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Pharmacogenetics-guided Isoniazid Dosing in TB-HIV

NCT05124678 · Status: UNKNOWN · Phase: PHASE2 · Type: INTERVENTIONAL · Enrollment: 40

Last updated 2022-01-25

No results posted yet for this study

Summary

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.

Conditions

Interventions

DRUG

Isoniazid Tablets

High dose of isoniazid

Sponsors & Collaborators

  • Makerere University

    lead OTHER

Principal Investigators

  • Christine Sekaggya-Wiltshire, MBChB, PhD · Infectious Diseases Institute-Kampala

Study Design

Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Model
PARALLEL

Eligibility

Min Age
18 Years
Max Age
90 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2021-12-07
Primary Completion
2022-03-30
Completion
2022-06-30

Countries

  • Uganda

Study Locations

More Related Trials

Entities

Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT05124678 on ClinicalTrials.gov