The MMC Pharmacogenetics team is involved in a collaborative project aiming at evaluation of possible benefit of isoniazid dose adjustment according to the genotype for NAT2 (arylamine N-acetyltransferase type 2) in patients with pulmonary tuberculosis project lead by Prof. Uwe Fuhr, Dept. of Pharmacology, Clinical Pharmacology Unit, University Hospital, University of Cologne, Germany. In most cases, tuberculosis can be cured by a 24 weeks multidrug therapy including isoniazid. Isoniazid is metabolized by the enzyme N-acetyltransferase type 2 (NAT2). Genetic variants of NAT2 cause a 3-fold difference in activity and resulting isoniazid concentrations between patients with two high activity alleles (rapid acetylators, RA) and those with two low activity alleles (slow acetylators, SA). Preliminary evidence suggests that tolerability and efficacy of isoniazid depends on NAT2 genotype. In this double-blind, multicentre, parallel group, randomised controlled phase IV trial, we plan to test whether a dose individualization based on NAT2 genotype may improve the risk/benefit ratio of isoniazid by reducing variation in drug concentrations. The results would be the basis for an implementation of NAT2 genotyping in clinical practice.
Members of the Pharmacogenetics team: