Single‐dose and steady‐state pharmacokinetics of celecoxib in children

Stempak, Diana; Gammon, Janet; Klein, Julia; Koren, Gideon; Baruchel, Sylvain

doi:10.1067/mcp.2002.129322

Cited by 80 publications

(56 citation statements)

References 11 publications

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“…Clearly, continuously providing celecoxib in the diet, resulting in a steady-state plasma concentration, was also an effective treatment regimen. By supplementing the diet with 250 to 2,500 ppm of celecoxib, we obtained plasma concentrations up to 6,373 nmol/L (2,447 Ag/L), which is within the same range as in children receiving 250 mg/m 2 celecoxib orally twice daily (33). The plasma levels of celecoxib were not significantly higher in animals receiving 2,500 ppm compared with animals receiving 1,500 ppm of celecoxib in their diet, which may be explained by a large variability in plasma concentrations between different animals within the same treatment group.…”

Section: Discussionmentioning

confidence: 52%

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Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo

Ponthan

Wickström

Gleissman

et al. 2007

Clinical Cancer Research

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Purpose: Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2^specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. Experimental Design: Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. Results: Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin, etoposide, irinotecan or vincristine in vitro. In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. Conclusions: Celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. Celecoxib could also be a potential drug for treatment of minimal residual disease.

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Section: Discussionmentioning

confidence: 52%

“…during 24 h of 118 versus 76 Amol/L, respectively. All oral celecoxib treatments were nontoxic and induced tumor growth inhibition at plasma levels that can be readily obtained in humans (33) and at a lower concentration needed to suppress neuroblastoma cell growth in vitro (17,34).…”

Section: Resultsmentioning

confidence: 99%

Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo

Ponthan

Wickström

Gleissman

et al. 2007

Clinical Cancer Research

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“…Second, in combination with chemotherapy, we detected additive and synergistic effects with celecoxib doses of 5-10 mM. Although pharmacokinetic data in children suggests peak levels in the 5 mM range (Stempak et al, 2002), the target tissue drug concentration is not known, and it is difficult to measure the final effective dosage in serum-containing media because celecoxib is >95% protein bound. However, particularly in murine xenografts, we and others have observed growth inhibition with celecoxib at dosages that result in measured peak levels in the 5 mM range (Ponthan et al, 2007), and at (a) cleaved-PARP, E2F-1, p73a (Ab2301), p53 (DO-1) and vinculin immunoblots of IMR-5 cells treated with OSU03012 at the indicated doses for 48 h. (b) IMR-5 cells were transfected with the indicated COX-2 siRNA oligonucleotides.…”

Section: Role Of Cox-2 In Celecoxib-mediated Effectsmentioning

confidence: 90%

Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

et al. 2009

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p73 encodes multiple functionally distinct isoforms. Proapoptotic TAp73 isoforms contain a transactivation (TA) domain, and like p53, have tumor suppressor properties and are activated by chemotherapies to induce cell death. In contrast, antiapoptotic DNp73 isoforms lack the TA domain and are dominant-negative inhibitors of p53 and TAp73. DNp73 proteins are overexpressed in a variety of tumors including neuroblastoma. Thus, identification of drugs that upregulate TAp73 and/or downregulate DNp73 represents a potential therapeutic strategy. Here, we report that cyclooxygenase (COX) inhibitors induce apoptosis independent of p53, and differentially modulate endogenous p73 isoforms in neuroblastoma and other tumors. COX inhibitor-mediated apoptosis is associated with the induction of TAp73b and its target genes. COX inhibitors also downregulate the alternative-spliced DNp73 AS isoforms, Dexon2 and Dexon2/3. Furthermore, forced expression of DNp73AS results in diminished apoptosis in response to the selective COX-2 inhibitor celecoxib. Celecoxib-mediated downregulation of DNp73AS is associated with decreased E2F1 levels and diminished E2F1 activation of the p73 promoter. These results provide the first evidence that COX inhibitors differentially modulate p73 isoforms leading to enhanced apoptosis, and support the potential use of COX inhibitors as novel regulators of p73 to enhance chemosensitivity in tumors with deregulated E2F1 and in those with wild-type (wt) or mutant p53.

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“…Metabolism of CEL takes place in liver by the enzymes cytochrome P450 2C9 (Cyp 2C9) (Sandberg et al, 2002;Sweetman et al, 2007), a cytochrome P450 isoform that is known to exist as several genetic variants (Stormer et al, 2003). CEL eliminated primarily by metabolism and about 3% is recovered in urine and faeces as unchanged compound (Stempak et al, 2002). The European Medicines Evaluation Agency (EMEA) requires generic products that enter the marketplace to show bioequivalence to assess the possibility of alternative use between the reference product and an essentially similar medicinal product (CHMP, 2008).…”

Section: Introductionmentioning

confidence: 99%

Bioequivalence assessment of two formulations of celecoxib: Open label, single dose and two-way cross over study in healthy human male volunteers

Akhtar

Ahmad²,

Ahmad³

et al. 2011

Afr. J. Pharm. Pharmacol.

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The purpose of this study was to assess bioequivalence of two marketed formulations of celecoxib capsules in healthy human male volunteers. The study was conducted according to a single dose, randomized sequence, open label, two-period and crossover design. Both test and reference formulations comprised labeled dose of 200 mg celecoxib and were administered to each subject after an overnight fasting on two treatment days separated by one week of washout period. After drug administration, blood samples were collected at predetermined time points for a period of 48 h. Plasma separated from blood was analyzed for celecoxib concentrations using validated reverse phase-high performance liquid chromatographic (RP-HPLC) method. Various pharmacokinetic parameters including C max , T max , AUC 0-t , AUC 0-∞ , T 1/2 and K el were determined from the plasma concentration for both formulations. C max , AUC 0-t and AUC 0-∞ , were evaluated for bioequivalence after log-transformation of data. The 90% confidence intervals for the ratio of C max (93.26 to 100.70%), AUC 0-t (87.00 to 117.50%) and AUC 0-∞ (86.49 to 118.56%), values for the test and reference products were within the acceptance range of 80 to 125%, proposed by Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA). Based on these statistical inferences, it was concluded that two formulations of celecoxib are bioequivalent in their rate and extent of absorption.

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Single‐dose and steady‐state pharmacokinetics of celecoxib in children

Cited by 80 publications

References 11 publications

Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo

Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo

Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

Bioequivalence assessment of two formulations of celecoxib: Open label, single dose and two-way cross over study in healthy human male volunteers

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