Development of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents

NCT01976078 | Completed

• 2 other identifiers: CCI-11-00334R01HD070996
• Study Type: observational
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

The death rate in children from the invasive fungal infection called aspergillosis is more than 50%. Voriconazole is the first-line therapy for this infection. In a previous publication the investigators have shown a highly significant relationship between voriconazole plasma concentrations and survival. However, voriconazole dosing is currently poorly established, and plasma drug exposure varies between children by 400% or more, even after intravenous dosing. The objective of this study is to investigate the reasons for this variability in voriconazole pharmacokinetics (PK).In two studies, the investigators will enroll 80 children/adolescents receiving oral or intravenous voriconazole, divided by age under 2 years (n=15), and 2-18 years (n=65). From each patient the investigators will collect the following: 1) a blood sample for detection of several genetic changes known to affect drug metabolizing enzyme (DME) activity; 2) up to 9 blood samples after a voriconazole dose for measurement of voriconazole ("PK sampling"); 3) follow-up samples after each PK sampling visit if necessary to adjust the dose so that voriconazole concentrations in the blood are satisfactory (known as therapeutic drug monitoring or TDM). At the time of the voriconazole dose prior to the PK sampling, we will also give single IV or oral (corresponding to the route of voriconazole administration) low doses of esomeprazole (an antacid), midazolam (a sedative), and ranitidine (an antacid) as a cocktail to test or probe DME activity. All of these medications are used commonly in children already. The investigators will estimate DME activity or phenotype using ratios of probe drug metabolite to parent drug concentrations, while simultaneously quantifying the amount of DME genetic material (mRNA) and protein in white blood cells. The investigators will test associations between DME activity, mRNA, protein, voriconazole PK, age, sex, and degree of illness. The investigators will also use a computer program to integrate all these data to develop a comprehensive model that will predict blood concentrations of voriconazole in children of all ages, as well as assist physicians and pharmacists to dose voriconazole more accurately.The total study duration for each subject will be until after the TDM follow up visit, generally about one week.

Conditions

Pharmacokinetics; Voriconazole

Keywords

Voriconazole; Pharmacokinetics; Ontogeny; Modeling; Bayesian

Outcome Measures

Primary Outcomes (1)

• Voriconazole steady-state pharmacokinetics

  8 (after intravenous dosing) or 9 (after oral dosing) samples are taken after a voriconazole dose over a 12 hour timeframe.

  During the 12 hours after a dose

Secondary Outcomes (1)

• Voriconazole drug metabolizing enzyme activity

  Within 12 hours after a study medication dosing

Other Outcomes (1)

• Accuracy of computer software for Bayesian dose optimization of voriconazole in individual patients

  Within 4 weeks of study completion for each subject

Study Arms (1)

Midazolam/Ranitidine/Esomeprazole

All enrolled subjects will have a study pharmacokinetic visit where they will be given the above cocktail of drugs along with their clinically indicated voriconazole dose, followed by blood sampling over the next 12 hours.

Drug: Midazolam/Ranitidine/Esomeprazole

Interventions

Midazolam/Ranitidine/Esomeprazole DRUG

Each of the three drugs will be given at 10% of their usual doses for age/weight.

Midazolam/Ranitidine/Esomeprazole

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Children with an invasive fungal infection

You may qualify if:

• Participants will be enrolled before their 18th birthday.
• Participant/parent/legal guardian must be able and willing to provide signed informed consent.
• Laboratory values obtained within 7 days prior to study entry (obtained for clinical purposes)
• Hemoglobin ≥ 7.0 g/dL (transfusion dependence acceptable)
• Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and total bilirubin ≤ 5 X upper limit of age-appropriate normal (ULN)
• Serum creatinine ≤ 3 X ULN

You may not qualify if:

• Pregnancy
• Active substance abuse or other psychiatric illness that would prevent adherence to the study protocol. Investigators will not record this information in the screening log, and the information will be obtained from existing documents in the medical record only.
• Known hypersensitivity or intolerance to study medications
• Not expected to survive \>1 week.
• Weight \< 4.5 kg (blood volume draw limitations)

Sponsors & Collaborators

• Children's Hospital Los Angeles: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Related Publications (3)

• Hope WW, Vanguilder M, Donnelly JP, Blijlevens NM, Bruggemann RJ, Jelliffe RW, Neely MN. Software for dosage individualization of voriconazole for immunocompromised patients. Antimicrob Agents Chemother. 2013 Apr;57(4):1888-94. doi: 10.1128/AAC.02025-12. Epub 2013 Feb 4.

  PMID: 23380734 BACKGROUND

• Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010 Jan 1;50(1):27-36. doi: 10.1086/648679.

  PMID: 19951112 BACKGROUND

• Neely M, Margol A, Fu X, van Guilder M, Bayard D, Schumitzky A, Orbach R, Liu S, Louie S, Hope W. Achieving target voriconazole concentrations more accurately in children and adolescents. Antimicrob Agents Chemother. 2015;59(6):3090-7. doi: 10.1128/AAC.00032-15. Epub 2015 Mar 16.

  PMID: 25779580 DERIVED

MeSH Terms

Interventions

Midazolam

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Michael N Neely, MD

  Children's Hospital Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: September 18, 2013
• First Posted: November 5, 2013
• Study Start: September 1, 2012
• Primary Completion: April 22, 2015
• Study Completion: April 22, 2015
• Last Updated: February 20, 2018

Record last verified: 2018-02

Locations

US (1)