Population pharmacokinetics of levofloxacin in South African adults treated for rifampicin-resistant tuberculosis.
Sharon Sawe (1), Kamunkhwala Gausi (1), Richard Court (1), Tasnim Badat (2), Asanda Poswa (2), Leilani Novem (2), Tamsin Economou (2), Gary Maartens (1), Francesca Conradie (2), Paolo Denti (1).
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, (2) Department of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.
Objectives: Rifampicin-resistant TB (RR-TB) is a global public health concern. Incident cases increased globally by 3% from 2020 to 2021 [1]. Levofloxacin is a group A drug recommended by the World Health Organization (WHO) for priority inclusion in RR-TB regimens [2]. Levofloxacin is mainly excreted unchanged in urine, has half-life ranging approximately between 6-8 hours with limited metabolism, and is bound to serum albumin [3]. There is limited knowledge of the pharmacokinetics (PK) of levofloxacin in RR-TB patients. We aimed to characterize the pharmacokinetics of levofloxacin in South African patients with RR-TB.
Methods: BEAT-TB is an open-label, randomized controlled trial aiming to establish the efficacy and safety of 6 months of bedaquiline, delamanid, linezolid, levofloxacin, and clofazimine compared to the current 9-12 months South African standard of care for the treatment of RR-TB [4]. Levofloxacin was administered once daily at 500, 750, or 1000 mg, based on body weight. Blood samples were drawn pre-dose, and at 2, 4, 6, 8, 10, and 24 post-dose. Levofloxacin concentrations were assayed using HPLC-MS/MS with a lower limit of quantification (LLOQ) of 0.0781 mg/L. Levofloxacin concentrations were analysed using non-linear mixed-effects modelling in NONMEM 7.5.1. One- and two-compartment disposition models with first-order elimination and absorption with or without lag or with transit absorption compartments were tested. Model variability was quantified testing between-subject variability (BSV) on disposition parameters and between-occasion variability (BOV) on absorption parameters. A combined proportional and additive error was used to describe the residual error model. Observations below the limit of quantification (BLQ) were imputed to half of the LLOQ (0.03905 mg/L) [5], and their additive error component was inflated by 50% of LLOQ. Allometric scaling of clearance (with a fixed exponent of 0.75) and volume of distribution (with a fixed exponent of 1) parameters scaled by either weight or fat-free mass (FFM) was investigated [6]. We also explored the effect of renal function and HIV status on clearance. We calculated the creatinine clearance using the Cockcroft-Gault formula [7].
Results: PK samples were available for 16 participants, contributing 112 concentrations of which 6.25% were BLQ. The median (IQR) age, weight, FFM, and creatinine clearance were 36 (30 - 42) years, 51 (43 - 57) kg, 41 (34 – 46) kg, and 89 (71 - 115) mL/min respectively. 6 (43%) and 8 (57%) participants were dosed with 750 mg and 1000 mg of levofloxacin respectively, 6 (43%) were male, and 8 (57%) were living with HIV, all of whom were treated with dolutegravir based antiretroviral therapy.
A one-compartment disposition model with first-order elimination and absorption with lag-time best described the data. Allometric scaling of disposition parameters using FFM significantly improved the model fit in comparison to using total body weight (∆OFV = -37.4). BSVCL decreased from 16.1% to 14.6%. The typical value of clearance and central volume of distribution was 5.8 L/h and 85.5 L respectively. The effect of HIV status and renal function on clearance did not significantly improve the model.
Conclusions: A one-compartment model with first-order absorption and elimination best described the data. The findings are consistent with previous studies on the pharmacokinetics of levofloxacin in TB patients [8], [9]. As for other anti-tubercular drugs, fat-free mass is a better body size descriptor for disposition parameters than total body weight.
References:
[1] WHO, “Global Tuberculosis Report 2022,” 2022. Accessed: Mar. 06, 2023. [Online]. Available: http://apps.who.int/bookorders.
[2] WHO, “WHO consolidated guidelines on tuberculosis Module 4: Treatment Drug-resistant tuberculosis treatment 2022 update,” 2022. Accessed: Mar. 17, 2023. [Online]. Available: https://www.who.int/publications/i/item/9789240063129
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[4] Conradie Francesca, “Building Evidence for Advancing New Treatment for Rifampicin Resistant Tuberculosis (RR-TB) Comparing a Short Course of Treatment (Containing Bedaquiline, Delamanid and Linezolid) With the Current South African Standard of Care - Full Text View - ClinicalTrials.gov,” 2019. https://clinicaltrials.gov/ct2/show/NCT04062201 (accessed Mar. 17, 2023).
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