Kamunkhwala Gausi (1); Maxwell Chirehwa (1); Elisa Ignatius (5); Richard Court (1); Xin Sun (2); Laura Moran (6); Richard Hafner (7); Lubbe Wiesner (1); Susan L Rosenkranz (2); Tawanda Gumbo (9); Susan Swindells (8); Andreas Diacon (3); Helen McIlleron (1); Kelly Dooley (5); Paolo Denti (1)
1. Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa.; 2. Harvard T.H. Chan School of Public Health, Boston, MA, USA; 3. Stellenbosch University and Task Applied Science, Cape Town, South Africa.; 4. University of Nebraska Medical Center, Omaha, NE, USA.; 5. Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6. Social & Scientific Systems, a DLH Company, Silver Spring, MD, USA.; 7. Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.; 8. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 9. Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
Objectives: High dose isoniazid has been reported to be effective against tuberculosis with low to moderate isoniazid resistance (1). The shorter-course multidrug-resistant tuberculosis (MDR-TB) regimen endorsed by the World Health Organization includes high-dose isoniazid (2, 3). Still, there is little information on the pharmacokinetics of high-dose isoniazid or drug-drug interactions with the co-administered MDR-TB drugs. This study aims to investigate the pharmacokinetics of standard to high-dose isoniazid in adults with MDR-TB and to assess drug-drug interactions between isoniazid and concomitant drugs within the MDR-TB regimen.
Methods: We combined data from two studies conducted in South Africa: INHindsight (4) and PODRtb (5), with participants on standard to high isoniazid doses (5-15 mg/kg). INHindsight was a 7-day early bactericidal activity (EBA) study with isoniazid monotherapy, while in PODRtb isoniazid was co-administered with MDR-TB drugs. PK samples in INHindsight were captured on day 6 after start of treatment. In PODRtb study, pharmacokinetics was evaluated ≥2 weeks after initiation of treatment. A subset of participants had a second pharmacokinetic visit 1-3 weeks later, in which the tablets were crushed and mixed with water before administration. To describe the PK of isoniazid, one- and two-compartment models were tested with first-order absorption (with or without lag time or a chain of transit compartments) and first-order elimination. Since isoniazid is mainly hepatically cleared, we tested a well-stirred liver model to capture the effect of first-pass metabolism as described by Gordi et al. (6). We tested saturation of hepatic extraction (Eh) using a Michaelis-Menten parameterization. Concentrations below the limit of quantification (BLQ) were imputed as half of the lower limit of quantification (LLOQ) (7) and their additive error was inflated by 50% of the LLOQ.
Results: Data of 58 and 103 participants from INHindsight and PODRtb, respectively, were analyzed. NAT2 genotype was determined in 93% of INHindsights participants, while no genotype information was available for participants from PODRtb. A mixture model was used to allocate participants with missing genotype into three subpopulations: rapid, intermediate, and slow NAT2 acetylators with proportions fixed to the values observed amongst the patients with available genetic information, as recommended by Keizer et al. (8).
The pharmacokinetics of isoniazid was well described using a two-compartment disposition model with first-order absorption through a chain of transit compartments and first-order elimination implemented using a well-stirred liver model with saturation of hepatic extraction (6). The well-stirred liver model required the following assumption: isoniazid protein binding of 5%, and for a 70kg male, a fixed hepatic blood flow of 90L/h, and a fixed liver volume of 1L. Allometric scaling based on fat-free mass was applied on all clearance and volume parameters, including hepatic blood flow and volume. As expected, NAT2 genotype effect on oral clearance was significant. The model predicted a typical individual with fat-free mass of 44kg to have clearance of 11.9, 28.1, and 49.1L/h for slow, intermediate, and rapid acetylators, respectively. Saturation of first-pass was parameterized using the Michealis-Menten model and had a Km of 19.5 (14.2 – 34.5)mg/L. PODRtb participants, who were co-administered MDR-TB drugs (including terizidone, pyrazinamide, moxifloxacin, ethionamide, ethambutol and kanamycin), had distinctively reduced exposures, with a 65.5% lower prehepatic bioavailability compared to INHindsight study participants. Finally, ethionamide co-administration led to a 29% decrease in isoniazid clearance.
Conclusions: We have developed a PK model of isoniazid characterizing saturation of drug metabolism when a high dose of isoniazid is administered. The effect of this dose-exposure nonlinearity should be taken into account when identifying safe and effective high isoniazid doses for patients with MDR-TB. Importantly, we report markedly reduced isoniazid concentrations in participants on concomitant MDR-TB treatment. The reason for this is unclear, but it could be due to a drug-drug interaction with one of the MDR-TB agents, possibly in absorption. Given the large size of this effect and its potential effect on treatment outcome, this finding needs further confirmation in other studies and further investigation.
References:
[1] Lempens P, Meehan CJ, Vandelannoote K, Fissette K, de Rijk P, Van Deun A, Rigouts L, de Jong BC. Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations. Sci Rep 2018;8:3246.
[2] World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment.
[3] World Health Organization. Frequently asked questions about the implementation of the new WHO recommendation on the use of the shorter MDR-TB regimen under programmatic conditions. 2016. at <https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/FAQshorter_MDR_regimen.pdf>.
[4] Dooley KE, Miyahara S, von Groote-Bidlingmaier F, Sun X, Hafner R, Rosenkranz SL, Ignatius EH, Nuermberger EL, Moran L, Donahue K, Swindells S, Vanker N, Diacon AH. Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial. Am J Respir Crit Care Med 2020;doi:10.1164/rccm.201910-1960oc.
[5] Court R, Chirehwa MT, Wiesner L, de Vries N, Harding J, Gumbo T, Maartens G, McIlleron H. Effect of tablet crushing on drug exposure in the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2019;23:1068–1074.
[6] Gordi T, Xie R, Huong N V., Huong DX, Karlsson MO, Ashton M. A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction. Br J Clin Pharmacol 2005;59:189–198.
[7] Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 2001;28:481–504.
[8] Keizer RJ, Zandvliet AS, Beijnen JH, Schellens JHM, Huitema ADR. Performance of Methods for Handling Missing Categorical Covariate Data in Population Pharmacokinetic Analyses. AAPS J 2012;14:601–611
Reference: PAGE 29 (2021) Abstr 9821 [www.page-meeting.org/?abstract=9821]
Poster: Drug/Disease Modelling - Infection