Dolutegravir Pharmacokinetics Among HIV/TB Coinfected Children Receiving Standard and High-dose Rifampicin

Sponsor

Brigham and Women's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05069688

Collaborator

APIN Public Health Initiatives (Other), University of Cape Town (Other)

Enrollment

Arm

38.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Tuberculosis (TB) is the leading cause of death among children with HIV, yet insufficient data are available on the pharmacokinetics of newer HIV/TB cotreatment strategies in children. Current WHO-recommended rifampicin dosages result in low concentrations in most children, and high-dose rifampicin may improve outcomes and shorten treatment duration. Yet the impact of high-dose rifampicin on dolutegravir exposures has not been examined in children. This study aims to evaluate the safety and pharmacokinetics of dolutegravir twice daily among HIV/TB coinfected children receiving standard-dose and high-dose rifampicin.

Condition or Disease	Intervention/Treatment	Phase
Pediatric HIV Infection Tuberculosis Infection	Drug: rifampicin	Phase 1

Detailed Description

This study is a prospective, single-arm, open-label, intensive and sparse pharmacokinetic (PK) and safety study to evaluate steady-state dolutegravir (DTG) concentrations among 20 HIV/TB coinfected children 4 weeks to <6 years of age requiring concurrent TB treatment. Ten patients will be recruited into each of two age cohorts: 4 weeks to <2 years and ≥2 years to <6 years.

Children will be recruited from two large pediatric HIV clinics in Nigeria. Children in this study will receive HIV/TB cotreatment that is considered standard of care consisting of DTG twice daily during rifampicin (RIF)-containing TB treatment. For this portion of the study, the primary intervention is additional blood sampling for drug concentration determination and biomarker assessment. Additionally, during a two week period (study weeks 20-21), the RIF dose will be increased from standard-dose to high-dose RIF, during which two-way PK and toxicity monitoring will occur. Clinical and laboratory monitoring for toxicity during HIV/TB cotreatment is consistent with routine care.

PK sampling for drug concentration determination will occur at three time points during the 48-week study. Specifically, PK sampling will occur at week-20 to evaluate DTG twice daily during standard-dose RIF, week-22 to evaluate DTG twice daily during high-dose RIF, and at week-30 to evaluate DTG once daily after TB treatment is complete.

Additionally, the endogenous biomarker of CYP3A4 activity, 4-beta-hydroxycholesterol to cholesterol ratio, will be evaluated to advance understanding of underlying mechanisms of drug action. Blood sampling to quantify this biomarker will occur at either 4 (among ART-experienced children) or 5 (ART-naive) time points during the 48-week study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Prospective single-arm, open-label, pharmacokinetic and safety studyProspective single-arm, open-label, pharmacokinetic and safety study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Mind the Gaps: Pharmacokinetic Research to Advance Pediatric HIV/TB Cotreatment and TB Prevention

Anticipated Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Mar 31, 2025

Anticipated Study Completion Date :

Mar 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dolutegravir PK during standard and high-dose rifampicin This is a single arm study: all patients are started on HIV/TB cotreatment considered standard of care and then for two weeks (study weeks 20-21) high-dose rifampicin is given during which safety and pharmacokinetics are examined.	Drug: rifampicin Patients will receive standard TB and HIV treatment, however, for two weeks (study weeks 20-21) the dose of rifampicin will be increased from standard-dose to high-dose to assess pharmacokinetics and safety

Arm

Intervention/Treatment

Experimental: Dolutegravir PK during standard and high-dose rifampicin

This is a single arm study: all patients are started on HIV/TB cotreatment considered standard of care and then for two weeks (study weeks 20-21) high-dose rifampicin is given during which safety and pharmacokinetics are examined.

Drug: rifampicin

Patients will receive standard TB and HIV treatment, however, for two weeks (study weeks 20-21) the dose of rifampicin will be increased from standard-dose to high-dose to assess pharmacokinetics and safety

Outcome Measures

Primary Outcome Measures

Dolutegravir AUC during standard-dose rifampicin [week 20]
Dolutegravir area under the concentration time curve (AUC) will be compared to therapeutic ranges established in the adult and pediatric literature
Dolutegravir AUC during high-dose rifampicin [week 22]
Dolutegravir AUC will be compared against therapeutic ranges established in the literature and during standard-dose rifampicin

Secondary Outcome Measures

Rifampicin maximum concentration (Cmax) during standard-dose rifampicin [week 20]
Rifampicin Cmax will be determined during standard rifampicin
Rifampicin Cmax during high-dose rifampicin [week 22]
Rifampicin Cmax will be determined during high-dose rifampicin and compared to that observed during standard-dose rifampicin
Proportion of participants experiencing severe (grade 3 or 4) clinical or laboratory adverse events [Week 48]
Laboratory and clinical toxicities are monitored at 8 time points throughout the study and the proportion of children experiencing severe adverse events will be determined

Eligibility Criteria

Criteria

Ages Eligible for Study:

4 Weeks to 5 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

ART-naïve or ART-experienced HIV-infected children between 4 weeks and <6 years of age
Active TB diagnosis
Weight of at least 3 kilograms
Consent of the parent or legal guardian

Exclusion Criteria:

Baseline labs with evidence of ≥grade 3 abnormalities: ALT, total bilirubin, absolute neutrophil count (ANC), platelets, or creatinine
Suspected TB meningitis or presenting with acute respiratory distress or decompensation
Receipt of a medication that has drug-drug interactions with dolutegravir or rifampicin