A Fixed-Dose Combination Of Gemigliptin And Rosuvastatin Exhibits Similar Pharmacokinetics, Pharmacodynamics, And Safety Compared To That Of A Loose Combination In Healthy Subjects.

PURPOSE: Fixed-dose combination (FDC) of gemigliptin and rosuvastatin may improve medication compliance of patients with comorbid type 2 diabetes and dyslipidemia. Pharmacokinetics (PK), pharmacodynamics (PD), and safety of gemigliptin/rosuvastatin 50/20 mg FDC was compared with a loose combination of individual tablets in healthy subjects. PATIENTS AND METHODS: A randomized, open-label, single-dose, two-period, two-sequence, two-treatment crossover study was conducted. Subjects received FDC or a loose combination of gemigliptin (50 mg) and rosuvastatin (20 mg) during each period, with a 14-day washout. Serial blood samples were collected up to 72 hrs after dosing to measure plasma concentrations of gemigliptin, its active metabolite LC15-0636, and rosuvastatin for PK assessment, and DPP-4 activity for PD assessment. PK and PD parameters were calculated using a non-compartmental method. Safety profiles were evaluated throughout the study. RESULTS: Thirty-seven subjects completed the study. The concentration-time profiles of gemigliptin, LC15-0636, and rosuvastatin were similar between FDC and loose combination, respectively. For each of the three compounds, the geometric mean ratios (90% confidence interval) of FDC to loose combination for Cmax and AUClast fell within the bioequivalence range of 0.8-1.25. Inhibition of DPP-4 activity-time profiles after administration of FDC and loose combination was overlapping, and Imax and AUEClast were similar. Both FDC and the loose combination were well tolerated. CONCLUSION: PK, PD, and safety profiles of gemigliptin, its metabolite, and rosuvastatin were similar between FDC and loose combination. The FDC of gemigliptin (50 mg) and rosuvastatin (20 mg) can be used as an alternative to a loose combination, which is expected to improve patient compliance.

A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects.

BACKGROUND: In type 2 diabetes mellitus, fixed-dose combination (FDC) can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD), pharmacokinetic (PK), and tolerability profiles of gemigliptin and extended-release metformin (metformin XR) between FDC and separate tablets. METHODS: A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1) and metformin XR (500 mg ×2) were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4) activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs) of FDC to separate tablet formulations and their 90% confidence intervals (CIs) were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study. RESULTS: The plasma DPP-4 activity-time curves of the FDC and the separate tablets almost overlapped, leading to a GMR (90% CI) of the FDC to separate tablets for the plasma DPP-4 activity and its maximum inhibition of 1.00 (0.97-1.04) and 0.92 (0.82-1.05), respectively. Likewise, all of the GMRs (90% CIs) of FDC to separate tablets for the area under the plasma concentration-time curve and maximum plasma concentration of gemigliptin and metformin fell entirely within the conventional bioequivalence range of 0.80-1.25. Both the FDC and separate tablets were well tolerated. CONCLUSION: The PD, PK, and tolerability profiles of gemigliptin and metformin XR in FDC and separate tablets were found to be comparable. The FDC tablet of gemigliptin and metformin sustained release can be a convenient therapeutic option in patients with type 2 diabetes mellitus requiring a combination approach.

Effects of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1,000 mg (25/500 mg x 2 tablets) fixeddose combination tablet in healthy male volunteers.

OBJECTIVES: For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. MATERIALS AND METHODS: This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. RESULTS: Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. CONCLUSION: The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.

Absorption, metabolism and excretion of [14C]gemigliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans.

1. Gemigliptin (formerly known as LC15-0444) is a newly developed dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes. Following oral administration of 50 mg (5.4 MBq) [(14)C]gemigliptin to healthy male subjects, absorption, metabolism and excretion were investigated. 2. A total of 90.5% of administered dose was recovered over 192 hr postdose, with 63.4% from urine and 27.1% from feces. Based on urinary recovery of radioactivity, a minimum 63.4% absorption from gastrointestinal tract could be confirmed. 3. Twenty-three metabolites were identified in plasma, urine and feces. In plasma, gemigliptin was the most abundant component accounting for 67.2% ∼ 100% of plasma radioactivity. LC15-0636, a hydroxylated metabolite of gemigliptin, was the only human metabolite with systemic exposure more than 10% of total drug-related exposure. Unchanged gemigliptin accounted for 44.8% ∼ 67.2% of urinary radioactivity and 27.7% ∼ 51.8% of fecal radioactivity. The elimination of gemigliptin was balanced between metabolism and excretion through urine and feces. CYP3A4 was identified as the dominant CYP isozyme converting gemigliptin to LC15-0636 in recombinant CYP/FMO enzymes.

