Pharmacokinetic analysis of pyrazinamide in a South African population with tuberculosis meningitis and HIV
Jose Miguel Calderin Miranda (1), Sean Wasserman (2, 3), Juan Eduardo Resendiz-Galvan (1), Noha Abdelgawad (1), Angharad Davis (2), Cari Stek (2), Lubbe Wiesner (1), Robert J. Wilkinson (2), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. (2) Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa. (3) Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Objectives: Tuberculosis meningitis (TBM) is a devastating manifestation of infection by Mycobacterium tuberculosis and is associated with severe morbidity and high mortality, especially in individuals with HIV [1]. Some TBM patients may die prior to starting treatment or even establishing diagnosis [2]. Pyrazinamide is an antimicrobial agent used in the standard first-line anti-TB treatment regimen, including for TBM. Pyrazinamide achieves excellent brain concentrations in animal models and may have an important role in TBM therapy [3]. Although well-studied in patients with pulmonary TB, pyrazinamide pharmacokinetics (PK) still requires further research in TBM where differences in clinical phenotype and severity may influence drug exposure, and potentially efficacy. In this work, we aimed to describe the population PK of pyrazinamide in South African adults with TBM associated with HIV.
Methods: This PK study was nested in LASER-TBM, a phase 2a, randomized and multicentre clinical trial evaluating the safety of intensified antituberculosis and anti-inflammatory therapy among HIV-positive adults with newly diagnosed TBM in South Africa. Participants were enrolled within 5 days of starting antituberculosis treatment and randomly allocated to one of three treatment groups. Group 1 (control arm) received the standard TB regimen comprising rifampicin (10 mg/kg), isoniazid (5 mg/kg), pyrazinamide (25 mg/kg) and ethambutol (15 mg/kg). Groups 2 and 3 (experimental arms) received the standard TB regimen plus an additional dose of rifampicin (total daily rifampicin dose 35 mg/kg) plus a daily oral linezolid dose of 1200 mg for the first 28 days, then reduced to 600 mg. Participants assigned to group 3 received an additional 1000 mg/day of oral aspirin.
Blood samples were intensively collected at or before day 3 of study enrolment, at pre-dose and 0.5, 1, 2, 3, 6, 8-10, and 24 hours post-dose. Sparse sampling was performed on day 28 at pre-dose, 2, and 4 hours post-dose. Plasma pyrazinamide concentrations were assayed using LC-MS/MS. The lower limit of quantification (LLOQ) was 0.2 mg/L. Between-subject, between-visit and between-occasion variabilities were tested on different PK parameters. Data were analysed with NONMEM (v7.5.0) using the first-order conditional estimation with eta-epsilon interaction method.
Results: A total of 317 plasma concentrations were available from 49 participants during the first PK visit on day 3, and 97 concentrations were available from 34 participants during the second visit on day 28 for the PK analysis. Only 5 (1.2%) observations were below the LLOQ. The study population had median (1st – 3rd quartile) age, weight, and fat-free mass (FFM) of 38 (34 – 45) years, 60 (54 – 74) kg, and 46 (39 – 51) kg, respectively.
The pharmacokinetics of pyrazinamide was best described by a one-compartment disposition model with first-order elimination and first-order absorption with transit compartments. The typical values of clearance and volume of distribution were estimated to be 4.47 L/h and 45.5 L, respectively. Disposition parameters were best allometrically scaled by FFM. Clearance was increased by 37% on day 28 compared with day 3 of study. Between-occasion variability was included on bioavailability, absorption rate constant, and mean transit time. A 1.65-fold change in the variability for absorption parameters was estimated for the dose before the sampling visit and the pre-dose observation, representing the uncertainty of dosing times from the previous day.
Conclusions: We developed a one-compartment disposition model that adequately described pyrazinamide PK. Our estimates are consistent with published PK models using data from pulmonary TB patients [4, 5], suggesting that pyrazinamide PK in TBM patients is similar to pulmonary TB. Higher clearance with treatment duration has been previously described by Chirehwa et al. [5] in pulmonary TB patients. This phenomenon could be related to factors such as drug-drug interactions or recovery of clearance processes with improvement on treatment, but further exploration. More research is needed to investigate pyrazinamide exposure at the site of disease in TBM, and this plasma PK model could be applied to future analyses incorporating site of disease concentrations.
References:
[1] Efsen A, Panteleev A, Grint D, Podlekareva D, Vassilenko A, Rakhmanova A, et al. TB Meningitis in HIV-Positive Patients in Europe and Argentina: Clinical Outcome and Factors Associated with Mortality. Biomed Res Int. 2013; 373601. https://doi.org/10.1155/2013/373601
[2] Imran D, Hill PC, McKnight J, van Crevel R; Tuberculous Meningitis International Research Consortium. Establishing the cascade of care for patients with tuberculous meningitis. Wellcome Open Res. 2019 Nov 13;4:177. doi: 10.12688/wellcomeopenres.15515.2. PMID: 32118119; PMCID: PMC7008603.
[3] Liu L, Xu Y, Shea C, Fowler JS, Hooker JM, Tonge PJ. Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons. J Med Chem. 2010 Apr 8;53(7):2882-91. doi: 10.1021/jm901858n. PMID: 20205479; PMCID: PMC2866172.
[4] Mugabo P, Mulubwa M. Population Pharmacokinetic Modelling of Pyrazinamide and Pyrazinoic Acid in Patients with Multi-Drug Resistant Tuberculosis. Eur J Drug Metab Pharmacokinet. 2019; 44: 519–530. https://doi.org/10.1007/s13318-018-00540-w
[5] Chirehwa MT, McIlleron H, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, Denti P. Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00490-17. doi: 10.1128/AAC.00490-17. PMID: 28607022; PMCID: PMC5527644.