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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Pediatric HIV Infection, Tuberculosis Infection

Intervention / Treatment
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* Drug: rifampicin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 4 Weeks
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective single-arm, open-label, pharmacokinetic and safety study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dolutegravir PK during standard and high-dose rifampicin<br>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<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rifampicin maximum concentration (Cmax) during standard-dose rifampicin | Rifampicin Cmax will be determined during standard rifampicin | week 20 | 
| Rifampicin Cmax during high-dose rifampicin | Rifampicin Cmax will be determined during high-dose rifampicin and compared to that observed during standard-dose rifampicin | week 22 | 
| Proportion of participants experiencing severe (grade 3 or 4) clinical or laboratory adverse events | 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 | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rifampicin, pharmacokinetic, dolutegravir