Clinical predictors of 3-month isoniazid rifapentine (3HP)-related adverse drug reactions (ADR) during tuberculosis preventive therapy (PAnDoRA-3HP study): an observational study protocol.

Publication date: Dec 31, 2024

Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for TB preventive therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings. This is an observational cohort study with a nested case-control study. We enrolled consecutive patients who had been initiated on TPT using the 3HP regimen. These are followed up biweekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2, AADAC and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes. The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. χ tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modelling will establish population parameters and factors influencing rifapentine and isoniazid concentrations. Ethical approval of this study inclusive of all the appropriate documents was obtained from the Infectious Diseases Institute Research and Ethics Committee and the Uganda National Council of Science and Technology. The study adheres to legal, ethical and Good Clinical Practice (GCP) guidelines. Deidentified genotype data from 300 patients will be shared after publication. The protocol and phenotype data will be publicly accessible. Abstracts will be submitted to conferences, and a manuscript will be published poststudy.

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Concepts Keywords
3hp Adult
Monthly Adverse events
Pharmacogenomics Antitubercular Agents
Tuberculosis Antitubercular Agents
Uganda Arylamine N-Acetyltransferase
Arylamine N-Acetyltransferase
Case-Control Studies
Female
Humans
Isoniazid
Isoniazid
Male
NAT2 protein, human
Pharmacology
PREVENTIVE MEDICINE
Rifampin
Rifampin
rifapentine
Tuberculosis
Tuberculosis

Semantics

Type Source Name
drug DRUGBANK Isoniazid
drug DRUGBANK Rifapentine
disease MESH adverse drug reactions
disease MESH tuberculosis
pathway KEGG Tuberculosis
disease MESH cause of death
disease MESH Infectious Diseases
disease MESH death
disease MESH latent infection
drug DRUGBANK Coenzyme M
drug DRUGBANK Rifampicin
drug DRUGBANK Uridine
drug DRUGBANK Aspartame
disease IDO facility
disease IDO history
drug DRUGBANK Trestolone
disease MESH substance abuse
disease IDO blood
drug DRUGBANK Dolutegravir
disease MESH drug interactions
disease MESH AIDS
disease IDO assay
disease MESH Leprosy
disease MESH Allergy
disease MESH Latent Tuberculosis Infection
disease IDO immunodeficiency
drug DRUGBANK Carboxyamidotriazole
drug DRUGBANK Vorinostat
pathway REACTOME Metabolism
disease IDO algorithm

Original Article

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