Noha Abdelgawad (1), Maxwell Chirehwa (1), Charlotte Schutz (2,3), David Barr (4), Amy Ward (2,3), Saskia Janssen (5), Rosie Burton (3,6), Robert J Wilkinson (2,3,7,8), Muki Shey (2), Lubbe Wiesner (1), Helen McIlleron (1,2), Gary Maartens (1,2), Graeme Meintjes (2,3), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa (2) Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa (3) Department of Medicine, University of Cape Town, Observatory, South Africa (4) Wellcome Trust Liverpool Glasgow Centre for Global Health Research, University of Liverpool, Liverpool, United Kingdom (5) Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands (6) Khayelitsha Hospital, Department of Medicine, Cape Town, South Africa (7) Department of Infectious Diseases, Imperial College, London, W2 1PG, United Kingdom (8) The Francis Crick Institute, London, NW1 1AT, United Kingdom
Objectives: Hospitalised tuberculosis (TB) patients co-infected with human immunodeficiency virus (HIV) have high early mortality, more than 50% of deaths occur within 2 weeks and many patients present with a clinical syndrome compatible with sepsis (1). We developed a population pharmacokinetic (PK) model of pyrazinamide in hospitalised HIV-TB patients and TB & HIV-TB out-patients to investigate the differences in pyrazinamide’s pharmacokinetics between hospitalised and outpatients.
Methods: Hospitalised TB patients co-infected with HIV and a control cohort of TB outpatients with and without HIV were recruited at Khayelitsha Hospital in South Africa and at a clinic in the same area as part of an observational cohort study investigating factors associated with mortality in hospitalised HIV-TB patients (2). Patients received weight-adjusted daily doses of rifampicin (10 mg/kg), isoniazid (5 mg/kg), pyrazinamide (25 mg/kg) with ethambutol (15 mg/kg). PK sampling was performed on the 3rd day of treatment and blood samples were collected pre-dose and at 1, 2.5, 4, 6, and 8 hours post-dose. Plasma pyrazinamide was quantified using HPLC-MS/MS with a lower limit of quantification (LLOQ) of 0.203 mg/L. Data were analysed using non-linear mixed effects modelling in NONMEM v.7.4.4 with FOCE-I. The effect of physiologically plausible covariates such as lactate (a sepsis marker), HIV status, and drug formulation was assessed. Model evaluation was performed using visual predictive checks, and diagnostic plots, in addition to the OFV.
Results: 60 hospitalised patients and 48 outpatients, contributed 108 PK profiles with a total of 633 observations, were analysed. Median (range) weight, fat-free mass (FFM), and age were 56 (35-88) kg, 43.2 (26.4-64.2) kg, and 37 (19-77) years, respectively. Pyrazinamide PK was described by a one-compartment model with first-order absorption (Ka = 1.93 h-1, t1/2 = 0.359 h) and first-order elimination. A delay in absorption was described by a transit-compartment model with a mean transit time (MTT) of 0.30 hour. The typical values of CL/F and V/F, which were best allometrically scaled with FFM, were 2.6 L/h and 36.1 L, respectively. No significant differences were found in clearance, bioavailability or absorption between the hospitalised and outpatients, and between hospitalised patients who survived and those who later died after PK sampling but within the first 12 weeks of treatment initiation. However, the between-subject variability in CL/F was significantly higher among hospitalised patients (20% for outpatients vs. 33% for hospitalised patients who survived vs. 71% for hospitalised patients who died). The effect of other covariates including HIV status, CD4 count, lactate, albumin, creatinine, urea, and drug formulation was not detected by the model.
Conclusions: Overall, pyrazinamide exposure was similar among both hospitalised patients & outpatients. Comparing hospitalised patients who survived to those who died within 12 weeks, did not reveal any difference in pyrazinamide exposure. The only difference detected was in the greater between-subject variability in clearance between the hospitalised and outpatients.
References:
[1] Kyeyune R, den Boon S, Cattamanchi A, et al. Causes of early mortality in HIV- infected TB suspects in an East African referral hospital. J Acquir Immune Defic Syndr (2010)
[2] Schutz, C. et al. Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus associated tuberculosis. Br. J. Clin. Pharmacol. (2020)
Reference: PAGE () Abstr 9500 [www.page-meeting.org/?abstract=9500]
Poster: Drug/Disease Modelling - Infection