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Rifampicin and isoniazid dosage adjustment according to TDM and acetylator status: a single centre prospective observational study

M Schiuma(1) A Torre(2) A Civati(1) A Jacobs(3) A Giacomelli(1,2) S Antinori(1,2)

1:Department of Biomedical & Clinical Sciences "Luigi Sacco", Università degli Studi di Milano, Italy.; 2:III Infectious Diseases Unit, ASST Fatebenefratelli Sacco, Milano, Italy.; 3:University of Cape Town, Cape Town, South Africa

Individualized dosing of rifampicin and isoniazid may improve treatment outcomes. We describe how rifampicin therapeutic drug monitoring (TDM) and N-acetyltransferase 2 (NAT2) assessment could affect drug dosage in patients with tuberculosis (TB) disease/infection.

A prospective observational study enrolling consecutive subjects managed at Sacco Hospital (Italy) for TB disease/infection (July 2020-April 2023) was performed. Rifampicin TDM levels (range 8-24 mg/L) were systematically determined (mass spectrometry) within two weeks from enrollment at 2, 4 and 6 hours after intake. A reference area under the curve (AUC) of 67.5 mg*h/L was assumed. NAT2 acetylator status was determined (RT-PCR) at enrollment and defined as slow, intermediate or rapid.

100 rifampicin TDM and 120 acetylator statuses were determined in 129 subjects. 51.9% (n=67) were males, median age 49 (IQR 37-63), 79% (n=102) had TB disease. Median rifampicin dose administered was 9.93 mg/kg (IQR 9.02-11.15). Median AUC was 57.73 mg*h/L (IQR 42.58-82.98). In 70% (n=70) of cases rifampicin concentration was > 8 mg/L, in 40% (n=40) the AUC was > 67.5 mg*h/L. Rifampicin dosage was modified in 42% (n=42) cases: increased in 92.9% (n=39), reduced in 7.1% (n=3).
10 patients were rapid, 65 intermediate, 45 slow acetylators. Isoniazid dosage was modified in 21.7% (n=26) cases: increased to 7.5 mg/kg in 90% of rapid acetylators (n=9), reduced to 2.5 mg/kg in slow acetylators with hepatotoxicity (26.1%, n=17).

Rifampicin TDM and/or genotyping led to modification of drug dosage in 47.3% (n=61) cases. TDM and pharmacogenetics could guide TB treatment individualization. Further studies are required to determine its effect on hard clinical outcomes.

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