Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis

Noha Abdelgawad; Maxwell Chirehwa; Charlotte Schutz; David Barr; Amy Ward; Saskia Janssen; Rosie Burton; Robert J Wilkinson; Muki Shey; Lubbe Wiesner; Helen McIlleron; Gary Maartens; Graeme Meintjes; Paolo Denti

doi:10.12688/wellcomeopenres.17660.3

Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis

Wellcome Open Res. 2024 Mar 1:7:72. doi: 10.12688/wellcomeopenres.17660.3. eCollection 2022.

Authors

Noha Abdelgawad¹, Maxwell Chirehwa¹, Charlotte Schutz^{2

3}, David Barr⁴, Amy Ward^{2

3}, Saskia Janssen⁵, Rosie Burton^{3

6}, Robert J Wilkinson^{2

3

7

8}, Muki Shey², Lubbe Wiesner¹, Helen McIlleron^{1

2}, Gary Maartens^{1

2}, Graeme Meintjes^{2

3}, Paolo Denti¹

Affiliations

¹ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
² Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South Africa.
³ Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
⁴ Wellcome Trust Liverpool Glasgow Centre for Global Health Research, University of Liverpool, Liverpool, L3 5QA, UK.
⁵ Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, 19268, The Netherlands.
⁶ Khayelitsha Hospital, Department of Medicine, Khayelitsha, 7784, South Africa.
⁷ Department of Infectious Diseases, Imperial College London, London, W12 0NN, UK.
⁸ The Francis Crick Institute, London, NW1 1AT, UK.

Abstract

Background: Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups.

Methods: Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ^® was used to analyze the data.

Results: Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients.

Conclusions: We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.

Keywords: hospitalization; isoniazid; pyrazinamide; rifampicin; tuberculosis.

Abstract

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