Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)
Information source: University of Cape Town
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Tuberculosis; HIV
Intervention: 8 hourly LPV/r during TB treatment (Drug); Nevirapine (Drug); Lopinavir/Ritonavir (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: University of Cape Town Official(s) and/or principal investigator(s): Helen M McIlleron, PhD, Principal Investigator, Affiliation: University of Cape Town Heather Zar, PhD, Principal Investigator, Affiliation: University of Cape Town
Overall contact: Heln McIlleron, PhD, Phone: 27214066292, Email: helen.mcilleron@uct.ac.za
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.
Clinical Details
Official title: Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Area under the concentration time curve (AUC) for rifampicin, isoniazid, pyrazinamide, ethambutol, lopinavir and nevirapine
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.
Eligibility
Minimum age: 1 Month.
Maximum age: 12 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
ALL STUDY PARTICIPANTS
- 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:
- Indication for increased or reduced doses of 1st-line antiTB drugs (e. g. marked
hepatic or renal impairment, TB meningitis).
Locations and Contacts
Heln McIlleron, PhD, Phone: 27214066292, Email: helen.mcilleron@uct.ac.za
Queen Elizabeth Central Hospital, Blantyre, Malawi; Recruiting Carmen Gonzalez, MD, MSc, Phone: 0026 5991416730, Email: Gonzalez@liverpool.ac.uk Gerraint Davies, PhD, Principal Investigator
Desmond Tutu Centre, Cape Town, Western Cape, South Africa; Recruiting Adrie Bekker, MMed, Phone: 27219389198, Email: adrie@sun.ac.za Anneke Catharina Hesseling, PhD, Principal Investigator
Red Cross Childrens Hospital, Cape Town, Western Cape 7700, South Africa; Recruiting Heather ZAR, PhD, Phone: 27216585350, Email: heather.zar@uct.ac.za Margaretha Prins, Phone: 27216863163, Email: margaretha.prins@uct.ac.za Heather ZAR, PhD, Principal Investigator
Additional Information
Starting date: November 2012
Last updated: December 2, 2014
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