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Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study) (DATiC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01637558
Recruitment Status : Completed
First Posted : July 11, 2012
Last Update Posted : October 27, 2017
Liverpool School of Tropical Medicine
Uppsala University
University of North Carolina
Information provided by (Responsible Party):
Helen Margaret McIlleron, University of Cape Town

Brief Summary:

The aims of this project are to:

  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.

Condition or disease Intervention/treatment Phase
Tuberculosis HIV Drug: 8 hourly LPV/r during TB treatment Drug: Nevirapine Drug: Lopinavir/Ritonavir Phase 4

Detailed Description:

HIV and tuberculosis are a major public health problem in children. Challenges to treat children with tuberculosis include a lack of knowledge about optimal dosing of first line antituberculosis drugs across ages, nutritional status and HIV infection status, the absence of an appropriate regimen to co-administer rifampin and lopinavir/ritonavir, the key first line drugs for tuberculosis and HIV, and uncertainty about NVP exposure in young children during rifampin-based tuberculosis therapy.

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)
Actual Study Start Date : November 2012
Actual Primary Completion Date : July 31, 2017
Actual Study Completion Date : July 31, 2017

Arm Intervention/treatment
No Intervention: Main TB cohort
Children with tuberculosis 0-12 years of age
Experimental: Lopinavir/Ritonavir - Cases
children 3-20 kg with tuberculosis and indication for LPV/r-based ART
Drug: 8 hourly LPV/r during TB treatment
8 hourly LPV/r during TB treatment

Experimental: Lopinavir/Ritonavir - Controls
Children 3-20 kg on LPV/r-based ART; no TB
Drug: Lopinavir/Ritonavir
Experimental: Nevirapine arm
children with TB and indication for nevi rapine-based ART
Drug: Nevirapine

Primary Outcome Measures :
  1. Area under the concentration time curve (AUC) for rifampicin, isoniazid, pyrazinamide, ethambutol, lopinavir and nevirapine [ Time Frame: 5 years ]
    Population PK model-derived AUC's (in mg.h/L)for each of the first line anti-TB drugs, and for the substudies, lopinavir and nevirapine respectively.

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.


  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).



    • 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.


    - 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.


    - 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).


    • 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:

  • Indication for increased or reduced doses of 1st-line antiTB drugs (e.g. marked hepatic or renal impairment, TB meningitis).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01637558

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Queen Elizabeth Central Hospital
Blantyre, Malawi
South Africa
Red Cross Childrens Hospital
Cape Town, Western Cape, South Africa, 7700
KIDCRU, Tygerberg Hospital, Department of Paediatrics and Child Health, Stellenbosch University, South Africa.
Cape Town, Western Cape, South Africa, 7725
Desmond Tutu Centre
Cape Town, Western Cape, South Africa
Sponsors and Collaborators
University of Cape Town
Liverpool School of Tropical Medicine
Uppsala University
University of North Carolina
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Principal Investigator: Helen M McIlleron, PhD University of Cape Town
Principal Investigator: Heather Zar, PhD University of Cape Town
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Helen Margaret McIlleron, Assistant Prof, University of Cape Town Identifier: NCT01637558    
Other Study ID Numbers: DATiC
First Posted: July 11, 2012    Key Record Dates
Last Update Posted: October 27, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers