PK, PD, PG Variability of Caffeine in Neonates


Status: Not yet recruiting
Keywords: Neonates , Pediatrics , Caffeine
IRB Number: 00064254
Specialty: Neonatology
Sub Specialties:

Brief Summary

This study will address the working hypothesis that applying design techniques for sample size calculation, sampling times for PK studies, effectiveness outcome measurements during the study, and drug-drug interactions improves clinical trial outcome.  In addition, application of population pharmacokinetic modeling can be used to predict caffeine exposure and response. This will determine the influence of biomarkers and specify the impact that the inclusion of genetic variants will have on clinical outcomes and improved treatment outcomes. Additionally, the identification of genetic predictors of variability in exposure and response, using population PK/PD analysis, will test the hypothesis that exposure and response, are associated with potential safety concerns. CYP1A2 is responsible for approximately 90% of caffeine metabolism in humans. Testing the hypothesis that level of caffeine exposure and extent of toxicity are associated with genetic variants in CYP1A2.


The information obtained from this approach is critically needed to accurately and prospectively determine drug dosing, therefore predicting clinical response and toxicity. This project proposes an innovative strategy for the application of modeling and validation techniques: this will lead to the development of neonatal-specific algorithms that will improve the safety and efficacy of drug administration reduce potential harm. This will lead to physiologic and metabolic model development. The overall goal is to develop a universal model that can be adapted to any medication given to a neonate.


The objectives are

  1. Describe the clinical pharmacology of caffeine citrate or theophylline in newborns.
  2. Describe the demographic characteristics in newborns with apnea and brief hypoxic spells.
  3. Model the pharmacokinetics of caffeine citrate or theophylline in newborns.
  4. Compare the pharmacokinetic model with the published literature.


Hypothesis: Variability in caffeine citrate or theophylline response, specifically the development of apnea and brief hypoxic spells, is associated with identifiable factors, such as age, sex, or drug metabolizing enzyme polymorphisms, when methylxanthines are metabolized by those enzymes.


Specific Aim #1:

To evaluate the pharmacokinetic and pharmacodynamic variability of caffeine or theophylline used in neonates to treat apnea.


Specific Aim #2:

Model relevant clinical biomarkers and genetic factors to improve clinical outcomes using caffeine exposure and response variability in neonates, characterizing PKPDPG variability and determine the influence of clinical predictors on individuals.

Principal Investigator: Catherine Sherwin
Department: Pediatric Administration
Co Investigator: Michael Spigarelli
Co Investigator: Robert Ward
Co Investigator: Michael Varner

Contact Information

Name:Casey Tak
Phone: 801-213-3395

Inclusion Criteria

Any neonate NICU patient receiving caffeine or theophylline for apenia and/or hypoxic episodes

Exclusion Criteria

  1. Having not been prescribed caffeine citrate  (per Medication Administration Record or Medication Reconciliation information)
  2. Discharge diagnoses which could influence outcome measures, including anatomical respiratory tract anomalies such as tracheoesophageal fistula, pulmonary atresia, congenital diaphragmatic hernia or related conditions.
  3. Participated in a clinical trial in which medication or dose is unknown, or the patient may have received placebo
  4. Any patient who, in the judgment of the investigators, has insufficient data or any condition that would otherwise interfere with outcomes or analysis