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Hussey E.K.,Glaxosmithkline | Kapur A.,Glaxosmithkline | O'Connor-Semmes R.,Glaxosmithkline | Tao W.,Glaxosmithkline | And 4 more authors.
BMC Pharmacology and Toxicology

Background: The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the renal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An inhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose concentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as monotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral antihyperglycemic agent widely used for the treatment of T2DM.Methods: This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with T2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin alone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable duration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for the duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma glucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid) assessments were performed at check-in and throughout the treatment periods. Pharmacokinetic sampling occurred on Day 3 of each treatment period.Results: This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin did not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly lower for remogliflozin and its metabolite after co-administration with metformin compared with administration of RE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of metformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in lactic acid.Conclusions: Coadministration of metformin and RE was well tolerated in this study. The results support continued development of RE as a treatment for T2DM.Trial registration: ClinicalTrials.gov, NCT00376038. © 2013 Hussey et al.; licensee BioMed Central Ltd. Source

Tse S.,Pfizer | Powell K.D.,Tandem Labs | MacLennan S.J.,BioCryst Pharmaceuticals | Moorman A.R.,Alta Vetta Pharmaceutical Consulting L.L.C. | And 2 more authors.
Journal of Pain Research

Purpose: This study compared the pharmacokinetic profile, and systemic and local absorption of diclofenac, following dermal patch application and oral administration in Yorkshire- Landrace pigs. Patients and methods: Twelve anesthetized, female, Yorkshire-Landrace pigs were randomized to receive either the dermal patch (FLECTOR® patch, 10 × 14 cm; Alpharma Pharmaceuticals, a subsidiary of Pfizer Inc, New York, NY) or 50 mg oral diclofenac (Voltaren®; Novartis, East Hanover, NJ). Tissue (skin area of 2 × 2 cm and underlying muscles approximately 2-3 cm in depth) and blood (10 mL) samples were collected at timed intervals up to 11.5 hours after initial patch application or oral administration. The concentrations of diclofenac in plasma, skin, and muscle samples were analyzed using validated ultra performance liquid chromatography tandem mass spectrometric methods. Results: Peak systemic exposure of diclofenac was very low by dermal application compared with oral administration (maximum concentration [Cmax] values of 3.5 vs 9640 ng/mL, respectively). Absorption of diclofenac into underlying muscles beneath the dermal patch was sustained, and followed apparently zero-order kinetics, with the skin serving as a depot with elevated concentrations of diclofenac. Concentrations of diclofenac in muscles beneath the patch application site were similar to corresponding tissues after oral administration (Cmax values of 879 and 1160 ng/mL, respectively). In contrast to the wide tissue distribution of diclofenac after oral administration, dermal patch application resulted in high concentrations of diclofenac only on the treated skin and immediate tissue underneath the patch. Low concentrations of diclofenac were observed in the skin and muscles collected from untreated areas contralateral to the site of dermal patch application. Conclusion: Dermal patch application resulted in low systemic absorption and high tissue penetration of diclofenac compared with oral administration. © 2012 Tse et al, publisher and licensee Dove Medical Press Ltd. Source

Myler H.,Bristol Myers Squibb | Felix T.,Tandem Labs | Zhu J.,WuXi AppTec | Hruska M.,Bristol Myers Squibb | Piccoli S.P.,Bristol Myers Squibb

Background: This article presents case study data demonstrating the importance of having a thorough understanding of matrix-interference in support of global clinical trials. Methods/Results: A ligand-binding assay used in the measurement of interferon lambda in human serum was transferred from the reference laboratory to a US-based comparator laboratory and then to a China-based comparator laboratory. The method was successfully validated at each laboratory, however, during cross-validation, there were notable differences, including 30-60% difference in incurred study sample results. The differences were attributed to matrix factors included in the serum pool used to prepare standards and quality controls. Newly procured serum (n = 75 individuals) was tested for assay interference. 12% contained either pre-existing antibodies (auto-antibodies) or were identified as pharmacokinetic assay outliers. Conclusion: Prescreening of serum to exclude reactive individuals resulted in successful cross-validation and the establishment of a high integrity pharmacokinetic assay in support of global clinical trials. © 2014 Future Science Ltd. Source

Kapur A.,Glaxosmithkline | O'Connor-Semmes R.,Glaxosmithkline | Hussey E.K.,Glaxosmithkline | Dobbins R.L.,Glaxosmithkline | And 7 more authors.
BMC Pharmacology and Toxicology

Background: Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans.Methods: This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661.Results: RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T1-Feb of ~25 min; mean plasma T1-Feb for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes.Conclusions: The results support progression of RE as a potential treatment for T2DM.Trial registration: ClinicalTrials.gov NCT01571661. © 2013 Kapur et al.; licensee BioMed Central Ltd. Source

Xu X.S.,Bristol Myers Squibb | Demers R.,Tandem Labs | Gu H.,Bristol Myers Squibb | Christopher L.J.,Bristol Myers Squibb | And 7 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences

A liquid chromatography and tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine the concentrations of saxagliptin (Onglyza™, BMS-477118) and its major active metabolite, 5-hydroxy saxagliptin to support pharmacokinetic analyses in clinical studies. The dynamic range of the assay was 0.1-50ng/mL for saxagliptin and 0.2-100ng/mL for 5-hydroxy saxagliptin. Protein precipitation (PPT) with acetonitrile was used to extract the analytes from plasma matrix before injecting on an Atlantis ® dC18 column (50mm×2.1mm, 5μm) for LC-MS/MS analysis. The sample pre-treatment process was carefully controlled to disrupt DPP4-specific binding and non-specific binding observed at lower concentrations. The recoveries for both analytes were >90%. The assay was selective, rugged and reproducible; storage stability of at least 401 days at -20°C was demonstrated. Under these chromatographic conditions, the isomers of saxagliptin and 5-hydroxy saxagliptin were chromatographically separated from saxagliptin and 5-hydroxy saxagliptin. The assay has been used to support multiple clinical studies and regulatory approvals. © 2012. Source

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