CELECOXIB Plasma and Cerebral Spinal Fluid Pharmacokinetics 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.

Celecoxib may influence CSF levels of various drugs, possibly via a P-gp regulation mechanism. Brain uptake of drugs is limited by both an anatomic (passive) and a biochemical (active) blood brain barrier (BBB). Metabolic enzymes and efflux protein transport systems represent the latter; the best known group is the ATP-binding cassette (ABC) protein transporters and best studied is P-gp encoded by the ABCB1 (aka MDR1) gene. P-gp actively pumps drugs and toxins out of the central nervous system (CNS) and acts in concert with detoxification enzymes to defend against cell damage. Celecoxib has been shown to down-regulate P-gp expression. Ondansetron and fentanyl are substrates of P-gp and CNS levels are influenced by its activity. Clinically, NSAIDs augment opioid effect and reduce nausea and vomiting, possibly by preventing the CNS extrusion of opioids and ondansetron via P-gp down-regulation. We will use peripheral blood mononuclear cells P-gp activity, as measured by RT-PCR and ELISA, as a surrogate for P-gp activity at the BBB and correlate with celecoxib plasma levels. Also, there are single-nucleotide polymorphisms (SNPs) of the ABCB1 gene associated with pain and drug transport in humans (rs2032582, rs2229109, rs9282564, rs1045642 and rs1128503) and they may influence CSF drug levels including ondansetron and fentanyl based on their associated drug efflux capacity or susceptibility to celecoxib down-regulation. In addition, SNPs of the CYP2C9 P450 enzymes (rs1057910 and rs1799853) have been implicated in altered PK of celecoxib in humans. Although controversial in children, in adults they have been associated with "slow" to "poor" metabolism and increased area under the curve (AUC) up to three fold.

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: