Aziz Karim

Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes.

BACKGROUND Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D). OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Disposition Kinetics and Tolerance of Escalating Single Doses of Ramelteon, a High-Affinity MT1 and MT2 Melatonin Receptor Agonist Indicated for Treatment of Insomnia

Ramelteon is a selective MT1/MT2 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). Cmax and AUC∞ (mean [%CV]) increased with each dose: Cmax = 1.15 (109), 5.73 (97), 6.92 (77), 17.4 (76), and 25.9 (77) ng/mL, respectively, and AUC∞ = 1.71 (114), 6.95 (108), 9.88 (78), 22.5 (80), and 36.1 (71 ng•h/mL), respectively. Mean Tmax 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.

Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects.

BACKGROUND Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. OBJECTIVE This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects. METHODS 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. RESULTS 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). CONCLUSION 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.

Simultaneous assessment of drug interactions with low- and high-extraction opioids application to parecoxib effects on the pharmacokinetics and pharmacodynamics of fentanyl and alfentanil

Background Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids. Methods After Institutional Review Board–approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 &mgr;g/kg) and fentanyl (5 &mgr;g/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography–mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores. Results There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time–concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 ± 0.25 ml · kg−1 · min−1) and 61% (9.35 ± 3.07) of control (5.53 ± 2.16 and 15.3 ± 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin. Conclusions Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or “cocktail,” dosing is useful for assessing drug interactions in humans.

Age and Gender Effects on the Pharmacokinetics and Pharmacodynamics of Ramelteon, a Hypnotic Agent Acting via Melatonin Receptors MT1 and MT2

Effects of age and gender on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic acting via binding to melatonin MT1 and MT2 receptors, were evaluated in healthy young (18–34 years) and elderly (63–79 years) volunteers. Part 1 evaluated the pharmacokinetics of open‐label oral ramelteon, 16 mg. Part 2 was a double‐blind, randomized, 2‐trial crossover pharmacodynamic study of 16‐mg ramelteon and matching placebo. Ramelteon clearance was significantly reduced in elderly vs young volunteers (384 vs 883 mL/min/kg, P < .01) and half‐life significantly increased (1.9 vs 1.3 h, P < .001). Gender did not significantly influence clearance or half‐life. Ramelteon was extensively transformed to its hydroxylated M‐II metabolite, with serum AUC values averaging about 30 times those of the parent drug. Compared to placebo, ramelteon increased self‐ and observer‐rated sedation, but age and gender did not influence the magnitude of the ramelteon‐placebo difference. Ramelteon did not significantly impair digit‐symbol substitution test performance or impair information acquisition and recall. Thus, the reduced clearance and higher serum levels of ramelteon in elderly subjects were not associated with enhanced pharmacodynamic effects. The usually recommended clinical dose of ramelteon (8 mg) does not require modification based on age or gender.

Coadministration of Pioglitazone or Glyburide and Alogliptin: Pharmacokinetic Drug Interaction Assessment in Healthy Participants

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 = 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.

Oral antidiabetic drugs: bioavailability assessment of fixed-dose combination tablets of pioglitazone and metformin. Effect of body weight, gender, and race on systemic exposures of each drug.

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∞) 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∞ values between gender and race (Caucasians, Blacks, and Hispanics), making neither gender‐ nor racial‐based dosing of pioglitazone or metformin necessary.

Clinical pharmacology of alogliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of Type 2 diabetes

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.

Oral Antidiabetic Drugs: Effect of Food on Absorption of Pioglitazone and Metformin From a Fixed‐Dose Combination Tablet

An open‐label, randomized, crossover study involving 28 healthy subjects was conducted to compare the peak (Cmax) and total (AUClqc, AUC) 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 AUClqc, and 1.11 (1.01–1.22) for AUC∞. For metformin, these values were 0.72 (0.65–0.79) for Cmax, 0.87 (0.81–0.94) for AUClqc, and 0.87 (0.81–0.94) for AUC∞. 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.

Replicate study design in bioequivalency assessment, pros and cons: bioavailabilities of the antidiabetic drugs pioglitazone and glimepiride present in a fixed-dose combination formulation.

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∞ 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 ≥0.86 and the 90% confidence intervals of these ratios for pioglitazone and glimepiride of between 0.80 and 1.25 for Cmax, AUClqc, and AUC∞ 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∞ 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.