Bonginkosi Ndzamba1, Prof Paolo Denti2, Prof Helen McIlleron2, Prof Peter Smith2, Dr Thuli Mthiyane3, Dr Roxana Rustomjee4, Dr Philip Onyebujoh5, Dr Eduardo Reséndiz-Galván2
1Rhodes university, Faculty of pharmacy, 2University of cape town,Division of Clinical Pharmacology, Department of Medicine, 3Clinical Operations Quality Management, IQVIA , 4Strategic Health Innovation Partnerships (SHIP), South African Medical Research Council, 5Genetic Immunity Ltd.
Introduction: Ethambutol is used to treat tuberculosis (TB) in individuals living with human immunodeficiency virus (HIV). Low concentrations of ethambutol have been reported in patients dosed with the World Health Organization (WHO)-recommended first-line regimen [1,2]. The suboptimal exposure of ethambutol has been linked to high incidences of treatment failure, adverse drug reactions, and antibiotic resistance, particularly in patients living with HIV [1,3]. However, there are no reports on ethambutol interaction with antiretroviral therapy (ART) that could explain the suboptimal levels in patients with HIV. According to a systematic review conducted by Daskapan et al. [4], there is conflicting evidence on whether the presence of HIV causes pharmacokinetic (PK) variability of the first-line anti-TB drugs. Although some studies have shown no significant impact of HIV [5,6], others have demonstrated a potential influence on bioavailability of anti-TB drugs [1,7,8]. We aimed to characterize the population PK of ethambutol in individuals newly diagnosed and treated for drug-susceptible TB and HIV, investigating available covariates with potential influence. Additionally, using Monte Carlo simulations of different dosing scenarios, we evaluated the achieved exposures across WHO weight bands. Method: We analysed the pharmacokinetics of ethambutol in 61 HIV-positive individuals diagnosed with drug-susceptible TB enrolled in the tuberculosis and highly active antiretroviral therapy (TB-HAART) study. The study participants were enrolled and followed for 28 days, with PK visits on days 0, 7, 14, and 28 after TB treatment initiation. The participants were divided into 6 arms (stratified according to CD4+ T cell count and treatment). Ethambutol was administered within the 4-in-1 fixed-dose combination formulation (FDC) containing 275 mg of ethambutol HCl, 75 mg of isoniazid, 400 mg of pyrazinamide, and 150 mg of rifampicin. Ethambutol doses were 550 mg for participants with a body weight of <37.9 kg, 825 mg for 38–54.9 kg, 1,100 mg for 55–70 kg, and 1,375 mg for weights >70 kg. Participants started on TB treatment and were randomized to early or later introduction of efavirenz-based antiretroviral treatment. We explored potential covariate effects and evaluated the current WHO dosing recommendations for ethambutol in drug-susceptible and multidrug-resistant (MDR)-TB. Results: A two-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption best described the pharmacokinetics of ethambutol. Clearance was estimated to be 40.3 L/h for a typical individual with a fat-free mass (FFM) of 42 kg. The Antib-4 formulation had 26% higher bioavailability and slower mean transit time by 37% compared with Rifafour. Simulations showed that individuals in the lower weight bands (<55 kg) who were administered ethambutol at WHO-recommended doses had relatively low drug exposures. These individuals would need doses of 825 mg if their body weight is <37.9 kg and 1,100 mg if it is between 38 and 54.9 kg to achieve the reference maximum concentrations of 2–6 mg/L and an area under the concentration-time curve (0–24) of 16–29 mg·h/L. To achieve these targets in MDR-TB treatment, a dose increment of 400 mg (extra tablet) would be required for individuals in the lower weight band (<46 kg). Conclusion: Our dose adjustments are consistent with the literature and can be recommended for consideration by the WHO for first-line drug-susceptible and MDR-TB treatment. *Published manuscript based on the same work: Pharmacokinetics of ethambutol and weight banded dosing in South African adults newly diagnosed with tuberculosis and HIV. Bonginkosi Ndzamba, Paolo Denti, Helen McIlleron, Peter Smith, Thuli Mthiyane, Roxana Rustomjee, Philip Onyebujoh, Juan Eduardo Reséndiz-Galván
[1] McIlleron H, Rustomje R, Vahedi M, Mthiyane T, Denti P, Connolly C, et al. Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: Implications for international dosing guidelines. Antimicrob Agents Chemother 2012;56:3232–8. https://doi.org/10.1128/AAC.05526-11. [2] Sekaggya-Wiltshire C, Chirehwa M, Musaazi J, Von Braun A, Buzibye A, Muller D, et al. Low antituberculosis drug concentrations in HIV-tuberculosis-coinfected adults with low body weight: Is it time to update dosing guidelines? Antimicrob Agents Chemother 2019;63. https://doi.org/10.1128/AAC.02174-18. [3] Korenromp EL, Scano F, Williams BG, Dye C, Nunn P. Effects of Human Immunodeficiency Virus Infection on Recurrence of Tuberculosis after Rifampin-Based Treatment: An Analytical Review. Clinical Infectious Diseases 2003;37:101–12. https://doi.org/10.1086/375220. [4] Daskapan A, Idrus LR, Postma MJ, Wilffert B, Kosterink JGW, Stienstra Y, et al. A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs. Clin Pharmacokinet 2019;58:747–66. https://doi.org/10.1007/s40262-018-0716-8. [5] B Taylor, P J Smith. Does AIDS impair the absorption of antituberculosis agents? . Int J Tuberc Lung Dis 1998;2:670–5. [6] Requena-Méndez A, Davies G, Waterhouse D, Ardrey A, Jave O, López-Romero SL, et al. Effects of Dosage, Comorbidities, and Food on Isoniazid Pharmacokinetics in Peruvian Tuberculosis Patients. Antimicrob Agents Chemother 2014;58:7164–70. https://doi.org/10.1128/AAC.03258-14. [7] McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P. Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients. Antimicrob Agents Chemother 2006;50:1170–7. https://doi.org/10.1128/AAC.50.4.1170-1177.2006. [8] Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, et al. Decreased Bioavailability of Rifampin and Other Antituberculosis Drugs in Patients with Advanced Human Immunodeficiency Virus Disease. Antimicrob Agents Chemother 2004;48:4473–5. https://doi.org/10.1128/AAC.48.11.4473-4475.2004.
Reference: PAGE 33 (2025) Abstr 11590 [www.page-meeting.org/?abstract=11590]
Poster: Drug/Disease Modelling - Infection