Population Pharmacokinetics of Anti-tuberculosis Drugs in Children With Tuberculosis

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.

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: anti-tuberculosis drug

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.

• Study Type: Observational
• Enrollment (Anticipated): 800

Contacts and Locations

• Study Contact: Name: A-Dong Shen, Master; Phone Number: +86-010-59616898; Email: shenad16@hotmail.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Beijing Children's Hospital of Capital Medical University
    • Contact: Adong Shen, Master; Phone Number: 13370115087; Email: shenad16@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Children with anti-tuberculosis therapies.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
maximum concentration (Cmax)	Cmax is a term used in pharmacokinetics refers to the maximum (or peak) serum	up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time to achieve maximum concentration (Tmax)	Tmax is the term used in pharmacokinetics to describe the time at which the Cmax	up to 4 weeks
absorption rate constant (ka)	Ka is the rate constant of drug absorption.	up to 4 weeks
elimination rate constant (kel)	The elimination rate constant is a value used in pharmacokinetics to describe the rate at which a drug is removed from the system.	up to 4 weeks
half-life (t1/2)	Half-life is the time required for a quantity to reduce to half its initial value.	up to 4 weeks

Collaborators and Investigators

• Sponsor: Beijing Children's Hospital
• Collaborators: Hopital Universitaire Robert-Debre; Shandong University; Rennes University Hospital
• Investigators: Principal Investigator: A-Dong Shen, Master, Beijing Children's Hospital of Capital Medical University; Study Director: Yu-Jie Qi, Master, Beijing Children's Hospital of Capital Medical University; Study Director: Wei Zhao, Doctor, Children's Hospital of Hebei Province;Shandong Provincial Qianfoshan Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Anticipated): October 1, 2026
• Study Completion (Anticipated): December 31, 2026

Study Registration Dates

• First Submitted: August 8, 2018
• First Submitted That Met QC Criteria: August 8, 2018
• First Posted (Actual): August 10, 2018

Study Record Updates

• Last Update Posted (Actual): August 15, 2018
• Last Update Submitted That Met QC Criteria: August 14, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; Pharmaceutical Solutions; Antibiotics, Antitubercular; Cytochrome P-450 CYP1A2 Inhibitors; beta-Lactamase Inhibitors; Ophthalmic Solutions; Anti-Infective Agents, Urinary; Renal Agents; Fatty Acid Synthesis Inhibitors; Moxifloxacin; Imipenem; Amoxicillin; Levofloxacin; Gatifloxacin; Cycloserine; Bedaquiline; Clavulanic Acid; Amoxicillin-Potassium Clavulanate Combination; Amikacin; Isoniazid; Pyrazinamide; Ethambutol; Clofazimine; Aminosalicylic Acid; Streptomycin; Ethionamide; Kanamycin; Capreomycin; Thioacetazone; Antitubercular Agents
• Other Study ID Numbers: BCH_PPK003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No