Aziz Laurent

University of Texas at Austin, Austin, Texas, United States

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Publications (9)24.76 Total impact

  • [Show abstract] [Hide abstract]
    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: 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
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    ABSTRACT: This two-way crossover study evaluated the effect of fluconazole on the pharmacokinetics and selective COX-2 inhibition of lumiracoxib. Thirteen healthy subjects were randomized to fluconazole (day 1: 400 mg; days 2-4: 200 mg) or no drug. On day 4, all subjects received a single dose of lumiracoxib (400 mg). Lumiracoxib pharmacokinetics were assessed during the following 48 hours. Thromboxane B(2) (TxB(2)) inhibition was measured prior to lumiracoxib dosing and 2 hours afterwards. Fluconazole caused a small (18%) but not clinically relevant increase in lumiracoxib mean AUC(0- infinity ) but had no effect on lumiracoxib mean C(max). The geometric mean ratio (lumiracoxib plus fluconazole/lumiracoxib alone) for AUC(0- infinity ) was 1.19 (90% confidence interval [CI] = 1.12, 1.27) and for C(max) was 1.11 (90% CI = 0.98, 1.27). The decrease in TxB(2) from predose was not significantly different for lumiracoxib (11.8%) or lumiracoxib plus fluconazole (7.1%); no correlation between lumiracoxib concentration and TxB(2) decrease was seen. As fluconazole is a strong inhibitor of cytochrome P450 (CYP) 2C9, other CYP2C9 inhibitors are unlikely to affect lumiracoxib pharmacokinetics with clinical relevance, making dosage adjustment unnecessary.
    The Journal of Clinical Pharmacology 03/2004; 44(2):193-9. DOI:10.1177/0091270003262110 · 2.48 Impact Factor
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    ABSTRACT: Recent clinical trials in melanoma and leukemia have demonstrated potential for increased survival time and improved remission when histamine dihydrochloride is added to cytokine monotherapy. In the present study, the pharmacokinetics of subcutaneous histamine (1 mg) in 21 healthy subjects and 12 melanoma patients was determined via model-dependent methods. Drug-drug interactions with subcutaneous interleukin-2 (1.1 mg) were evaluated in a combined cohort of patients with melanoma (n = 8) or renal cell carcinoma (n = 4). Histamine dihydrochloride administered over 10 minutes in healthy subjects peaked at 18 minutes (Cmax 38 nmol/L), attained a distribution volume of 59 L, and was eliminated at 6%/min. The results were similar in a 20-minute infusion in melanoma patients. No gender effects were observed (p > 0.05). Interleukin-2 injected either 10 minutes prior to or 10 minutes following histamine dihydrochloride had no effect on histamine kinetics. Histamine dihydrochloride administered 10 minutes prior to injection of interleukin-2 also had no effect on interleukin-2 kinetics. Maximal concentration of interleukin-2 (2,442 pg/ml) occurred at 2.5 hours with an elimination half-life of 1.7 hours, area under the curve (AUC) of 15,746 pg x h/ml, and volume of distribution and plasma clearance of 194 L and 74 L/h, respectively. However, interleukin-2 Cmax (1,758 pg/ml) and AUC (12,448 pg x h/ml) were reduced when histamine dihydrochloride was infused 10 minutes following interleukin-2, likely due to the pharmacodynamic effects of histamine, including increased heart rate and reduced blood pressure. It is concluded that histamine dihydrochloride and interleukin-2 can be safely coadministered with minimal interaction.
    The Journal of Clinical Pharmacology 07/2002; 42(7):774-81. DOI:10.1177/009127000204200708 · 2.48 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
  • Noveck R.J · Aziz Laurent · Michael Kuss · Sheela Talwalker · Hubbard R.C ·
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    ABSTRACT: Objective: To compare the effects of parecoxib sodium, an injectable prodrug of a cyclo-oxygenase-2-specific inhibitor, and ketorolac on platelet function and bleeding time in elderly individuals and non-elderly adults.Design and Setting: Double-blind, randomised, active- and placebo-controlled, parallel-group studies.Patients and Participants: Healthy men and women, between the ages of 65 and 95 years (62 elderly individuals) or 18 and 55 years (48 non-elderly individuals).Methods: Participants received placebo or active medication: parecoxib sodium 40mg twice daily intravenously for 8 days (both studies), ketorolac 15mg four times daily intravenously for 5 days (elderly individuals) or 30mg four times daily intravenously for 5 days (non-elderly individuals). Ex vivo platelet aggregation responses to arachidonate, collagen and adenosine diphosphate (ADP), bleeding time and serum thromboxane B (TxB) levels were measured.Results: In both studies, parecoxib sodium had little or no effect on arachidonate-induced platelet aggregation, whereas ketorolac caused statistically significant and sustained decreases in platelet aggregation throughout the entire drug administration period. Parecoxib sodium also had little or no effect on collagen- or ADP-induced aggregation compared with ketorolac. Although there was a high degree of variability in bleeding times, significant prolongation of bleeding times was observed only in the ketorolac groups in both studies. Parecoxib sodium had no effect on serum TxB concentrations in non-elderly individuals. In elderly individuals, ketorolac significantly and profoundly reduced TxB levels at all assessments, whereas parecoxib sodium showed less of a reduction.Conclusion: Although a direct correlation has not been proven, patients with reduced platelet function do appear to be at a higher risk of experiencing increased bleeding during surgery. Thus, the absence of effect on platelet aggregation and bleeding time observed in these studies suggests that parecoxib sodium is less likely to be associated with excessive bleeding during surgery, and therefore is potentially safer than ketorolac for use in patients undergoing surgery, irrespective of age.
    Clinical Drug Investigation 06/2001; 21(7):465-476. DOI:10.2165/00044011-200121070-00002 · 1.56 Impact Factor
  • Aziz Karim · Aziz Laurent · Jiang Qian · Michael Kuss · Richard Hubbard ·

    Anesthesiology 09/2000; 93(Supplement):A-945. DOI:10.1097/00000542-200009001-00945 · 5.88 Impact Factor