Juan Eduardo Resendiz-Galvan (1), Mahmoud Tareq Abdelwahab (1), Prerna R. Arora (2), Zarir F. Udwadia (2), Camilla Rodrigues (2), Amita Gupta (3), Tester F. Ashavaid (2), Jeffrey A. Tornheim (3), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. (2) Research Laboratories, P.D. Hinduja National Hospital and Medical Research Centre, Mumbai, India. (3) Center for Clinical Global Health Education, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Introduction: Moxifloxacin (MFX) is an 8-methoxy quinolone metabolized in the liver through sulfate and glucuronide conjugation by uridine diphosphate- glucuronosyltransferases [1]. MFX is one of the drugs from group A recommended by the World Health Organization (WHO) to be included in the regimen to treat multi-drug resistance tuberculosis. Multidrug-resistant tuberculosis incidence is increasing worldwide, and India is the country with the highest absolute burden of MDR-TB with 27% [2]. It has been reported that differences in MFX clearance can be related to ethnicities [3], probably to the frequency and effect of glucuronosyltransferases alleles [1,4]. This highlights the necessity to describe the pharmacokinetics of MFX in different populations.
Objectives:
- Describe the pharmacokinetics of MFX in an Indian population with multidrug-resistant tuberculosis.
- Simulate dosing regimens according to different scenarios.
Methods: We recruited patients with multidrug-resistant tuberculosis from the Hinduja Hospital, Mumbai, India. The patients were treated with one of the following regimens 400, 600, or 800 mg daily based on empirical treatment or drug susceptibility test. Blood samples were drawn at pre-dose, 1, 2, 4, 6, and 8 h post-dose during the first or second month after treatment initiation. MFX was quantified using liquid chromatography tandem mass spectrometry with a calibration range of 0.125-16.4 mg/L.
The pharmacokinetic analysis was performed in NONMEM 7.5 and FOCE-I. Different structural models (one- and two-compartments) were tested to describe the pharmacokinetics of MFX. Between-subject variability was tested on disposition parameter and between-occasion variability on all absorption parameters. Monte-Carlo simulations were performed using the final model to estimate the probability of target attainment according to the ƒAUC0 –24/MIC ratio target of 53 for Mycobacterium tuberculosis [5]. Different scenarios were simulated using weight bands suggested by WHO vs. MFX flat dosing (standard regimen) [6]. The simulations included the MICs from the original distribution in the population (0.06 – 16 mg/L).
Results: A total of 234 concentrations were available from 39 patients (24 females and 15 males), with median weight, fat-free mass (based on weight, height, and sex [7]), and age of 56 (range 35–103) kg, 40 (26–73) kg, and 28 (17–46) years, respectively. Only two patients with HIV were included in the analysis and therefore this covariate was not tested. The pharmacokinetics of MFX was best described by a two-compartment model with first-order elimination and transit compartment absorption. The allometry was implemented using fat-free mass. The typical values for clearance, intercompartmental clearance, central and peripheral volume were 10.9 L/h, 4.84 L/h, 92.7 L, and 48.3L, respectively. During the covariate exploration, it was observed an influence of para-aminosalicylic acid on MFX clearance, however, this should be studied further to determine if there is a significant correlation between these two drugs.
The simulations of 10,000 individuals showing that MFX flat-dose of 400 mg daily is enough to achieve an adequate ƒAUC0 –24/MIC ratio >53 with a probability of target attainment >90% only when MIC is ≤0.25 mg/L regardless the weight of the simulated patients. A dose of 600 mg daily is enough to get a ƒAUC0 – 24/MIC ratio >53 in >90% of the simulated individuals when the weight is <36 kg and if MIC is ≤0.5 mg/L. However, a dose of 800 mg daily will be necessary to achieve a ƒAUC0 – 24/MIC ratio >53 with probability of target attainment >90% if weight is higher than 36 kg and the MIC is ≤0.5 mg/L. For MIC ≥1 mg/L the MFX dose should be higher.
Conclusion: The pharmacokinetics of linezolid in Indian patients was described by a two-compartment model, and this is in accordance with the clearance (10.6 L/h) reported for South African and Zimbabwean patients [8]. However, the clearance in our population is higher than the one reported from a one compartment model in Korean patients (8.05 L/h) [9]. The dosing regimen for MFX of 400 mg once daily could be suboptimal to reach therapeutic concentrations in Indian patients with multidrug-resistance tuberculosis. Therefore, higher doses of 600 or 800 mg daily should be considered to achieve the target for ƒAUC0 –24/MIC ratio based on weight and MICs; however, safety and tolerability should be monitored.
References:
[1] Naidoo Anushka et. al. (2017). A review of moxifloxacin for the treatment of drug-susceptible tuberculosis
[2] World Health Organization (WHO). 2020. Global tuberculosis report.
[3] Xu Feng-Yan et al. (2017). Population pharmacokinetics of moxifloxacin and its concentration–QT interval relationship modeling in Chinese healthy volunteers.
[4] Naidoo Anushka et. al. (2017). Effect of genetic variation in UGT1A and ABCB1 on moxifloxacin pharmacokinetics in South African patients with tuberculosis.
[5] Gumbo T. et al. (2004). Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling.
[6] World Health Organization (WHO). 2020. WHO Operational handbook on tuberculosis. Module 4: Treatment. Drug-resistance tuberculosis treatment.
[7] Anderson Brian J et al. (2017). What is the best size predictor for dose in the obese child?
[8] P. Zvada Simbarashe et al. (2014). Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients.
[9] Chang M. et al. (2017). Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis.
Reference: PAGE 30 (2022) Abstr 10229 [www.page-meeting.org/?abstract=10229]
Poster: Drug/Disease Modelling - Infection