Clinical trial NCT03800381: Adequacy of the New Pediatric Isoniazid/Rifampin/Pyrazinamide (HRZ) Tablet
Official title: Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tuberculosis
Human Immunodeficiency Virus
Coinfection
Keywords: Pharmacokinetic
Pharmacogenomic
Antituberculosis drugs
Children
Tuberculosis
TB/HIV coinfection
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2019-01-11
Enrollment: 92
Sex: ALL
Minimum age (years): 3
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children aged 3 months to14 years with active TB with or without HIV co-infection

Brief summary: Lack of quality-assured pediatric formulations of the first-line antituberculosis (anti-TB) drugs is barrier to optimized tuberculosis (TB) treatment outcome in children. In 2010 and subsequently modified in 2014, the World Health Organization (WHO) recommended increased dosages of the first-line anti-TB drugs for children, but there were no child-friendly fixed-dose combination (FDC) formulations based on the guidelines. A large proportion of children treated with the new guidelines using old formulations did not achieve the desired rifampin peak concentration (Cmax) \> 8 mg/L and pyrazinamide Cmax \> 35 mg/L. The TB Alliance and the WHO led the development of a new child-appropriate isoniazid/rifampin/pyrazinamide (HRZ) and isoniazid/rifampin (HR) FDC formulation in line with current WHO recommended dosing guidelines. The new formulations dissolve quickly in liquid, have palatable fruit flavors, and are expected to improved daily adherence but no studies have evaluated the pharmacokinetics (PK) of the FDC formulation in children. The study team hypothesize that the new dispersible HRZ FDC tablet, dosed according to current WHO weight-band dosing recommendations will result in better PK parameters for each drug component than that achieved by the old formulation.

Detailed description: This study will evaluate the PK of the new pediatric HRZ FDC tablet in Ghanaian children with TB with and without HIV coinfection. The new HRZ FDC dispersible tablet was designed to be child-friendly and to achieve recommended dosages for each weight-band. The formulation has been rolled out in Africa without PK studies in the target population to verify that the tablets achieves adequate drug concentrations. The current study will evaluate the adequacy of the formulation by examining the PK of the component drugs as well as the effect of HIV coinfection. The direct PK data will be used in a population PK model and stimulations to define optimal weight-band dosages and proportions of the components of the pediatric FDC tablets.

Eligibility criteria: Inclusion Criteria:

* Children with active TB with or without HIV coinfection. Active TB diagnosis defined by clinical criteria consistent with active TB and/or a positive AFB smear.
* Available for follow-up until completion of TB treatment and/or achievement of a study endpoint like discontinuation of therapy, and/or pharmacokinetic sampling.

Exclusion Criteria:

* Children with concurrent conditions other than HIV, have acute hepatitis within 30 days of study entry, persistent vomiting, and diarrhea will be excluded from the study.
* Unable to obtain informed signed consent from parent(s) or legal guardian.
* Have AIDS-related opportunistic infections other than TB, history of or proven acute hepatitis within 30 days of study entry, persistent vomiting, or diarrhea.
* Hemoglobin \< 6 g/dl, white blood cells \< 2500/mm3, serum creatinine \> 1.5 mg/dl, aspartate transaminase (AST) and alanine transaminase (ALT) \> 2 times upper limit of normal.

Primary outcomes:
measure: Peak concentration (Cmax) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.
timeFrame: After at least 4 weeks of anti-TB therapy
measure: Area under the time-concentration curve from 0-8 hours (AUC0-8h) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.
timeFrame: After at least 4 weeks of anti-TB therapy
measure: Cmax of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection
timeFrame: After at least 4 weeks of anti-TB therapy
measure: AUC0-8h of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection.
timeFrame: After at least 4 weeks of anti-TB therapy
Secondary outcomes:
measure: AUC0-8h of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.
timeFrame: After at least 4 weeks of anti-TB therapy
measure: Cmax of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.
timeFrame: After at least 4 weeks of anti-TB therapy
measure: Proportion of children treated with new pediatric HRZ FDC tablet who develop with liver enzymes elevations.
timeFrame: After at least 4 weeks of anti-TB therapy
measure: Identify optimal weight-band dosages of the new HRZ FDC tablet
timeFrame: After at least 4 weeks of anti-TB therapy
Other outcomes:
Locations:
city: Kumasi
country: Ghana
facility: Kwame Nkrumah University of Science and Technology
Study officials:
affiliation: University of Florida
name: Awewura Kwara, MD
role: PRINCIPAL_INVESTIGATOR
References: