III-01 Noha Abdelgawad

Population Pharmacokinetic Modeling of Linezolid in Plasma and Cerebrospinal Fluid in Adults with Tuberculous Meningitis (LASER-TBM Study)

Noha Abdelgawad (1), Sean Wasserman (2, 3), Mahmoud T. Abdelwahab (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, Observatory 7925, 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: 

Tuberculous  meningitis (TBM) is associated with severe outcome, particularly among people living with HIV where mortality approaches 50% despite antituberculosis therapy [1]. The standard treatment regimen for TBM is based on drugs and doses used in pulmonary TB, which does not account for the ability of drugs to penetrate the blood-brain barrier, possibly resulting in suboptimal drug exposures at the site of action. Linezolid is highly effective in extracranial TB  [2,3] and has good CSF penetration during treatment for Gram-positive meningitis [4], making it an attractive option for TBM. Several randomized controlled trials are evaluating linezolid together with high dose rifampicin as a strategy to improve outcomes [5,6]. However, the optimal dose of linezolid for TBM is unknown, particularly when administered with rifampicin which may increase clearance, and the pharmacokinetics of linezolid are not well characterised in this population. This pharmacokinetic (PK) model aims to describe the plasma and CSF pharmacokinetics of linezolid and investigate the impact of high dose rifampicin on linezolid exposure.

Methods: 

The Phase 2b LASER-TBM trial enrolled adults living with HIV from 4 public hospitals in South Africa to determine safety of intensified antituberculosis therapy and high dose aspirin for TBM. Participants were randomized into one of three treatment groups: arm 1 (control) received the standard TB regimen (R10mg/kgHZE); experimental arms 2 and 3 received additional rifampicin (total oral dose 35 mg/kg/day) plus oral linezolid 1200 mg daily for the first 28 days, reduced to 600 mg daily for the next 28 days, with or without aspirin.

Intensive plasma sampling was done on day 3 after study entry (within 5 days of initiating TB therapy) at pre-dose, and at 0.5, 1, 2, 3, 6, 8-10, and 24 hours and sparse plasma sampling performed on day 28, at pre-dose, 2, and 4 hours after dose. A lumbar CSF sample was obtained on day 3 and another on day 28. The timing of the lumbar puncture was randomized to intervals of 1-3, 3-6, 6-10, and 24 hours post-dose. Only results from the participants in the experimental arms who received linezolid are included in this analysis.

Missing heights were imputed using a multiple regression model based on weight and sex, accounting for residual variability in heights [7] using patient characteristics from a similar study [8]. Linezolid concentrations were measured using LC-MS/MS with a lower limit of quantification of 0.1 mg/L for both plasma and CSF samples. The plasma and CSF data were analyzed with nonlinear mixed-effects modelling in NONMEM® version 7.5 using first-order conditional estimation with eta-epsilon interaction (FOCE-I).

Results: 

Thirty participants received linezolid, providing 237 plasma concentrations and 28 CSF concentrations for the PK analysis. Median (min – max) age and weight were 40 (27 – 56) years and 60 (30 – 96) kg, respectively.

Linezolid plasma PK was described by a one-compartment model with first-order elimination and first-order absorption with transit compartments. The typical values for CL/F & V/F were 5 L/h and 37 L, respectively and were best allometrically scaled by fat-free mass. Between-visit variability in CL/F, between-subject variability in CL/F, and between-occasion variability (BOV) in bioavailability (F) were low, and BOV in absorption rate constant (ka), and mean transit time (MTT) were high.

The effect of duration of rifampicin treatment was tested on CL/F & F, as well as the effects of creatinine clearance and age on CL/F, all of which were not statistically significant.

CSF concentrations were modeled as a separate hypothetical effect compartment. The partitioning of linezolid between the plasma and the CSF compartment was described by a pseudo-partition coefficient (PPC) with a typical value of 29%. The equilibration speed between the central compartment and the effect compartment was described by an equilibration rate constant of 0.198 h-1 (i.e., half-life of 3.5 h).

