Jesper Sundell(1), Emile Bienvenu(2), Sofia Birgersson(1), Angela Äbelö(1) and Michael Ashton(1)
(1) Unit for Pharmacokinetics and Drug Metabolism, Dept. Pharmacology, Sahlgrenska Academy at University of Gothenburg, Sweden (2) Department of Pharmacy, School of Medicine and Pharmacy, University of Rwanda, Rwanda
Objectives: Tuberculosis (TB) is the most common cause of death in HIV-infected individuals. Isoniazid in combination with rifampicin, pyrazinamide and ethambutol is used as first-line treatment to combat TB infection. Isoniazid primarily undergoes metabolic elimination resulting in formation of acetyl-isoniazid via polymorphic N-acetyltransferase 2 and isonicotinic acid via amidase metabolism of parent drug (1). Isoniazid-induced hepatotoxicity has been proposed to be a consequence of exposure to toxic metabolites (2, 3). Moreover, low exposure to isoniazid may result in treatment failure and resistance development. Hence, determination of clinical factors affecting the pharmacokinetics of isoniazid and its metabolites will benefit clinical outcome. We therefore aimed to investigate factors which influence the variability of isoniazid and its two major metabolites in patients co-infected with TB and HIV.
Methods: Concentration-time profiles with observations up to eight hours post dose were analysed using non-linear mixed effects modeling. Study participants were either on concomitant efavirenz-based antiretroviral therapy or HIV treatment naïve. Acetylator status was determined using a molar ratio of AUC(acetyl-isoniazid, 0-8h)/AUC(isoniazid, 0-8h) with a cut off value of 0.9 (4). Isoniazid was assumed to be eliminated via either two or three pathways where two parallel pathways were responsible for the formation of acetyl-isoniazid and isonicotinic acid. Acetyl-isoniazid was assumed to be eliminated via two pathways where one resulted in the formation of isonicotinic acid.
Results: A total of 1247 observations of isoniazid, acetyl-isoniazid and isonicotinic acid from 63 TB/HIV co-infected patients were used for the present analysis. Isoniazid pharmacokinetics were most adequately described by a two-compartment disposition model with three elimination pathways. Acetyl-isoniazid and isonicotinic acid observations were fitted by one-compartment disposition models, respectively. Isoniazid clearance and fraction of isoniazid metabolized to acetyl-isoniazid were 2.5-fold higher in rapid acetylators compared to slow acetylators. Simultaneous treatment for HIV significantly increased acetyl-isoniazid and isonicotinic acid clearances by 56% and 77%, respectively. Relative bioavailability was 36% higher in females compared to males. Furthermore, isoniazid bioavailability was affected by CD4 cell count.
AUC0-8h for isoniazid, acetyl-isoniazid and isonicotinic acid was analysed stratified by acetylator status and study arm. Median AUC0-8h was 44% higher in HIV treatment naïve rapid acetylators compared to rapid acetylators on concomitant HIV therapy. No exposure difference was found between slow acetylators on concomitant HIV treatment or HIV treatment naïve. In the present cohort, 21% had isoniazid exposures below the recommended threshold. Among the rapid acetylators 6/10 were undertreated, out of which 3/3 rapid acetylators on concomitant efavirenz-based antiretroviral therapy had low exposures.
Conclusions: The pharmacokinetics of isoniazid were affected by acetylator status, HIV treatment, CD4 cell count and sex in the present cohort. Furthermore, the clearances of isoniazids two major metabolites were higher in patients on concomitant efavirenz-based antiretroviral therapy. Rapid acetylators on simultaneous HIV treatment had an increase in isoniazid clearance resulting in exposures below the recommended threshold. A dose regimen based on NAT2 genotype and concomitant HIV treatment should be investigated.
References:
[1] Wang P, Pradhan K, Zhong XB, Ma X. Isoniazid metabolism and hepatotoxicity. Acta pharmaceutica Sinica B. 2016;6(5):384-92.
[2] Woo J, Chan CH, Walubo A, Chan KK. Hydrazine–a possible cause of isoniazid–induced hepatic necrosis. Journal of medicine. 1992;23(1):51-9.
[3]Woodward KN, Timbrell JA. Acetylhydrazine hepatotoxicity: the role of covalent binding. Toxicology. 1984;30(1):65-74.
[4]Hee KH, Seo JJ, Lee LS. Development and validation of liquid chromatography tandem mass spectrometry method for simultaneous quantification of first line tuberculosis drugs and metabolites in human plasma and its application in clinical study. Journal of pharmaceutical and biomedical analysis. 2015;102:253-60.
Reference: PAGE 28 (2019) Abstr 8826 [www.page-meeting.org/?abstract=8826]
Poster: Drug/Disease Modelling - Infection