Determination of L-691,121, a new class III antiarrhythmic, and its principal metabolite in plasma by differential radioimmunoassay.

A sensitive and specific method based on radioimmunoassay (RIA) has been developed for the analysis of L-691,121, a new antiarrhythmic agent, and its major metabolite, L-692,199, in plasma. Two RIAs using immunogens and radioligands prepared from different derivatives of L-691,121 were used in conjunction to determine both parent compound and metabolite concentrations by solving simultaneous equations, since neither assay alone was adequately specific. Variable cross-reactivity factors were incorporated into the calculations to correct for non-parallel drug and metabolite displacement curves. The direct assay using 30 microliters of plasma is sensitive to 0.1 ng ml-1 and has sufficient precision, accuracy and specificity for the analysis of clinical samples.

Nonlinear elimination of methyprylon (noludar) in an overdosed patient: correlation of clinical effects with plasma concentration.

This is a report of the pharmacokinetics of methyprylon and its major plasma metabolite, 5-methylpyrithyldione, in an overdosed patient using a reversed-phase HPLC assay. The decline in the concentration of plasma methyprylon was nonlinear between 66 and 30 micrograms/mL and linear at concentrations less than 30 micrograms/mL, with an apparent half-life of 4.4 h. The concentration of 5-methylpyrithyldione reached a maximum of 17 micrograms/mL approximately 13 h after admission and declined with a half-life of 8 h. Treatment of the patient was conservative, consisting of gastric lavage and supportive therapy. The patient regained consciousness when the methyprylon concentration fell below 43 micrograms/mL, and recovered from the overdose within 24 h. These results indicate that the pharmacokinetics of methyprylon are nonlinear (concentration dependent) in this overdosed patient; explanations include saturation of one or more of the metabolic pathways and/or product inhibition. The 4-h half-life of methyprylon, generally accepted for a therapeutic dose of 300 mg, is not appropriate in intoxicated patients and would greatly underestimate the time required to reach a safe therapeutic concentration of the drug.

[Extraction of glutethimide and methyprylon from blood using thin layer chromatography]. / Wykrywanie glutetimidu i metyprylonu we krwi metoda chromatografii cienkowarstwowej.

Glutethimide and methyprylone were extracted from blood and plasma at pH ca. 4 (acetate buffer) thrice with chloroform, using 2.5 solvent volume ratio to that of aqueous phase. Phenobarbital was used as an internal standard in thin-layer chromatography experiments on silica gel--to obtain of comparable ratios of Rf values of glutethimide and/or methyprylone to that of phenobarbital. Suitable conditions of the separation of three substances were established using one of following mobile phases: benzene-dioxane-aq.ammonia (15:4:1), chloroform-acetone-aq.ammonia (25:25:1), chloroform-acetone-diaethylamine (5:4:1) and chloroform-diethyl ether-acetone (5:3:2); on 7.5 x 2.5 cm plates; development time (at 5 cm distance) was up to 10 minutes. The concentrations as small as 0.1 microg of examined substances in 1 cm3 of plasma may be identified on chromatograms using 20% Na2CO3 solution.

Interpretation of blood glutethimide, meprobamate, and methyprylon concentrations in nonfatal and fatal intoxications involving a single drug.

We evaluated blood concentrations of three nonbarbiturate sedative-hypnotics in 19 nonfatal (NF) and five fatal (F) intoxications which were "pure" (i.e. which involved only one drug each): glutethimide, 4 (NF), 3 (F); meprobamate, 9 (NF), 1 (F); and methyprylon, 6 (NF), 1 (F). For each of the 24 cases, both a comprehensive toxicology panel (including blood and urine) and the clinical history established that only a single drug had been ingested. Blood drug concentrations showed statistically significant correlation with the level of consciousness for nonfatal meprobamate intoxication (p less than 0.01) and nonfatal methyprylon intoxication (p less than 0.05). Blood glutethimide concentrations did not show such correlation. Death was associated with a mean blood glutethimide concentration in excess of 4.0 mg/dL, a blood meprobamate concentration of 20.5 mg/dL, and a blood methyprylon concentration of 11.7 mg/dL. Interpretation of blood concentrations of these compounds is discussed, and physical findings and demographic data are presented.

Gas-liquid chromatography of undervatized drugs after chromatographic extraction from blood.

We have developed an integrated method that overcomes the two main procedural difficulties of gas-liquid chromatography, namely, solvent-solvent extraction and chemical derivatization. Drugs are extracted from serum by column chromatography on granular diatomaceous earth (kieselguhr). Subsequent gas-liquid chromatography of underivatized samples can be performed on either of two liquid phases. A mixed liquid phase, used for quantitative gas-chromatographic assay on patients with a known therapeutic regimen, has enabled quantitation of 12 drugs in serum. Alternatively, a single liquid phase, used with the mixed liquid phase, permits the gas-chromatographic identification of unknown drugs on the basis of the characteristic pattern of the two relative retention times; by this approach more than 40 drugs have been identified in cases of suspected intoxication, both in serum and in gastric aspirate. Besides providing ease of performance and wide applicability, the proposed procedure offers a degree of precision and accuracy that compares favorably with established methods.

Analysis of therapeutic and commonly abused drugs in serum and urine by gas-liquid chromatography using a photoionization detector.

A simple, rapid and sensitive gas chromatographic procedure using the photoionization detector (PID) was developed for the detection and quantitation of several drugs in serum and urine. In order to evaluate the performance of the PID, the results were compared with those of the flame-ionization detector (FID). The data indicate that the PID is 8-16 times more sensitive than the FID for the drugs studied in the barbiturate group. Excellent reproducibility was found for samples quantitated with the PID on a routine basis. The PID and FID produced statistically similar results on extracted serum samples. The correlation coefficient was 0.99. The PID also produced chromatograms with less background than those obtained with the FID for many extracted serum samples. The advantages of the PID for drug analysis in biological fluids include simplicity of operation, lack of solvent response, universal drug response, non-destructive character and stability.

[A simple gas chromatographic method for the determination of hypnotics in the serum (author's transl)]. / Eine einfache gaschromatographische Methode zur Bestimmung von Schlafmitteln im Serum.

In the extract of the serum, prepared as described by Külpmann (1979) (this J. 17, 89-96), other hypnotics, in addition to the barbiturates can be determined by gas chromatography; these are: carbromal, 2,2-diethylallylacetamide, ethinamate, glutethimide, methyprylone and pyrithyldione. Methaqualone can be detected qualitatively. The coefficient of variation for the precision in the series is dependent on the hypnotic investigated and ranges from 2.1 to 8.5%, the recovery from 76 to 92%; the detection limit is estimated to be 1.6 up to 4.6 mumol/l. The specificity was proved by comparison 1) of analyses of sera from poisoned patients or animals before and after the additional purification of the extract by thin-layer chromatography, 2) with the retention times of about 100 drugs under the gas chromatographic conditions that were used. The method allows the determination of 18 barbiturates and 7 non-barbiturates within one to two hours.

[Determination of the plasma level and excretion to tempidon in man after oral use]. / Opredeliane na plazmeno nivo i ekskretsiia na tempidon u khora sled oralno prilozhenie.

Tempidone is original Bulgarian preparation, synthetized in NIHFI (Zelayskov Bikova). The plasma level of the preparation is determined after single oral administration in doses of 60 and 120 mg and for a period of five days in a dose of 20 mg three times daily per a person. It is shown that tempidone is quickly resorbed and is excreted unchanged mainly in urine. The preparation does not cumulate. The content of tempidone in plasma is determined by the method of thin-layer chromatography, but in urine-spectrophotometricaly.

Hemodialysis in methyprylon overdose. Some pharmacokinetic considerations.

Serial measurements of serum methyprylon concentration were made in the case of a 14-year-old girl who ingested an overdose of the drug. Our data indicate that, in the presence of high plasma levels of the drug, much longer half-lives than the usually reported four hours may be observed. It is postulated that saturation kinetics may be a possible mechanism for this observation. The striking clinical improvement after six hours of hemodialysis demonstrated the efficacy of this mode of treatment in our patient.

Simultaneous determination of glutethimide, methyprylon, and methaqualone in serum by gas liquid chromatography.

A gas chromatographic method is described that permits the simultaneous determination of glutethimide, methyprylon, and methaqualone in serum samples. The threshold of sensitivity for each of the three hypnotics is 0.2 mg/1.