Trial Information

The Impact of Genotype on Plasma and Cerebral Spinal Fluid Pharmacokinetics of Celecoxib in Children

Background: Celecoxib is a selective cyclooxygenase-2 (Cox-2) inhibitor belonging to the
non-steroidal anti-inflammatory drugs (NSAIDs) class of medications. Adult studies have
evaluated single dose and short term courses of Celecoxib and shown improved postoperative
analgesia. One pharmacokinetic (PK) study suggested that celecoxib had faster clearance in
pediatric patients implying the need for a higher dose in children. Adult literature has
reported Cox-2 inhibitor administration up to 10 times the typical dose without adverse side
effects. One adult chemotherapy drug trial involved high dose Celecoxib for a median of 8.4
months with very limited side effects. Another study demonstrated that blood brain barrier
(BBB) permeable selective Cox-2 inhibitors effectively reduced central nervous system
Prostaglandin (PG) E2, (a surrogate marker of Cox-2 activity) concentrations and
postoperative pain.

Genotypic variability of the CYP2C9 liver enzymes has been implicated in altered PK of
celecoxib in humans. Understanding the blood and CSF pharmacokinetics of celecoxib in
children and the influence of genetics on metabolism would aid in the development of
appropriate celecoxib dosing schedules for various pain models.

At our institution, children diagnosed with hematologic malignancies routinely undergo
general anesthesia for bone marrow aspiration/biopsy (BM) and diagnostic/ therapeutic lumbar
punctures (LP). Post intervention site pain may be associated with a post dural puncture or
atypical headache. Recently there have been reports of elevated Cox-2 expression in
patients with CML and lymphomas. Data suggests that the combination of Cox-2 inhibitors
with standard chemotherapeutics may enhance the potential of treatment for some
hematological malignancies. Access to blood and cerebral spinal fluid provide a unique
opportunity to determine celecoxib concentrations in the respective compartments.

Objectives and Hypothesis: Our primary objective will be to create a pediatric
pharmacokinetic profile of celecoxib in the blood and the central nervous system as well as
explore the relationship between CYP2C9 polymorphisms and documented adverse events. The
investigators hypothesize that the CSF concentrations of Celecoxib post ingestion are lower
than plasma levels with a delayed peak concentration and directly related to dose, genotype,
and age. The investigators expect that Celecoxib will improve quality of life and reduce
discomfort when administered before and after a LP +/- BM.

Experimental Design The study consists of two prospective cohort arms. A dose timing cohort
to develop the pharmacokinetic profile for blood and CSF concentrations, and a dose
escalation cohort in which increasing doses of a celecoxib suspension will be administered.
A single blood sample to determine the CYP2C9 alleles will be drawn from each patient upon
study entry.

Potential Impact: CSF penetration of Cox-2 inhibitors may reduce the incidence of acute pain
evolving into a chronic pain model. The results of this study will establish the safety of
this class of medications in children and enable a more rational approach to their dosing in
acute pain models and perhaps future chemotherapeutic protocols