CELECOXIB Plasma and Cerebral Spinal Fluid Pharmacokinetics in Children

Pharmacokinetics of Celecoxib in Children

Pharmacokinetics, Celecoxib, Children, Pharmacogenetic, ABCB1 genotype, CYP2C9 genotype, CSF, Plasma

Celecoxib is effective for reducing postoperative pain in adults. Children use celecoxib more rapidly than adults and require higher doses. Celecoxib is partially metabolized in the liver by a certain enzyme. A person's genetic variation of this enzyme can influence how well their body uses Celecoxib. Furthermore, Celecoxib down-regulates P-glycoprotein (P-gp), a drug efflux transporter located at the blood brain barrier responsible for central nervous system (CNS) extrusion of ondansetron and possibly fentanyl; therefore celecoxib may augment the CNS effects of these drugs. Understanding the blood and cerebrospinal fluid (CSF) profile of celecoxib in children and the influence of genetics on metabolism would help to develop appropriate celecoxib dosing in children for various treatment options.

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: The primary objectives are to determine CSF concentrations (ug/L) of celecoxib 121-180 minutes following ingestion of a 7 or 14 mg/kg dose of a celecoxib suspension (20 mg/ml), to develop a pediatric population-based CSF and plasma 24 hour pharmacokinetic (PK) profile of a 14 mg/kg and 7 mg/kg dose of a celecoxib suspension (20 mg/ml), and to integrate this information into a PK model that explores the relationship between plasma and CSF celecoxib concentrations and the impact of covariates using nonlinear mixed effects models. The investigators hypothesize that a 14 mg/kg front end loaded dose of a celecoxib suspension (20 mg/ml) will achieve a target CSF concentration of at least 15 ug/L (equivalent to 50% of the COX-2 enzyme inhibition) approximately 121-180 minutes after oral ingestion and that these concentrations will be significantly higher than those CSF concentrations (ug/L) achieved with a 7 mg/kg traditional allometric adjusted dose. Experimental Design: This is a two-phased double-blind randomized controlled study of sixty-five (65) children aged 2-12 years in maintenance therapy for leukemia, who will receive a single dose of celecoxib prior to a scheduled lumbar puncture. In Phase I, twenty (20) children will receive either celecoxib 14 or 7 mg/kg 121-180 minutes prior to lumbar puncture (LP). In Phase II, forty-five (45) children will receive celecoxib 14 mg/kg, 7 mg/kg or placebo in one of 5 time intervals, 1-24 hours prior to LP. Drug levels in CSF and plasma will be measured using established HPLC-Mass Spec techniques. Pharmacogenetic data of the ABCB1 & CYP2C9 genotypes will be determined. Patient follow-up will be on Day 1 & 7 after ingestion to document adverse events. 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

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