Aziz Karim

American College of Clinical Pharmacology, Американ Форк, Utah, United States

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Publications (25)76.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: This double-blind, randomized, placebo- and positive-controlled, parallel-group study evaluated the effect of vortioxetine (Lu AA21004), an investigational multimodal antidepressant, on QT interval in accordance with current guidelines of the International Conference on Harmonisation (ICH-E14). A total of 340 healthy men were randomized to receive 1 of 4 treatments for 14 days: (1) vortioxetine 10 mg once daily (QD), (2) vortioxetine 40 mg QD, (3) placebo QD, or (4) placebo QD on Days 1 through 13 followed by a single dose of moxifloxacin 400 mg (positive control). The primary endpoint was the largest time-matched, baseline-adjusted least-squares (LS) mean difference for the individual-corrected QT interval (QTcNi [linear]) between vortioxetine and placebo. Alternative QT correction formulas (i.e., Fredericia [QTcF], Bazett [QTcB], Framingham [QTcFm], and QTcNi [nonlinear]) were used as secondary endpoints. The upper bound of the 2-sided 90% confidence interval around the LS mean difference from placebo for baseline-adjusted QTcNi (linear), QTcF, QTcB, QTcFm, and QTcNi (nonlinear) did not exceed 10 ms at any time point after multiple doses of vortioxetine 10 mg (therapeutic) or 40 mg (supratherapeutic). Overall, the study results indicate that vortioxetine is unlikely to affect cardiac repolarization in healthy subjects.
    Clinical Pharmacology in Drug Development 10/2013; 2(4). DOI:10.1002/cpdd.51
  • A Karim · P Covington · R Christopher · M Davenport · P Fleck · X Li · E Wann · Q Mekki ·
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    ABSTRACT: The dipeptidyl peptidase-4 inhibitor alogliptin, under development for treatment of Type 2 diabetes, primarily is excreted renally. This study investigated (1) the effect of food on alogliptin pharmacokinetics and tolerability and (2) pharmacokinetic interactions between alogliptin and metformin or cimetidine and tolerability of alogliptin when administered with either drug. This randomized, open-label, two-phase, crossover study recruited healthy adults. In the single-dose phase, 36 subjects received an oral dose of alogliptin 100 mg under fed or fasted conditions. In the multiple-dose phase, subjects in one arm (n = 17) received 6 days each of alogliptin 100 mg once daily (q.d.), metformin 1,000 mg twice daily (b.i.d), and alogliptin q.d. + metformin b.i.d; subjects in the other arm (n = 18) received 6 days each of alogliptin 100 mg q.d., cimetidine 400 mg q.d., and alogliptin q.d. + cimetidine b.i.d. Pharmacokinetic parameters were determined after the last dose in each period. Tolerability was assessed through adverse events and clinical findings. Food had no effect on alogliptin area under the concentration-time curve (AUC) from 0 h to infinity and a small, clinically insignificant effect on maximum plasma concentration (C(max)) (fed/fasted least squares (LS) geometric mean ratio, 0.856; 90% confidence interval (CI), 0.798 - 0.917). Metformin and cimetidine did not affect alogliptin pharmacokinetics. Alogliptin had no effect on metformin C(max) and a small, clinically insignificant effect on AUC over the dosing interval ((alogliptin + metformin)/metformin LS geometric mean ratio, 1.19; 90% CI, 1.095 - 1.291). Alogliptin did not affect cimetidine pharmacokinetics. Alogliptin tolerability was similar under all conditions. Alogliptin can be administered without regard to meals and with metformin or cimetidine without the need for dose adjustment.
    International journal of clinical pharmacology and therapeutics 01/2010; 48(1):46-58. DOI:10.5414/CPP48046 · 1.22 Impact Factor
  • Ronald Christopher · Aziz Karim ·
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    ABSTRACT: Alogliptin is a new, potent, highly selective, orally available inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme developed for the treatment of Type 2 diabetes mellitus (T2DM). Inhibition of the DPP-4 enzyme, prevents the inactivation of the incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP), both of which have very short half-lives. GLP-1 and GIP are released in response to food ingestion; they enhance nutrient-induced insulin secretion and inhibit postprandial glucagon secretion. The pharmacokinetics and pharmacodynamics of alogliptin are suitable for once-daily dosing. In two Phase I clinical trials, one in healthy subjects and one in early-diagnosed patients with T2DM, alogliptin has been shown to be safe and well tolerated. In a Phase II clinical trial, alogliptin was shown to be safe and demonstrated efficacy in patients with T2DM with a dose-response profile suitable for Phase III dose selection.
    Expert Review of Clinical Pharmacology 11/2009; 2(6):589-600. DOI:10.1586/ecp.09.45 · 2.18 Impact Factor
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    ABSTRACT: Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.
    The Journal of Clinical Pharmacology 08/2009; 49(10):1210-9. DOI:10.1177/0091270009338938 · 2.48 Impact Factor
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    ABSTRACT: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D). This study was conducted to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and explore the efficacy of multiple oral doses of alogliptin in patients with T2D. In this randomized, double-blind, placebo-controlled, parallel-group study, patients with T2D between the ages of 18 and 75 years were assigned to receive a single oral dose of alogliptin 25, 100, or 400 mg or placebo (4:4:4:3 ratio) once daily for 14 days. PK profiles and plasma DPP-4 inhibition were assessed on days 1 and 14. Tolerability was monitored based on adverse events (AEs) and clinical assessments. Efficacy end points included 4-hour postprandial plasma glucose (PPG) and insulin concentrations, and fasting glycosylated hemoglobin (HbA(1c)), C-peptide, and fructosamine values. Of 56 enrolled patients (57% women; 93% white; mean age, 55.6 years; mean weight, 89.8 kg; mean body mass index, 31.7 kg/m(2)), 54 completed the study. On day 14, the median T(max) was ~1 hour and the mean t(1/2) was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P=0.008), 100 mg (-37.2; P=0.002), and 400 mg (-65.6 mg/dL; P<0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [P=0.030]; -29.2 mg/dL [P=0.002]; -27.1 mg/dL [P=0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [P=0.017]; -39.7 mg/dL [P<0.001]; -35.3 mg/dL [P=0.003]; and +12.8 mg/dL). Significant decreases in mean HbA(1c) from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P=0.044), 100 mg (-0.40%; P<0.001), and 400 mg (-0.28%; P=0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 micromol/L; P=0.001) and 400 mg (-19.9 micromol/L; P=0.010) compared with placebo (+15.0 micromol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose. In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity.
    Clinical Therapeutics 04/2008; 30(3):499-512. DOI:10.1016/j.clinthera.2008.03.004 · 2.73 Impact Factor
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    ABSTRACT: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects. This was a randomized, double-blind, placebo-controlled study in which healthy, nonobese male subjects between the ages of 18 and 55 years were assigned to 1 of 6 cohorts: alogliptin 25, 50, 100, 200, 400, or 800 mg. One subject in each cohort received placebo. An ascending-dose strategy was used, in which each cohort received its assigned dose only after review of the safety data from the previous cohort. Blood and urine were collected over 72 hours after dosing for pharmacokinetic analysis and determination of plasma DPP-4 inhibition and active glucagon-like peptide -1(GLP-1) concentrations. Thirty-six subjects (66 per cohort) were enrolled and completed the study (29/36 [81% ] white; mean age, 26.6 years; mean weight, 76.0 kg). Alogliptin was rapidly absorbed (median T(max), 1-2 hours) and eliminated slowly (mean t(1/2), 12.4-21.4 hours), primarily via urinary excretion (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60%-71%). C(max) and AUC(0-infinity) increased dose proportionally over the range from 25 to 100 mg. The metabolites M-I (N-demethylated) and M-II (N-acetylated) accounted for <2% and <6%, respectively, of alogliptin concentrations in plasma and urine. Across alogliptin doses, mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%. Exposure to active GLP-1 was 2- to 4-fold greater for all alogliptin doses compared with placebo; no dose response was apparent. Hypoglycemia (asymptomatic) was reported in 5 subjects (11 receiving alogliptin 50 mg, 2 receiving alogliptin 200 mg, 1 receiving alogliptin 400 mg, 1 receiving placebo). Other adverse events were reported in 1 subject each: dizziness (alogliptin 100 mg), syncope (alogliptin 200 mg), constipation (alogliptin 200 mg), viral infection (alogliptin 400 mg), hot flush (placebo), and nausea (placebo). In these healthy male subjects, alogliptin at single doses up to 800 mg inhibited plasma DPP-4 activity, increased active GLP-1, and was generally well tolerated, with no dose-limiting toxicity.
    Clinical Therapeutics 04/2008; 30(3):513-27. DOI:10.1016/j.clinthera.2008.03.005 · 2.73 Impact Factor
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    ABSTRACT: An open-label, randomized, 2-sequence, 4-period crossover (7-day washout period between treatment), replicate design study was conducted in 37 healthy subjects to assess intersubject and intrasubject variabilities in the peak (Cmax) and total (AUC) exposures to 2 oral antidiabetic drugs, pioglitazone and glimepiride, after single doses of 30 mg pioglitazone and 4 mg glimepiride, given under fasted state, as commercial tablets coadministered or as a single fixed-dose combination tablet. Variabilities for AUC(infinity) for coadministered and fixed-dose combination treatments were similar: 16% to 19% (intra) and 23% to 25% (inter) for pioglitazone and 18% to 19% (intra) and 29% to 30% for glimepiride (inter, excluding 1 poor metabolizer). Fixed-dose combination/coadministered least squares mean ratios of >or=0.86 and the 90% confidence intervals of these ratios for pioglitazone and glimepiride of between 0.80 and 1.25 for Cmax, AUC(lqc), and AUC(infinity) met the bioequivalency standards. Gender analysis showed that women showed mean of 16% and 30% higher exposure than men for glimepiride (excluding 1 poor metabolizer) and pioglitazone, respectively. There was considerable overlapping in the AUC(infinity) values, making gender-dependent dosing unnecessary. Patients taking pioglitazone and glimepiride as cotherapy may replace their medication with a single fixed-dose combination tablet containing these 2 oral antidiabetic drugs.
    The Journal of Clinical Pharmacology 07/2007; 47(7):806-16. DOI:10.1177/0091270007300954 · 2.48 Impact Factor
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    ABSTRACT: Bioavailability of pioglitazone and metformin, in 2 dose strengths, given either as a fixed-dose combination tablet or as coadministration of commercial tablets (coad), was studied in young healthy subjects in 2 separate studies. In study I (n = 63), single oral doses of 15-mg pioglitazone/500-mg metformin fixed-dose combination tablets or equivalent doses of commercial tablets were administered, in a fasting state, in an open-label, randomized, crossover study with a 7-day washout period between treatments. Study II (n = 61) was similar in design to study I, except the 15/850-mg fixed-dose combination tablet and coad treatments were evaluated. Least squares mean (fixed-dose combination/coad) ratios and 90% confidence intervals of the ratios for the 15/500-mg dose strength for the maximum observed serum concentration (Cmax) and area under the serum concentration-time curve from time 0 to infinity (AUC(infinity)) were 0.95 (0.86-1.05) and 1.02 (0.98-1.08), respectively, for pioglitazone and 0.99 (0.95-1.03) and 1.03 (0.98-1.08), respectively, for metformin. Bioequivalency for pioglitazone and metformin between fixed-dose combination tablets and coad treatments was met for both strengths of fixed-dose combination tablets. In a post hoc meta-analysis of combined data from the 2 studies (n = 124), there was considerable overlapping in AUC(infinity) values between gender and race (Caucasians, Blacks, and Hispanics), making neither gender- nor racial-based dosing of pioglitazone or metformin necessary.
    The Journal of Clinical Pharmacology 02/2007; 47(1):37-47. DOI:10.1177/0091270006293755 · 2.48 Impact Factor
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    ABSTRACT: An open-label, randomized, crossover study involving 28 healthy subjects was conducted to compare the peak (Cmax) and total (AUC(lqc), AUC(infinity)) exposures to pioglitazone and metformin after single-dose administration of a fixed-dose combination tablet containing 15 mg of pioglitazone plus 850 mg metformin when given under fasted versus fed states, with a washout period of 7 days between treatments. Two different fixed-dose combination formulations (bilayer and pioglitazone-micronized fixed-dose combination tablets) were tested. The pioglitazone-micronized fixed-dose combination formulation was selected for clinical development and regulatory approval; the present study describes food effect results with this formulation. For pioglitazone, least squares mean ratios (fed/fasted) and the 90% confidence intervals of these ratios were 1.05 (0.93-1.18) for Cmax, 1.13 (1.02-1.25) for AUC(lqc), and 1.11 (1.01-1.22) for AUC(infinity). For metformin, these values were 0.72 (0.65-0.79) for Cmax, 0.87 (0.81-0.94) for AUC(lqc), and 0.87 (0.81-0.94) for AUC(infinity). Dosing with food resulted in median prolongation of tmax values by 1.5 hours for metformin and 2.0 hours for pioglitazone. Because bioequivalency criteria were met (fed/fasted 90% confidence interval between 0.80 and 1.25) for both pioglitazone and metformin AUC, fixed-dose combination tablets can be taken with or without food, but to minimize gastrointestinal adverse effects of metformin, the fixed-dose combination tablets are recommended to be taken with food.
    The Journal of Clinical Pharmacology 02/2007; 47(1):48-55. DOI:10.1177/0091270006293756 · 2.48 Impact Factor
  • Aziz Karim · Dwain Tolbert · Charlie Cao ·
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    ABSTRACT: Ramelteon is a selective MT(1)/MT(2) receptor agonist, indicated for insomnia treatment. Safety, tolerance, pharmacokinetics, and cognitive performance were evaluated following increasing ramelteon doses. Healthy adults (35-65 years) were randomly assigned to receive 1 of 5 oral ramelteon doses (4, 8, 16, 32, or 64 mg; n = 8 per group) or placebo (n = 20). C(max) and AUC(infinity) (mean [%CV]) increased with each dose: C(max) = 1.15 (109), 5.73 (97), 6.92 (77), 17.4 (76), and 25.9 (77) ng/mL, respectively, and AUC(infinity) = 1.71 (114), 6.95 (108), 9.88 (78), 22.5 (80), and 36.1 (71 n x h/mL), respectively. Mean T(max) values of 0.75 to 0.94 hours and mean elimination half-life of 0.83 to 1.90 hours remained relatively constant. Ramelteon was extensively metabolized. Besides ramelteon, 4 metabolites, M-I, M-II, M-III, and M-IV, were measured in serum. Metabolite M-II, which has shown weak ramelteon-like activity in vitro, was the major metabolite in serum. Digit Symbol Substitution Test and visual analog scale alertness scores were similar across all dose groups and did not differ from placebo. All adverse events were mild or moderate and resolved before study completion.
    The Journal of Clinical Pharmacology 03/2006; 46(2):140-8. DOI:10.1177/0091270005283461 · 2.48 Impact Factor
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    ABSTRACT: Objectives: To evaluate the plasma and cerebrospinal fluid (CSF) of subjects with Alzheimer's disease (AD) to assess celecoxib pharmacokinetics (PK) and its effects on pharmacodynamic (PD) outcome measures, prostaglandin (PG) synthesis, inflammation processes, and protein markers for AD progression and cognition. Methods: This was a 4‐week, double‐blind, placebo‐controlled trial evaluating 3 dose levels of celecoxib (50, 200 and 400 mg BID), placebo, or 1 dose level of celecoxib 400 mg BID in age‐matched controls in concurrent panels of 5 subjects each. Results: 21 subjects with AD and 5 age‐matched controls were controlled. The mean concentration of celecoxib in CSF gradually increased and peaked at 4 hours post‐dose on Day 28 for all groups, and decreased to near or below the 30‐minute pre‐dose levels by 12 hours post‐dose. Mean peak celecoxib plasma concentration peaked at 2 hours post dose on Day 28 and was not dose dependent. PD analysis revealed that Prostaglandin E2 (PGE2) levels in the CSF indicated COX‐2 inhibition at Day 28, however other inflammatory markers (Interleukin‐6) and markers for disease progression (Aβ1–42 and tau protein) were unaffected by celecoxib treatment. Cognitive performance on the ADAS‐COG improved in all treatment groups except for 50 mg BID group. The mean MMSE (Mini‐Mental Status Exam) score improved in the 50 mg BID and 400 mg BID groups, worsened in the 200 mg BID and age‐matched control groups, and remained unchanged in placebo. Computerized Neuropsychological Test Battery (CNTB) scores showed a varied response by parameter. All reported AEs were mild or moderate in intensity. The most frequently reported AEs were headache, dizziness, back pain and abdominal pain. Conclusion: Celecoxib penetrates the blood brain barrier. The PK profile is similar in AD and age‐matched control subjects. The PD analysis was inconclusive. None of the markers tested represented a useful surrogate for any effect of celecoxib. Tests of cognitive ability did not show notable or consistent improvements during celecoxib administration. Oral doses of celecoxib 50, 200, 400 mg BID were well tolerated in patient with AD and the age‐matched control subjects.
    Clinical Research and Regulatory Affairs 10/2004; 21(1):49-66. DOI:10.1081/CRP-120030034
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    ABSTRACT: Adverse reactions to medications account for a substantial number of hospitalizations and in some cases fatalities. The nature of the many drug-drug interactions caused by the inhibition of drug-metabolizing enzymes can now be predicted and examined with a greater deal of accuracy due to research developments in the understanding of the drug-metabolizing enzymes. However, the more troubling aspects of drug-drug interactions are the idiosyncratic reactions that are unpredictable and quite often life-threatening. These reactions are often caused by a prior sensitization of a person's immune system to a given drug or class of drugs. The following work offers a technique to examine in a medium-throughput system the cross-reactivity of drugs to antibodies in order to predict if structures share the same antigenic potential toward a sensitized individual. Two commercially important sulfonamide drugs, sulfamethazine and furosemide, were taken and their binding to their respective antibodies were tested in the presence of other structurally related sulfonamide drugs. The BIACORE 3000 biosensor was used for the study and the solution-phase equilibrium assay principle was employed. The data obtained help us determine which drugs can react, and to what extent, with sulfamethazine and furosemide, giving rise to possible allergic or hypersensitivity reactions. Though sulfamethazine and furosemide were used in this study; this principle and methodology can be applied to study any drug molecule-antibody pair.
    Analytical Biochemistry 02/2002; 300(2):177-84. DOI:10.1006/abio.2001.5467 · 2.22 Impact Factor
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    ABSTRACT: A single-center, double-blind, placebo-controlled, randomized study was conducted to determine the pharmacokinetics, safety, and tolerability of single, rising intramuscular (i.m.) doses and the single maximum tolerated dose of parecoxib sodium, a prodrug of the novel COX-2 selective anti-inflammatory analgesic drug valdecoxib, in 56 healthy male volunteers, ages 18 to 45 years inclusive. Cohorts of up to 6 subjects in each dose schedule were administered either parecoxib sodium (1 mg, 2 mg, 5 mg, 10 mg, 20 mg, or 40 mg) or matching placebo. Following i.m. administration, serial blood samples for measurement of plasma concentrations of parecoxib, valdecoxib, and valdecoxib metabolite (M1) were collected at predetermined intervals (from 15 minutes prior to dose and through 96 hours postdose). Urine collections were obtained for drug assay (from -12 to 0 hours, 0 to 12 hours, and 12 to 24 hours postdose). After i.m. administration, peak plasma concentrations of parecoxib were reached within 15 minutes and then declined rapidly as prodrug was converted to the active moiety, valdecoxib. Change in plasma concentrations of valdecoxib, which declined more slowly (t(1/2) = 5.4-9.9 hours), reflected transformation to several metabolites, one of which was the minor active metabolite M1. As measured by the AUC(0-infinity), Cmax, and XU(0-24) of valdecoxib, parecoxib sodium demonstrated dose proportionality when administered in the range of 1 mg to 40 mg of parecoxib. All single i.m. doses up to the maximum of 40 mg of parecoxib, as well as concentrations of up to 20 mg/ml, were well tolerated.
    The Journal of Clinical Pharmacology 11/2001; 41(10):1111-9. DOI:10.1177/009127000104101010 · 2.48 Impact Factor
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    ABSTRACT: Activation of coagulation induces a proinflammatory response in in vitro and animal experiments. Inhibition of the tissue factor-dependent pathway of coagulation inhibits cytokine release and prevents death in gram-negative sepsis models in primates. This study investigated the influence of blocking the coagulation system by tissue factor pathway inhibitor (TFPI) on endotoxin-induced inflammatory responses in healthy humans. Eight men were studied in a double-blind, randomized, placebo-controlled cross-over study. They received a bolus intravenous injection of 4 ng/kg of endotoxin, followed by a 6-h continuous infusion of either TFPI (0.2 mg/kg/h after a bolus of 0.05 mg/kg) or placebo. Endotoxin induced-activation of coagulation was prevented completely by TFPI. In contrast, TFPI did not influence leukocyte activation, chemokine release, endothelial cell activation, or the acute phase response. Thus, complete prevention of coagulation activation by TFPI does not influence activation of inflammatory pathways during human endotoxemia.
    The Journal of Infectious Diseases 07/2001; 183(12):1815-8. DOI:10.1086/320723 · 6.00 Impact Factor
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    ABSTRACT: Celecoxib pharmacokinetics was evaluated after single and multiple oral dosing; after dosing in a solution and as a solid; with and without food; and after administration into different sites of the GI tract using dog. After oral dosing in a solution, celecoxib was rapidly absorbed and reached maximum concentrations by 1 h; absorption was delayed another 1 to 2 h when administered as a solid. The absolute bioavailability of celecoxib was higher when given as a solution (64--88%) compared with capsule (22--40%). The absorption of celecoxib given in a capsule was delayed by food, although systemic exposure increased by 3- to 5-fold. The systemic availability of celecoxib given intragastrically in solution was similar to that obtained following direct instillation into the duodenum, jejunum, or colon through a chronic intestinal access port. Collectively, these data suggest that celecoxib is a highly permeable drug that can be absorbed throughout the GI tract and that dissolution may be a rate-limiting factor for absorption from solid dosage forms. Unlike dogs, celecoxib given to humans with a high fat meal exhibits only a slight increase in AUC(0--infinity) (11%) that is not clinically significant with regard to safety or efficacy. In humans, a lower dose and a longer GI residence time may promote the opportunity for absorption of a poorly soluble drug such as celecoxib that can be absorbed throughout the GI tract. This would minimize the effect of food on absorption; as such, patients with arthritis can be given celecoxib with or without food.
    Journal of Pharmacology and Experimental Therapeutics 06/2001; 297(2):638-45. · 3.97 Impact Factor

  • Anesthesiology 09/2000; 93(Supplement):A-945. DOI:10.1097/00000542-200009001-00945 · 5.88 Impact Factor
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    ABSTRACT: The objective of this study was to determine the effects of celecoxib, an anti-inflammatory/analgesic agent that primarily inhibits COX-2 and not COX-1 at therapeutic doses, on the steady-state pharmacokinetic profile and hypoprothrombinemic effect of racemic warfarin in healthy volunteers. Twenty-four healthy adult volunteers on maintenance doses of racemic warfarin (2-5 mg daily), stabilized to prothrombin times (PT) 1.2 to 1.7 times pretreatment PT values for 3 consecutive days, were randomized to receive concomitant celecoxib (200 mg bid) or placebo for 7 days in an open-label, multiple-dose, randomized, placebo-controlled, parallel-group study of warfarin pharmacokinetics and PT. Steady-state exposure of S- and R-warfarin (area under the curve [AUC]) and maximum plasma concentration (Cmax) in subjects receiving celecoxib were within 2% to 8% of the warfarin AUC and Cmax in subjects receiving placebo during the concomitant treatment period. In addition, PT values were not significantly different in subjects receiving warfarin and celecoxib concomitantly compared with subjects receiving warfarin and placebo. In conclusion, concomitant administration of celecoxib has no significant effect on PT or steady-state pharmacokinetics of S- or R-warfarin in healthy volunteers.
    The Journal of Clinical Pharmacology 07/2000; 40(6):655-63. DOI:10.1177/00912700022009305 · 2.48 Impact Factor
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    ABSTRACT: We determined the disposition of a single 300-mg dose of [(14)C]celecoxib in eight healthy male subjects. The [(14)C]celecoxib was administered as a fine suspension reconstituted in 80 ml of an apple juice/Tween 80/ethanol mixture. Blood and saliva samples were collected at selected time intervals after dosing. All urine and feces were collected on the 10 consecutive days after dose administration. Radioactivity in each sample was determined by liquid scintillation counting or complete oxidation and liquid scintillation counting. Metabolic profiles in plasma, urine, and feces were obtained by HPLC, and metabolites were identified by mass spectrometry and NMR. [(14)C]Celecoxib was well absorbed, reaching peak plasma concentrations within 2 h of dosing. [(14)C]Celecoxib was extensively metabolized, with only 2.56% of the radioactive dose excreted as celecoxib in either urine or feces. The total percentage of administered radioactive dose recovered was 84.8 +/- 4.9%, with 27.1 +/- 2.2% in the urine and 57.6 +/- 7.3% in the feces. The oxidative metabolism of celecoxib involved hydroxylation of celecoxib at the methyl moiety followed by further oxidation of the hydroxyl group to form a carboxylic acid metabolite. The carboxylic acid metabolite of celecoxib was conjugated with glucuronide to form the 1-O-glucuronide. The percentages of the dose excreted in the feces as celecoxib and the carboxylic acid metabolite were 2.56 +/- 1.09 and 54.4 +/- 6.8%, respectively. The majority of the dose excreted in the urine was the carboxylic acid metabolite (18.8 +/- 2.1%); only a small amount was excreted as the acyl glucuronide (1.48 +/- 0.15%).
    Drug Metabolism and Disposition 04/2000; 28(3):308-14. · 3.25 Impact Factor
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    ABSTRACT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit cyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory response mechanisms. Celecoxib, an antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses, is expected to have minimal effects on platelet function. A double-blind, randomized, placebo-controlled study of 10 days' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a conventional NSAID. Ex vivo platelet aggregation in response to standard agonists (collagen, arachidonate, or U46619 [a thromboxane A2 receptor agonist]), bleeding time, and serum thromboxane B2 (TxB2) level were measured. Unlike celecoxib or placebo, naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time. The results indicate that even at supratherapeutic doses, celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis, supporting the premise that celecoxib is COX-1 sparing relative to conventional NSAIDs.
    The Journal of Clinical Pharmacology 03/2000; 40(2):124-32. DOI:10.1177/009127000004000202 · 2.48 Impact Factor
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    ABSTRACT: Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin-antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response. (Blood. 2000;95:1124-1129)
    Blood 03/2000; 95(4):1124-9. · 10.45 Impact Factor

Publication Stats

1k Citations
76.40 Total Impact Points


  • 2013
    • American College of Clinical Pharmacology
      Американ Форк, Utah, United States
  • 2008
    • Center for Global Development
      Washington, Washington, D.C., United States
  • 2000
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands