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Mikko Niemi - One of the best experts on this subject based on the ideXlab platform.
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Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses
2020Co-Authors: Johanna Honkalammi, Mikko Niemi, Pertti J Neuvonen, Janne T. BackmanAbstract:ABSTRACT: Gemfibrozil 1-O--glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of gemfibrozil dose on CYP2C8 activity in humans using Repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of Repaglinide 1 h after different doses of gemfibrozil or placebo. Concentrations of plasma Repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. A single gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of Repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P < 0.001), and its peak concentration 1.4-, 1.7-, 2.1-, and 2.4-fold (P < 0.05), compared with placebo, respectively. Gemfibrozil pharmacokinetics was characterized by a slightly more than doseproportional increase in the area under the curve of gemfibrozil and its glucuronide. The gemfibrozil-Repaglinide interaction could be mainly explained by gemfibrozil 1-O--glucuronide concentration-dependent, mechanism-based inhibition of CYP2C8, with a minor contribution by competitive inhibition of organic aniontransporting polypeptide 1B1 at the highest gemfibrozil dose. The findings are consistent with ϳ50% inhibition of CYP2C8 already with a single 30-mg dose of gemfibrozil and >95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8
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Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses
Drug metabolism and disposition: the biological fate of chemicals, 2011Co-Authors: Johanna Honkalammi, Mikko Niemi, Jt T BackmanAbstract:Gemfibrozil 1-O-β-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of gemfibrozil dose on CYP2C8 activity in humans using Repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of Repaglinide 1 h after different doses of gemfibrozil or placebo. Concentrations of plasma Repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. A single gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of Repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P 95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.
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cyp2c8 activity recovers within 96 hours after gemfibrozil dosing estimation of cyp2c8 half life using Repaglinide as an in vivo probe
Drug Metabolism and Disposition, 2009Co-Authors: Jt T Backman, Aleksi Tornio, Mikko Neuvonen, Johanna Honkalammi, Kaisa J Kurkinen, Mikko NiemiAbstract:Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using Repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of Repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of Repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to Repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of Repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of Repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 +/- 6 h (mean +/- S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.
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the effect of slco1b1 polymorphism on Repaglinide pharmacokinetics persists over a wide dose range
British Journal of Clinical Pharmacology, 2008Co-Authors: Annikka Kalliokoski, Mikko NiemiAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Organic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes. • A common single nucleotide polymorphism, c.521TC (p.Val174Ala), of the SLCO1B1 gene has been associated with increased plasma Repaglinide concentrations in healthy volunteers. • Previous studies at low Repaglinide doses have suggested that the effect of SLCO1B1 c.521TC polymorphism on the pharmacokinetics of Repaglinide could be dose-dependent. WHAT THIS STUDY ADDS • Repaglinide peak plasma concentration and area under the plasma concentration–time curve increased linearly along with Repaglinide dose ranging from 0.25 to 2 mg in both the predominant c.521TT and rare c.521CC genotype group. • The effect of SLCO1B1 c.521TC polymorphism on Repaglinide pharmacokinetics persists over a wide dose range. AIMS To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521TC (p.Val174Ala) polymorphism on the pharmacokinetics of Repaglinide is dose-dependent. METHODS Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of Repaglinide in a dose-escalation study with a wash-out period of ≥1 week. RESULTS The mean area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) of 0.25, 0.5, 1 or 2 mg Repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P ≤ 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC0–∞ increased linearly along with Repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after Repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype. CONCLUSIONS The effect of SLCO1B1 c.521TC polymorphism on the pharmacokinetics of Repaglinide persists throughout the clinically relevant dose range.
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the effect of gemfibrozil on Repaglinide pharmacokinetics persists for at least 12 h after the dose evidence for mechanism based inhibition of cyp2c8 in vivo
Clinical Pharmacology & Therapeutics, 2008Co-Authors: Aleksi Tornio, Mikko Niemi, Annikka Kalliokoski, Mikko Neuvonen, Jouko Laitila, Jt T BackmanAbstract:Repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and 3A4. Gemfibrozil has the effect of increasing the area under the concentration-time curve (AUC) of Repaglinide eightfold. We studied the effect of dosing interval on the extent of the gemfibrozil-Repaglinide interaction. In a randomized five-phase crossover study, 10 healthy volunteers ingested 0.25 mg Repaglinide, with or without gemfibrozil pretreatment. Plasma Repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. When the last dose of 600 mg gemfibrozil was ingested simultaneously with Repaglinide, or 3, 6, or 12 h before, it increased the AUC(0-infinity) of Repaglinide 7.0-, 6.5-, 6.2- and 5.0-fold, respectively (P < 0.001). The peak Repaglinide concentration increased approximately twofold (P < 0.001), and the half-life was prolonged from 1.2 h to 2-3 h (P < 0.001) during all the gemfibrozil phases. The drug interaction effects persisted at least 12 h after gemfibrozil was administered, although plasma gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations were only 5 and 10% of their peak values, respectively. The long-lasting interaction is likely caused by mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide.
Harold E Lebovitz - One of the best experts on this subject based on the ideXlab platform.
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:Abstract This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months’ duration were randomized to receive monotherapy with Repaglinide ( n =383) or glyburide ( n =193). During weeks 1–8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80–140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5–4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effective glycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with Repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiveglycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.
Thomas Marbury - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of Repaglinide in subjects with renal impairment
Clinical Pharmacology & Therapeutics, 2000Co-Authors: Thomas Marbury, Vibeke Hatorp, Jon Ruckle, Michael P Andersen, Karin Kramer Nielsen, Won Chin Huang, Poul StrangeAbstract:Objective To evaluate the effect of renal impairment and renal failure on the pharmacokinetics and safety of Repaglinide. Methods We conducted a phase I, multicenter, parallel-group, pharmacokinetic comparison trial with single and multiple doses of Repaglinide in subjects with various degrees of renal impairment. Subjects with normal renal function (n = 6) and subjects with renal impairment (mild to moderate, n = 6; severe, n = 6) received treatment with 2 mg Repaglinide for 7 days. Subjects in the hemodialysis group (n = 6) received two single doses of 2 mg Repaglinide separated by a 7- to 14-day washout period. All subjects had Repaglinide serum pharmacokinetic profiles measured for the first and last doses administered. Serum steady-state levels, urine levels, and dialysate levels were also measured. Results Pharmacokinetic parameters did not show significant changes after single or multiple doses of Repaglinide, although the elimination rate constant in the group with severe renal impairment decreased after 1 week of treatment. Subjects with severe impairment had significantly higher area under the curve values after single and multiple doses of Repaglinide than subjects with normal renal function. No significant differences in values for maximum serum concentration or time to reach maximum concentration were detected between subjects with renal impairment and those with normal renal function. Hemodialysis did not significantly affect Repaglinide clearance. Conclusions Repaglinide was safe and well tolerated in subjects with varying degrees of renal impairment. Although adjustment of starting doses of Repaglinide is not necessary for renal impairment or renal failure, severe impairment may require more care when upward adjustments of dosage are made. Clinical Pharmacology & Therapeutics (2000) 67, 7–15; doi: 10.1067/mcp.2000.103973
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:Abstract This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months’ duration were randomized to receive monotherapy with Repaglinide ( n =383) or glyburide ( n =193). During weeks 1–8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80–140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5–4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effective glycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with Repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiveglycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.
Poul Strange - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of Repaglinide in subjects with renal impairment
Clinical Pharmacology & Therapeutics, 2000Co-Authors: Thomas Marbury, Vibeke Hatorp, Jon Ruckle, Michael P Andersen, Karin Kramer Nielsen, Won Chin Huang, Poul StrangeAbstract:Objective To evaluate the effect of renal impairment and renal failure on the pharmacokinetics and safety of Repaglinide. Methods We conducted a phase I, multicenter, parallel-group, pharmacokinetic comparison trial with single and multiple doses of Repaglinide in subjects with various degrees of renal impairment. Subjects with normal renal function (n = 6) and subjects with renal impairment (mild to moderate, n = 6; severe, n = 6) received treatment with 2 mg Repaglinide for 7 days. Subjects in the hemodialysis group (n = 6) received two single doses of 2 mg Repaglinide separated by a 7- to 14-day washout period. All subjects had Repaglinide serum pharmacokinetic profiles measured for the first and last doses administered. Serum steady-state levels, urine levels, and dialysate levels were also measured. Results Pharmacokinetic parameters did not show significant changes after single or multiple doses of Repaglinide, although the elimination rate constant in the group with severe renal impairment decreased after 1 week of treatment. Subjects with severe impairment had significantly higher area under the curve values after single and multiple doses of Repaglinide than subjects with normal renal function. No significant differences in values for maximum serum concentration or time to reach maximum concentration were detected between subjects with renal impairment and those with normal renal function. Hemodialysis did not significantly affect Repaglinide clearance. Conclusions Repaglinide was safe and well tolerated in subjects with varying degrees of renal impairment. Although adjustment of starting doses of Repaglinide is not necessary for renal impairment or renal failure, severe impairment may require more care when upward adjustments of dosage are made. Clinical Pharmacology & Therapeutics (2000) 67, 7–15; doi: 10.1067/mcp.2000.103973
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Repaglinide in type 2 diabetes a 24 week fixed dose efficacy and safety study
The Journal of Clinical Pharmacology, 2000Co-Authors: Lois Jovanovic, Won Chin Huang, Poul Strange, George Dailey, Barry J GoldsteinAbstract:In this 24-week multicenter, double-blind, randomized, fixed-dose trial, 361 patients having type 2 diabetes received daily preprandial treatment with placebo (n = 75), Repaglinide 1 mg (n = 140), or Repaglinide 4 mg (n = 146). By a last-observation carried-forward calculation, Repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by -47 mg/dL or -49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the Repaglinide treatment groups at the end of the study, changes in HbA1c from baseline values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repaglinide was well tolerated in a preprandial fixed-dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters.
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:Abstract This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months’ duration were randomized to receive monotherapy with Repaglinide ( n =383) or glyburide ( n =193). During weeks 1–8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80–140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5–4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effective glycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with Repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiveglycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.
Won Chin Huang - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of Repaglinide in subjects with renal impairment
Clinical Pharmacology & Therapeutics, 2000Co-Authors: Thomas Marbury, Vibeke Hatorp, Jon Ruckle, Michael P Andersen, Karin Kramer Nielsen, Won Chin Huang, Poul StrangeAbstract:Objective To evaluate the effect of renal impairment and renal failure on the pharmacokinetics and safety of Repaglinide. Methods We conducted a phase I, multicenter, parallel-group, pharmacokinetic comparison trial with single and multiple doses of Repaglinide in subjects with various degrees of renal impairment. Subjects with normal renal function (n = 6) and subjects with renal impairment (mild to moderate, n = 6; severe, n = 6) received treatment with 2 mg Repaglinide for 7 days. Subjects in the hemodialysis group (n = 6) received two single doses of 2 mg Repaglinide separated by a 7- to 14-day washout period. All subjects had Repaglinide serum pharmacokinetic profiles measured for the first and last doses administered. Serum steady-state levels, urine levels, and dialysate levels were also measured. Results Pharmacokinetic parameters did not show significant changes after single or multiple doses of Repaglinide, although the elimination rate constant in the group with severe renal impairment decreased after 1 week of treatment. Subjects with severe impairment had significantly higher area under the curve values after single and multiple doses of Repaglinide than subjects with normal renal function. No significant differences in values for maximum serum concentration or time to reach maximum concentration were detected between subjects with renal impairment and those with normal renal function. Hemodialysis did not significantly affect Repaglinide clearance. Conclusions Repaglinide was safe and well tolerated in subjects with varying degrees of renal impairment. Although adjustment of starting doses of Repaglinide is not necessary for renal impairment or renal failure, severe impairment may require more care when upward adjustments of dosage are made. Clinical Pharmacology & Therapeutics (2000) 67, 7–15; doi: 10.1067/mcp.2000.103973
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Repaglinide in type 2 diabetes a 24 week fixed dose efficacy and safety study
The Journal of Clinical Pharmacology, 2000Co-Authors: Lois Jovanovic, Won Chin Huang, Poul Strange, George Dailey, Barry J GoldsteinAbstract:In this 24-week multicenter, double-blind, randomized, fixed-dose trial, 361 patients having type 2 diabetes received daily preprandial treatment with placebo (n = 75), Repaglinide 1 mg (n = 140), or Repaglinide 4 mg (n = 146). By a last-observation carried-forward calculation, Repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by -47 mg/dL or -49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the Repaglinide treatment groups at the end of the study, changes in HbA1c from baseline values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repaglinide was well tolerated in a preprandial fixed-dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters.
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:Abstract This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months’ duration were randomized to receive monotherapy with Repaglinide ( n =383) or glyburide ( n =193). During weeks 1–8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80–140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5–4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effective glycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.
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Repaglinide versus glyburide a one year comparison trial
Diabetes Research and Clinical Practice, 1999Co-Authors: Thomas Marbury, Won Chin Huang, Poul Strange, Harold E LebovitzAbstract:This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that Repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with Repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of Repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with Repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naive patients suggest that patients given Repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiveglycemic control during this 1-year study. Patients using Repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.