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: Rifampicin and isoniazid are the backbone of the current first-line antitubercular therapy. Isoniazid is primarily eliminated by formation of acetyl-isoniazid via polymorphic N-acetyltransferase 2 and formation of isonicotinic acid via amidases. The amidase pathway also result in formation of hydrazine which has been suggested to be involved in isoniazid-induced hepatotoxicity (1). An early study on rifampicin/isoniazid co-administration suggested induction of the amidase pathway resulting in increased exposure to isonicotinic acid (2).
The present study aimed to describe a potential induction of isoniazid clearance by rifampicin in patients co-infected with tuberculosis and HIV and to quantify the effect on exposure to isoniazid and isonicotinic acid.
Methods: Plasma concentrations of isoniazid, acetyl-isoniazid and isonicotinic acid following first dose and at steady state from patients undergoing standard first-line antitubercular therapy were quantified by LC-MS/MS. Patients already receiving HIV therapy at initiation of tuberculosis therapy were excluded in this analysis. Data was analysed by non-linear mixed effects modelling. Isoniazid elimination was assumed to either result in the formation of acetyl-isoniazid or isonicotinic acid. Included patients had been genotyped for determination of acetylator status (3).
Results: Plasma concentration – time data from a total of 40 patients following first dose, out of which 28 patients also had plasma concentrations measured at steady state, were included in the present study. Isoniazid disposition was described by a two-compartment model and the dispositions of both metabolites were described by one-compartment models. Allometric scaling by total body weight was applied to all clearance and volume parameters by a power of 0.75 and 1, respectively. The clearance resulting in the formation of acetyl-isoniazid was 5.7-fold and 2.5-fold higher in rapid and intermediate acetylators, respectively, compared to slow acetylators. The isoniazid to isonicotinic acid clearance pathway was described by a maturation factor model with a maximal induction estimated at 2.6-fold higher compared to steady state. Further, the maximal induction linearly increased with higher total dose of rifampicin. Simulations indicated a 30% decrease in isoniazid area under the plasma concentration – time curve from first dose to steady state for an individual with intermediate acetylator status receiving 450 mg doses of rifampicin.
Conclusions: In addition to acetylator status, amidase induction by rifampicin is a significant effector of isoniazid exposure in patients treated for active tuberculosis. Our results further suggest an increased induction when higher doses of rifampicin are administered. The described drug-drug interaction may be of limited clinical relevance with regard to clinical outcome. However, lower exposure may promote resistance development to isoniazid and alter the risk of hepatotoxicity due to an increased formation of toxic metabolites. Evaluation of such risk should therefore be considered with regard to the current proposal of using higher doses of rifampicin.
References:
[1] 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.
[2] Sarma GR, Immanuel C, Kailasam S, Narayana AS, Venkatesan P. Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin. The American review of respiratory disease. 1986;133(6):1072-5.
[3] Sundell J, Bienvenu E, Janzén D, Birgersson S, Äbelö A, Ashton M. Model-Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co-Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy. Clinical pharmacology and therapeutics. 2020;108(1):73-80.
Reference: PAGE 29 (2021) Abstr 9777 [www.page-meeting.org/?abstract=9777]
Poster: Drug/Disease Modelling - Infection