Development of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents

Ontogeny of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents

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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Voriconazole
• Intervention / Treatment: Drug: Midazolam/Ranitidine/Esomeprazole

• Study Type: Observational
• Enrollment (Actual): 45

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Children with an invasive fungal infection

Description

Inclusion Criteria:

1. Participants will be enrolled before their 18th birthday.
2. Participant/parent/legal guardian must be able and willing to provide signed informed consent.

3. Laboratory values obtained within 7 days prior to study entry (obtained for clinical purposes)

   1. Hemoglobin ≥ 7.0 g/dL (transfusion dependence acceptable)
   2. Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and total bilirubin ≤ 5 X upper limit of age-appropriate normal (ULN)
   3. Serum creatinine ≤ 3 X ULN

Exclusion Criteria:

1. Pregnancy
2. 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.
3. Known hypersensitivity or intolerance to study medications
4. Not expected to survive >1 week.
5. Weight < 4.5 kg (blood volume draw limitations)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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; Each of the three drugs will be given at 10% of their usual doses for age/weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Voriconazole drug metabolizing enzyme activity	At the time of the voriconazole dose used for the primary outcome, an intravenous or oral cocktail of "probe drugs", depending on the route of the voriconazole dose, consisting of midazolam, ranitidine, and esomeprazole will be administered. Using the samples collected for the primary outcome, concentrations of all three probe drugs and their major metabolites will be measured and used to compute activity of the relevant drug metabolizing enzymes.	Within 12 hours after a study medication dosing

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accuracy of computer software for Bayesian dose optimization of voriconazole in individual patients	Using existing voriconazole pharmacokinetic data, we have constructed a population model of the drug's behavior in children and adults. We are testing the use of this model in study subjects to compare the doses predicted by the software to achieve actual, measured voriconazole concentrations obtained for routine clinical care after the study PK visit, with the real doses that were administered and resulted in those measured voriconazole concentrations.	Within 4 weeks of study completion for each subject

Collaborators and Investigators

• Sponsor: Children's Hospital Los Angeles
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Michael N Neely, MD, Children's Hospital Los Angeles

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Actual): April 22, 2015
• Study Completion (Actual): April 22, 2015

Study Registration Dates

• First Submitted: September 18, 2013
• First Submitted That Met QC Criteria: October 29, 2013
• First Posted (Estimate): November 5, 2013

Study Record Updates

• Last Update Posted (Actual): February 20, 2018
• Last Update Submitted That Met QC Criteria: February 16, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Voriconazole; Modeling; Bayesian; Ontogeny
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Histamine Antagonists; Histamine Agents; Histamine H2 Antagonists; Midazolam; Ranitidine; Ranitidine bismuth citrate; Esomeprazole
• Other Study ID Numbers: CCI-11-00334; R01HD070996 (U.S. NIH Grant/Contract)