Clinical trial NCT03625739: Population Pharmacokinetics of Anti-tuberculosis Drugs in Children With Tuberculosis
Official title: Population Pharmacokinetics of Anti-tuberculosis Drugs in Children With Tuberculosis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Tuberculosis
Lead sponsor: Beijing Children's Hospital
Sponsor class: OTHER
Collaborators: name: Shandong University
name: Hopital Universitaire Robert-Debre
name: Rennes University Hospital
First posted: 2018-08-10
Enrollment: 800
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children with anti-tuberculosis therapies.

Brief summary: This study is based on the hypothesis that the pharmacokinetics of anti-tuberculosis drugs in TB children are different from adults. The investigators aim to study the population pharmacokinetics of children receiving the anti-tuberculsis drugs for treatment of TB. In this study, the investigators will detect drug concentration in plasma by using residual blood samples of blood gas analysis and other clinical tests and employ computers for constructing population pharmacokinetic models. In addition, the investigators also want to correlate use of anti-tuberculsis drugs with treatment effectiveness and incidence of adverse effects in children. This novel knowledge will allow better and more rational approaches to the treatment of TB in children. It will also set the foundation for further studies to improve anti-tuberculosis drug therapies for children.

Detailed description: 1.Establish population pharmacokinetic (PPK) models of each anti-tuberculsis drug in children by nonlinear mixed effect modeling (NONMEM).

1. At different timepoint after anti-tuberculsis drug administration, plasma samples of 100 children will be collected from neonatal intensive care unit (NICU) and pneumology department for each drug. The clinical information includes demography, medication, concentration data, blood biochemical parameters and so on .
2. Plasma samples will be tested by high performance liquid chromatography (HPLC).
3. PPK models of anti-tuberculsis drug will be established by NONMEM program.
4. The reliability and stability of the PPK model will be evaluated by 1000 times of Bootstrap procedure and normalized predictive distribution error (NPDE).

2.Evaluation of the clinical feasibility and safety of individualized dosing.

1. According the results of PPK models, the investigators will use dosages recommended in models to cure TB children in prospective studies. For anti-tuberculsis drug, 50 children will be collected.
2. The investigators will compare the therapeutic effects and safety between children with conventional therapies and children with individualized therapies, including proportions of children with effective drug concentration, improvement speed of of children, liver and kidney functions of of children, adverse reactions of drugs and so on.

Eligibility criteria: Inclusion Criteria:

* Children (0-18 years old) with anti-tuberculosis therapy against TB.
* The anti-tuberculsis therapy includes drugs commonly used in children infectious diseases
* Informed consent signed by the parents and/or guardians.

Exclusion Criteria:

* Anti-tuberculosis drugs aren't involved in the therapies of children.
* It is unable to provide complete medical records or the current condition cannot accept the study process.
* Patients are allergic to anti-tuberculsis drugs.
* Parents and/or guardians do not agree to participate in this study.

Primary outcomes:
measure: maximum concentration (Cmax)
timeFrame: up to 4 weeks
Secondary outcomes:
measure: time to achieve maximum concentration (Tmax)
timeFrame: up to 4 weeks
measure: absorption rate constant (ka)
timeFrame: up to 4 weeks
measure: elimination rate constant (kel)
timeFrame: up to 4 weeks
measure: half-life (t1/2)
timeFrame: up to 4 weeks
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Children's Hospital of Capital Medical University
Study officials:
affiliation: Beijing Children's Hospital of Capital Medical University
name: A-Dong Shen, Master
role: PRINCIPAL_INVESTIGATOR
affiliation: Beijing Children's Hospital of Capital Medical University
name: Yu-Jie Qi, Master
role: STUDY_DIRECTOR
affiliation: Children's Hospital of Hebei Province;Shandong Provincial Qianfoshan Hospital
name: Wei Zhao, Doctor
role: STUDY_DIRECTOR
References:
citation: Jacqz-Aigrain E, Leroux S, Zhao W, van den Anker JN, Sharland M. How to use vancomycin optimally in neonates: remaining questions. Expert Rev Clin Pharmacol. 2015;8(5):635-48. doi: 10.1586/17512433.2015.1060124. Epub 2015 Aug 4.
citation: Ho PL, Lo PY, Chow KH, Lau EH, Lai EL, Cheng VC, Kao RY. Vancomycin MIC creep in MRSA isolates from 1997 to 2008 in a healthcare region in Hong Kong. J Infect. 2010 Feb;60(2):140-5. doi: 10.1016/j.jinf.2009.11.011. Epub 2009 Dec 2.
citation: Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003 Sep 18;349(12):1157-67. doi: 10.1056/NEJMra035092. No abstract available.