Maxwell T. Chirehwa (1), Helen McIlleron (1), Lubbe Wiesner (1), Dissou Affolabi (2), Oumou Bah Sow (3), Andrzej Bienczak (1), Corinne Merle (4) and Paolo Denti (1) on behalf of RAFATB-net
(1)Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa; (2)National TB programme, Benin; (3)Service de Pneumopthysiologie, Hopital Ignace Deen, Conakry, Guinea; (4)London School of Hygiene & Tropical Medicine (London, UK)
Objective: Isoniazid (INH) metabolism primarily involves acetylation by N-acetyltransferase-2 (NAT2) to AcINH, and the genes encoding NAT2 are highly polymorphic, causing differential expression among populations (1-3). Our objective is to describe pharmacokinetics (PK) of isoniazid (INH) and acetyl-isoniazid (AcINH) among TB/HIV co-infected patients.
Methods: Blood samples were collected from 150 TB/HIV co-infected patients from West Africa just before and at 2, 3, 6, and 10 hours after dose administration, at steady-state. Dosing was weight-adjusted according to WHO guidelines (4). NONMEM 7.3 was used to analyse PK data. Allometric scaling was employed to account for differences in body size.
Results: INH PK was best described by using a two-compartment disposition model and a well-stirred liver model accounting for first-pass metabolism. Hepatic volume of distribution and plasma flow (QH) were fixed to 1 L and 50 L/h and allometrically scaled, while INH unbound fraction was fixed to 95% (5). A mixture model with 2 approximately equal subpopulations was applied to intrinsic CL to describe the effect of NAT2 polymorphisms. Intrinsic CL for fast acetylators was around 5-fold that of slow acetylators, resulting in an EH of 0.39 for fast acetylators and 0.12 for slow. An additional clearance from central compartment was identified and estimated to be 8 L/h. AcINH was the product of the hepatic acetylation and was described using a two-compartment model and CL estimated to be 17 L/h.
Allometric scaling using FFM on all clearance and volume parameters was supported by the data. Between-subject variability was included for ka, and CL and volume of both INH and AcINH. Between-occasion variability was included on pre-hepatic bioavailability.
Conclusions: The proposed model was able to separate acetylation (responsible for formation of AcINH) from other elimination pathways, and it quantified the difference between fast and slow acetylators. The estimated values are consistent with previous literature reports (6,7). Similar to recent population PK models for antituberculosis treatment (3,8-9), FFM was found to be a better descriptor of body size than total weight for allometric scaling. This suggests that body composition should be taken into account when optimising the dosing strategy for antituberculosis drugs.
Funding: This project is funded by The European & Developing Countries Clinical Trials Partnership (EDCTP).
References
[1] Ellard GA, Gammon PT. 1976. Pharmacokinetics of isoniazid metabolism in man. J. Pharmacokinet. Biopharm. 4:83–113.
[2] Parkin DP, Vandenplas S, Botha FJ, Vandenplas ML, Seifart HI, van Helden PD, van der Walt BJ, Donald PR, van Jaarsveld PP. 1997. Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis. Am J Respir Crit Care Med, 1997/05/01 ed. 155:1717–1722.
[3] Denti P, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, Mcilleron H. 2011. Population pharmacokinetics of Isoniazid in South African TB patientsThe 4th international workshop on clinical pharmacology of TB drugs. Chicago, IL.
[4] World Health Organization. 2003. Treatment of tuberculosis: Guidelines for national programmes (3rd edition). WHO/CDS/TB/2003.313. Gevena, Switzerland.
[5] Alffenaar J-WC, Uges DRA, Greijdanus B, Kok WT, Jongedijk EM, Lijke H van der, Sturkenboom MGG. 2015. Quantification of isoniazid, pyrazinamide and ethambutol in serum using liquid chromatography-tandem mass spectrometry. J. Appl. Bioanal. 1:89–98.
[6] Weber WW, Hein DW. 1979. Clinical Pharmacokinetics of Isoniazid. Clin. Pharmacokinet. 4:401–422.
[7] Ramachandran G, Hemanth Kumar AK, Sarala K, Padmapriyadarsini C, Anitha S, Tharani CB, Kumaraswami V, Swaminathan S. 2007. Urine levels of rifampicin & isoniazid in asymptomatic HIV-positive individuals. Indian J. Med. Res. 125:763.
[8] Chirehwa MT, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, McIlleron H, Denti P. 2016. Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction. Antimicrob. Agents Chemother. 60:487–94.
[9] Denti P, Jeremiah K, Chigutsa E, Faurholt-Jepsen D, PrayGod G, Range N, Castel S, Wiesner L, Hagen CM, Christiansen M, Changalucha J, McIlleron H, Friis H, Andersen AB. 2015. Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania. PLoS One 10:e0141002
Reference: PAGE 25 () Abstr 5993 [www.page-meeting.org/?abstract=5993]
Poster: Drug/Disease modeling - Other topics