Rifabutin pharmacokinetics and safety among TB/HIV-coinfected children receiving lopinavir/ritonavir-containing second-line ART.
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
11 02 2021
11 02 2021
Historique:
received:
10
07
2020
accepted:
09
11
2020
pubmed:
10
12
2020
medline:
6
7
2021
entrez:
9
12
2020
Statut:
ppublish
Résumé
Treatment options are limited for TB/HIV-coinfected children who require PI-based ART. Rifabutin is the preferred rifamycin for adults on PIs, but the one study evaluating rifabutin with PIs among children was stopped early due to severe neutropenia. We evaluated rifabutin safety and plasma pharmacokinetics among coinfected children 3-15 years of age receiving rifabutin 2.5 mg/kg daily with standard doses of lopinavir/ritonavir. The AUC0-24 at 2, 4 and 8 weeks after rifabutin initiation was described using intensive sampling and non-compartmental analysis. Clinical and laboratory toxicities were intensively monitored at 12 visits throughout the study. Among 15 children with median (IQR) age 13.1 (10.9-14.0) years and weight 25.5 (22.3-30.5) kg, the median (IQR) rifabutin AUC0-24 was 5.21 (4.38-6.60) μg·h/mL. Four participants had AUC0-24 below 3.8 μg·h/mL (a target for the population average exposure) at week 2 and all had AUC0-24 higher than 3.8 μg·h/mL at the 4 and 8 week visits. Of 506 laboratory evaluations during rifabutin, grade 3 and grade 4 abnormalities occurred in 16 (3%) and 2 (0.4%) instances, respectively, involving 9 (60%) children. Specifically, grade 3 (n = 4) and grade 4 (n = 1) neutropenia resolved without treatment interruption or clinical sequelae in all patients. One child died at week 4 of HIV-related complications. In children, rifabutin 2.5 mg/kg daily achieved AUC0-24 comparable to adults and favourable HIV and TB treatment outcomes were observed. Severe neutropenia was relatively uncommon and improved with ongoing rifabutin therapy. These data support the use of rifabutin for TB/HIV-coinfected children who require lopinavir/ritonavir.
Sections du résumé
BACKGROUND
Treatment options are limited for TB/HIV-coinfected children who require PI-based ART. Rifabutin is the preferred rifamycin for adults on PIs, but the one study evaluating rifabutin with PIs among children was stopped early due to severe neutropenia.
METHODS
We evaluated rifabutin safety and plasma pharmacokinetics among coinfected children 3-15 years of age receiving rifabutin 2.5 mg/kg daily with standard doses of lopinavir/ritonavir. The AUC0-24 at 2, 4 and 8 weeks after rifabutin initiation was described using intensive sampling and non-compartmental analysis. Clinical and laboratory toxicities were intensively monitored at 12 visits throughout the study.
RESULTS
Among 15 children with median (IQR) age 13.1 (10.9-14.0) years and weight 25.5 (22.3-30.5) kg, the median (IQR) rifabutin AUC0-24 was 5.21 (4.38-6.60) μg·h/mL. Four participants had AUC0-24 below 3.8 μg·h/mL (a target for the population average exposure) at week 2 and all had AUC0-24 higher than 3.8 μg·h/mL at the 4 and 8 week visits. Of 506 laboratory evaluations during rifabutin, grade 3 and grade 4 abnormalities occurred in 16 (3%) and 2 (0.4%) instances, respectively, involving 9 (60%) children. Specifically, grade 3 (n = 4) and grade 4 (n = 1) neutropenia resolved without treatment interruption or clinical sequelae in all patients. One child died at week 4 of HIV-related complications.
CONCLUSIONS
In children, rifabutin 2.5 mg/kg daily achieved AUC0-24 comparable to adults and favourable HIV and TB treatment outcomes were observed. Severe neutropenia was relatively uncommon and improved with ongoing rifabutin therapy. These data support the use of rifabutin for TB/HIV-coinfected children who require lopinavir/ritonavir.
Identifiants
pubmed: 33294914
pii: 6028468
doi: 10.1093/jac/dkaa512
pmc: PMC7879135
doi:
Substances chimiques
Rifabutin
1W306TDA6S
Lopinavir
2494G1JF75
Ritonavir
O3J8G9O825
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
710-717Subventions
Organisme : Wellcome Trust
ID : 206379/Z/17/Z
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : K23 AI125122
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
Références
Am J Ophthalmol. 1998 Jun;125(6):872-3
pubmed: 9645728
J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):566-9
pubmed: 18197120
Lancet HIV. 2019 Nov;6(11):e760-e768
pubmed: 31585836
Lancet HIV. 2018 Dec 6;:
pubmed: 30529029
BMC Pharmacol Toxicol. 2014 Nov 19;15:61
pubmed: 25406657
J Pediatr Pharmacol Ther. 2014 Oct-Dec;19(4):262-76
pubmed: 25762871
J Antimicrob Chemother. 2019 Sep 1;74(9):2707-2715
pubmed: 31139825
Lancet HIV. 2015 Oct;2(10):e438-44
pubmed: 26423651
Clin Infect Dis. 2009 Nov 1;49(9):1305-11
pubmed: 19807276
Pediatr Infect Dis J. 1995 Mar;14(3):246-7
pubmed: 7761197
PLoS One. 2011 Feb 23;6(2):e17273
pubmed: 21383838
N Engl J Med. 2003 Sep 18;349(12):1157-67
pubmed: 13679531
Lancet Infect Dis. 2017 Mar;17(3):285-295
pubmed: 27964822
J Antimicrob Chemother. 2012 Oct;67(10):2470-3
pubmed: 22678727
J Int AIDS Soc. 2017 Mar 30;20(1):21437
pubmed: 28406275
J Antimicrob Chemother. 2015 Feb;70(2):543-9
pubmed: 25281400
Am J Health Syst Pharm. 1999 Feb 15;56(4):333-6
pubmed: 10690216
PLoS One. 2013 Nov 08;8(11):e79603
pubmed: 24282510
PLoS One. 2014 Jan 22;9(1):e84866
pubmed: 24465443
Clin Infect Dis. 2005 May 15;40(10):1481-91
pubmed: 15844071
Antimicrob Agents Chemother. 2004 May;48(5):1553-60
pubmed: 15105105
Int J Tuberc Lung Dis. 2013 Nov;17(11):1389-95
pubmed: 24125439