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Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness

Authors :
Prakruti S. Rao
Christopher C. Moore
Amir A. Mbonde
Edwin Nuwagira
Patrick Orikiriza
Dan Nyehangane
Mohammad H. Al-Shaer
Charles A. Peloquin
Jean Gratz
Suporn Pholwat
Rinah Arinaitwe
Yap Boum
Juliet Mwanga-Amumpaire
Eric R. Houpt
Leonid Kagan
Scott K. Heysell
Conrad Muzoora
Source :
Antibiotics, Vol 10, Iss 6, p 739 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, with and without meningitis, in Mbarara, Uganda that were starting first-line anti-TB therapy. Serum was collected two weeks after enrollment at 1-, 2-, 4-, and 6-h post-dose and drug concentrations quantified by validated LC-MS/MS methods. Non-compartmental analyses were used to determine total drug exposure, and population pharmacokinetic modeling and simulations were performed to determine optimal dosages. Eighty-one participants were enrolled. Forty-nine completed pharmacokinetic testing: 18 (22%) died prior to testing, 13 (16%) were lost to follow-up and one had incomplete testing. Isoniazid had the lowest serum attainment, with only 4.1% achieving a target exposure over 24 h (AUC0–24) of 52 mg·h/L despite appropriate weight-based dosing. Simulations to reach target AUC0–24 found necessary doses of rifampin of 1800 mg, pyrazinamide of 2500–3000 mg, and for isoniazid 900 mg or higher. Given the high case fatality ratio of TB-related critical illness in this population, an early higher dose anti-TB therapy should be trialed.

Details

Language :
English
ISSN :
20796382
Volume :
10
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Antibiotics
Publication Type :
Academic Journal
Accession number :
edsdoj.404158581a15492f82ccc0a276863989
Document Type :
article
Full Text :
https://doi.org/10.3390/antibiotics10060739