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Article

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

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Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA
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Faculty of Medicine, Mbarara University of Science and Technology, Mbarara 1410, Uganda
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Department of Microbiology, University of Global Health Equity, Kigali 6955, Rwanda
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Epicentre Mbarara Research Center, Mbarara 1956, Uganda
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Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
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Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
*
Author to whom correspondence should be addressed.
Antibiotics 2021, 10(6), 739; https://doi.org/10.3390/antibiotics10060739
Received: 1 June 2021 / Revised: 12 June 2021 / Accepted: 15 June 2021 / Published: 18 June 2021
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. View Full-Text
Keywords: TB bacteremia; sepsis; meningitis; HIV; pharmacokinetics; population modeling; simulation TB bacteremia; sepsis; meningitis; HIV; pharmacokinetics; population modeling; simulation
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MDPI and ACS Style

Rao, P.S.; Moore, C.C.; Mbonde, A.A.; Nuwagira, E.; Orikiriza, P.; Nyehangane, D.; Al-Shaer, M.H.; Peloquin, C.A.; Gratz, J.; Pholwat, S.; Arinaitwe, R.; Boum, Y.; Mwanga-Amumpaire, J.; Houpt, E.R.; Kagan, L.; Heysell, S.K.; Muzoora, C. Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness. Antibiotics 2021, 10, 739. https://doi.org/10.3390/antibiotics10060739

AMA Style

Rao PS, Moore CC, Mbonde AA, Nuwagira E, Orikiriza P, Nyehangane D, Al-Shaer MH, Peloquin CA, Gratz J, Pholwat S, Arinaitwe R, Boum Y, Mwanga-Amumpaire J, Houpt ER, Kagan L, Heysell SK, Muzoora C. Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness. Antibiotics. 2021; 10(6):739. https://doi.org/10.3390/antibiotics10060739

Chicago/Turabian Style

Rao, Prakruti S., 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, and Conrad Muzoora. 2021. "Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness" Antibiotics 10, no. 6: 739. https://doi.org/10.3390/antibiotics10060739

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