Conclusions: 

Plasma pharmacokinetics of linezolid are in line with previously published population PK models [8–10] with CSF concentrations comparable to those from other studies [11,12]. Linezolid PPC shows that CSF levels are on average 29% of the plasma levels, supporting ongoing clinical evaluation in efficacy trials for TBM. Despite co-administration of high-dose rifampicin, linezolid levels were in line with previous reports, providing reassurance for combined use.

References:

  1. Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DTT, Thoa NTC, et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis [Internet]. J Infect Dis; 2005 [cited 2022 Apr 4];192:2134–41. Available from: https://pubmed.ncbi.nlm.nih.gov/16288379/
  2. Sotgiu G, Centis R, D’Ambrosio L, Alffenaar JWC, Anger HA, Caminero JA, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J [Internet]. Eur Respir J; 2012 [cited 2022 Apr 4];40:1430–42. Available from: https://pubmed.ncbi.nlm.nih.gov/22496332/
  3. Schecter GF, Scott C, True L, Raftery A, Flood J, Mase S. Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis [Internet]. Clin Infect Dis; 2010 [cited 2022 Apr 4];50:49–55. Available from: https://pubmed.ncbi.nlm.nih.gov/19947856/
  4. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev [Internet]. 2010;23:858–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20930076
  5. Sun F, Ruan Q, Wang J, Chen S, Jin J, Shao L, et al. Linezolid manifests a rapid and dramatic therapeutic effect for patients with life-threatening tuberculous meningitis. Antimicrob Agents Chemother. American Society for Microbiology; 2014;58:6297–301.
  6. Li H, Lu J, Liu J, Zhao Y, Ni X, Zhao S. Linezolid is associated with improved early outcomes of childhood tuberculous meningitis. Pediatr Infect Dis J [Internet]. Lippincott Williams and Wilkins; 2016 [cited 2022 Apr 7];35:607–10. Available from: https://journals.lww.com/pidj/Fulltext/2016/06000/Linezolid_is_Associated_with_Improved_Early.3.aspx
  7. Johansson ÅM, Karlsson MO. Multiple imputation of missing covariates in NONMEM and evaluation of the method’s sensitivity to η-shrinkage. AAPS J. 2013;15:1035–42.
  8. Abdelwahab MT, Wasserman S, Brust JCM, Dheda K, Wiesner L, Gandhi NR, et al. Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis. Antimicrob Agents Chemother. American Society for Microbiology; 2021;65.
  9. Tietjen AK, Kroemer N, Cattaneo D, Baldelli S, Wicha SG. Population pharmacokinetics and target attainment analysis of linezolid in multidrug-resistant tuberculosis patients. Br J Clin Pharmacol. 2021;1–10.
  10. Alghamdi WA, Al-Shaer MH, An G, Alsultan A, Kipiani M, Barbakadze K, et al. Population Pharmacokinetics of Linezolid in Tuberculosis Patients: Dosing Regimen Simulation and Target Attainment Analysis. Antimicrob Agents Chemother [Internet]. 2020;64. Available from: http://doi.wiley.com/10.1177/0091270009337947
  11. Kempker R, Kempker RR, Smith AGC, Avaliani T, Gujabidze M, Bakuradze T, et al. Clinical Infectious Diseases Cerebrospinal Fluid Concentrations of Tuberculosis Drugs • CID 2022:XX (XX XX) • 1 Clinical Infectious Diseases ® 2022;XX(XX):1-8 Cycloserine and Linezolid for Tuberculosis Meningitis: Pharmacokinetic Evidence of Potential Usefulness. Available from: https://doi.org/10.1093/cid/ciab992
  12. Viaggi B, Paolo A Di, Danesi R, Polillo M, Ciofi L, Tacca M Del, et al. Linezolid in the central nervous system: Comparison between cerebrospinal fluid and plasma pharmacokinetics. http://dx.doi.org/103109/003655482011582140 [Internet]. Taylor & Francis; 2011 [cited 2022 Apr 4];43:721–7. Available from: https://www.tandfonline.com/doi/abs/10.3109/00365548.2011.582140

Reference: PAGE 30 (2022) Abstr 10052 [www.page-meeting.org/?abstract=10052]

Poster: Drug/Disease Modelling - Infection

PDF poster / presentation (click to open)