Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)
NCT ID: NCT01637558
Last Updated: 2017-10-27
Study Results
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Basic Information
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COMPLETED
PHASE4
200 participants
INTERVENTIONAL
2012-11-30
2017-07-31
Brief Summary
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1. To evaluate the pharmacokinetics of first line antituberculosis drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) when applying the 2010 WHO/IUATLD dosing guidelines across pediatric populations (0-12 years of age, HIV infected and uninfected, and with varied nutritional status) in Cape Town, South Africa and Blantyre, Malawi.
2. To evaluate an 8-hourly weight band-based dosing strategy for lopinavir/ritonavir using the commercially available lopinavir/ritonavir (4:1 ratio) in children in South Africa receiving rifampicin-based antituberculosis treatment.
3. To evaluate the pharmacokinetics of nevirapine in children in Malawi receiving rifampicin-based antituberculosis treatment.
Detailed Description
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In total, 240 children \< 12 years of age with tuberculosis will be enrolled at Red Cross Children's Hospital in Cape Town and Queen Elizabeth Central Hospital, Blantyre. In the second month of antituberculosis treatment, one dose of the drugs in their first-line regimens will be administered according to 2010 WHO/IUATLD guidelines (study drugs) and blood will be sampled for pharmacokinetic analysis over the following 8-10 hours.
Children on antiretroviral treatment (started prior to or during TB treatment) will receive 2 weeks of antiretrovirals (lopinavir/ritonavir or nevirapine) according in the study doses (adjusted 8 hourly doses of lopinavir/ritonavir, or nevirapine doses according to WHO's recommended weight band-based doses) in combination with antituberculosis treatment, prior to pharmacokinetic assessments of both antiretroviral and antituberculosis drugs. Children receiving nevirapine will also undergo pharmacokinetic evaluation 1 month after completion of antituberculosis treatment to evaluate nevirapine concentrations in the absence of antituberculosis drugs. In addition to the 240 children with tuberculosis, 25 HIV infected South African children without tuberculosis will be recruited to evaluate lopinavir concentrations in the absence of antituberculosis drugs.
A population approach will be used to estimate the optimal doses of rifampicin, isoniazid, pyrazinamide and ethambutol in children according to covariates (e.g. age, weight, HIV status, nutritional status) found to have an important influence on the drug concentrations. Similarly population models will be used to describe lopinavir/ritonavir and nevirapine pharmacokinetics in children receiving rifampicin-based antituberculosis treatment, evaluate the dosing approaches and to simulate alternative optimal dosing approaches as indicated.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Main TB cohort
Children with tuberculosis 0-12 years of age
No interventions assigned to this group
Lopinavir/Ritonavir - Cases
children 3-20 kg with tuberculosis and indication for LPV/r-based ART
8 hourly LPV/r during TB treatment
8 hourly LPV/r during TB treatment
Lopinavir/Ritonavir - Controls
Children 3-20 kg on LPV/r-based ART; no TB
Lopinavir/Ritonavir
Nevirapine arm
children with TB and indication for nevi rapine-based ART
Nevirapine
Interventions
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8 hourly LPV/r during TB treatment
8 hourly LPV/r during TB treatment
Nevirapine
Lopinavir/Ritonavir
Eligibility Criteria
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Inclusion Criteria
* Aged \< 12 years.
* Weighing \> 1.5 kg and \< 30 kg.
* Written informed permission of parent or legal guardian for their child to participate.
* Absence of clear indication of unwillingness or refusal to participate, and in children \> 7 years of age, assent to participate.
* No contraindications to PK sampling (children with obviously very poor venous access will not be included).
* Able to comply with study visits and procedures including regular adherence to routine medication, and adherence to the study medication.
* Enrollment will be deferred in children with acute severe illness which would likely jeopardize participation (such as illness causing severe respiratory impairment, acute severe diarrhea, acute central nervous system impairment, severe life threatening systemic illness, or other severe conditions requiring hospitalization which would jeopardize participation). Children may be enrolled after recovery from acute illness.
ADDITIONAL CRITERIA FOR THE MAIN TB COHORT AND SUBSTUDIES
1. Main TB cohort
INCLUSION A recent diagnosis of TB and receiving intensive phase antiTB treatment with 1st-line drugs (rifampicin, isoniazid, pyrazinamide with or without ethambutol, in standard doses).
2. LPV SUBSTUDY
CASES \& CONTROLS
* Children in whom ART with a LPV/r-containing regimen is indicated, OR, Children established on a LPV/r-containing regimen.
* ALT \< 5-times the upper limit of the normal range.
* Children weighing 3.0 - 19.9 kg.
* Neonates must have a postmenstrual age of at least 42 weeks and a postnatal age of at least 14 days.
CASES
\- HIV infected children enrolled to the main cohort with at least 2 weeks remaining before the end of intensive phase antiTB treatment such that PK sampling can be scheduled after 2 weeks of combined ART and antiTB treatment, but before the continuation phase of antiTB treatment is started.
CONTROLS
\- HIV infected children without TB.
Weighted enrollment of controls will be performed such that the number of controls in each of the age groups \< 6 months, 6 months to 2 years, and \> 2 years, will be approximately equal to the numbers of cases in those age groups. As most of the children with TB will be started on ART after their TB diagnosis, recruitment of controls will be focused on children who have recently started ART (on treatment \< 3 months).
3. NVP SUBSTUDY
* HIV infected children receiving intensive phase antiTB treatment and enrolled to the main study cohort
* Started on ART including NVP (in WHO's recommended weight band-based doses) and 2 nucleoside reverse transcriptase inhibitors.
Exclusion Criteria
1 Month
12 Years
ALL
No
Sponsors
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Liverpool School of Tropical Medicine
OTHER
Uppsala University
OTHER
University of North Carolina
OTHER
University of Cape Town
OTHER
Responsible Party
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Helen Margaret McIlleron
Assistant Prof
Principal Investigators
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Helen M McIlleron, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Cape Town
Heather Zar, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Cape Town
Locations
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Queen Elizabeth Central Hospital
Blantyre, , Malawi
Red Cross Childrens Hospital
Cape Town, Western Cape, South Africa
KIDCRU, Tygerberg Hospital, Department of Paediatrics and Child Health, Stellenbosch University, South Africa.
Cape Town, Western Cape, South Africa
Desmond Tutu Centre
Cape Town, Western Cape, South Africa
Countries
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References
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Galileya LT, Wasmann RE, Chabala C, Rabie H, Lee J, Njahira Mukui I, Hesseling A, Zar H, Aarnoutse R, Turkova A, Gibb D, Cotton MF, McIlleron H, Denti P. Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis. PLoS Med. 2023 Nov 21;20(11):e1004303. doi: 10.1371/journal.pmed.1004303. eCollection 2023 Nov.
Rabie H, Rawizza H, Zuidewind P, Winckler J, Zar H, Van Rie A, Wiesner L, McIlleron H. Pharmacokinetics of adjusted-dose 8-hourly lopinavir/ritonavir in HIV-infected children co-treated with rifampicin. J Antimicrob Chemother. 2019 Aug 1;74(8):2347-2351. doi: 10.1093/jac/dkz171.
Bekker A, Schaaf HS, Draper HR, van der Laan L, Murray S, Wiesner L, Donald PR, McIlleron HM, Hesseling AC. Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2171-9. doi: 10.1128/AAC.02600-15. Print 2016 Apr.
Other Identifiers
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DATiC
Identifier Type: -
Identifier Source: org_study_id