan Carapetis Sam Salman Laurens Manning
author_facet	Ezra B Ketema Nigus Z Gishen Abraha Hailu Abadi Leul Abera Hadgu Kiflom Hagos Samual Berhane Temesgen Tsega Madhu Page-Sharp Timothy Me Davis Brioni Moore Kevin T Batty Jonathan Carapetis Sam Salman Laurens Manning
author_sort	Ezra B Ketema
title	High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.
title_short	High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.
title_full	High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.
title_fullStr	High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.
title_full_unstemmed	High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.
title_sort	high risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin g injections in ethiopian children and adults with rheumatic heart disease.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a8be4e16c1974b01be6d3c664dcb0d1a
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High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.

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