NCT05124678: PHINX

Pharmacogenetics-guided Isoniazid Dosing in TB-HIV

Status unknown Phase 2 Last updated 25 January 2022

What this trial tests

Phase 2 trial testing Isoniazid Tablets in Tuberculosis in 40 participants. Status unknown.

Timeline

7 December 2021

Primary endpoint
30 March 2022

30 June 2022

Quick facts

Lead sponsor	Makerere University
Phase	Phase 2
Status	Status unknown
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	40
Start date	7 December 2021
Primary completion	30 March 2022
Estimated completion	30 June 2022
Sites	1 location across Uganda

Drugs / interventions tested

• Isoniazid Tablets — full drug profile →

Conditions studied

• Tuberculosis — all drugs for Tuberculosis →

Sponsor

Makerere University

Who can join

Adults 18 to 90, any sex, with Tuberculosis. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

The current TB treatment as recommended by World Health Organization (WHO) although capable of achieving 85% cure rates, has limitations, in particular drug interactions, toxicities, and the long treatment duration which increases the possibility of nonadherence.

Sub-therapeutic isoniazid concentrations were demonstrated in several studies, including our previous work, carried out among patients with tuberculosis receiving the standard dose (5mg/kg) of isoniazid. The investigators found 78% of patients with HIV had isoniazid concentrations below the recommended threshold. Malabsorption, drug-drug interactions, poor adherence due to high pill burden may contribute to this. Pharmacogenetic variation may compound these factors; isoniazid displays inter-individual variation in serum concentrations and clearance due to differences in individual acetylator status.

While patients who metabolize isoniazid slowly (slow acetylators) are at a higher risk of high drug concentrations and toxicities, fast acetylators are more likely to have sub-therapeutic isoniazid concentrations.

In other studies, insufficient exposure with isoniazid, one of the cornerstone drugs for TB treatment, has been associated with delayed sputum clearance, development of drug resistance, and treatment failure.

Isoniazid is metabolized by the enzyme N-acetyl transferase, which in turn is controlled by the N-acetyl transferase-2 (NAT-2) gene. Polymorphisms in this gene are responsible for the N-acetylation phenotypes, with the distribution of NAT-2 fast, intermediate, and slow acetylators being highly variable especially among African populations.

Given that NAT2 acetylator status explains most of the variability in INH exposures, knowledge of NAT2 status may be a simpler way to select the right dose for individual patients. The investigators will therefore provide higher doses to fast acetylators and compare the isoniazid pharmacokinetics in these patients to slow acetylators who receive the standard dose, who are more likely to already be achieving target concentrations.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Pharmacogenetics in Tuberculosis-HIV Coinfected Populations: A Systematic Review of Genetic Variants Influencing Antiretroviral and Anti-Tuberculosis Drug Response.
   Hardi H, Fitrianti Z, Mahata LE, Louisa M. · · 2025 · PMID 41216483 · DOI 10.2147/jmdh.s555909