Repaglinide pharmacokinetics in healthy young adult and elderly subjects

doi:10.1016/S0149-2918(00)88321-6

Clinical Therapeutics

Volume 21, Issue 4, April 1999, Pages 702-710

https://doi.org/10.1016/S0149-2918(00)88321-6 Get rights and content

Abstract

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (≥65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (C_max), time to C, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.

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Cited by (57)

Parallel artificial liquid membrane extraction coupled with UPLC-ESI-MS/MS method for high-throughput quantitation of repaglinide in diabetic patients
2024, Talanta
A high-throughput therapeutic monitoring method was developed for repaglinide (RPG) in diabetic patients, combining parallel artificial liquid membrane extraction (PALME) with ultraperformance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS). PALME was performed using a 96-well donor plate comprising a donor solution containing a plasma sample, 50 mM phosphate buffer (pH = 8.0), and cetirizine (CTZ) as internal standard. A polypropylene (PP) porous membrane served as a selective support for the liquid membrane (SLM), preventing nonspecific binding produced by other membranes. The extraction was accomplished across SLM made of PP membrane with dodecyl acetate and 1 % trioctylamine (w/w), and the acceptor solution comprised DMSO and 200 mM formic acid (50:50, v/v). The simple workflow for PALME provided analyte enrichment, highly efficient sample cleanup, high throughput analysis, and excellent reproducibility. Method validation met FDA criteria, with a linear plasma calibration range (0.1–100 ng mL⁻¹, r = 0.9995) and a lower limit of quantitation (LLOQ) of 0.1 ng mL⁻¹. Recovery results at 98.9 % affirmed method reliability. The ability to analyze 198 samples per hour, coupled with a reduced amount of solvents, underscores the method's high throughput and eco-friendly profile. The PALME-UPLC-ESI-MS/MS method was successfully applied to therapeutic drug monitoring of RPG in diabetic patients following 2 mg RPG tablet administration, establishing its effectiveness.
Hydrophilic interaction liquid chromatography–electrospray ionization mass spectrometry combined with fabric phase sorptive extraction for therapeutic drug monitoring of pioglitazone, repaglinide, and nateglinide in human plasma
2023, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Polypharmacy in type 2 diabetes is an issue of major concern as the prescription of multiple medi-cations for the management of diabetes-associated comorbidities can lead to drug-to-drug interactions, which can pose serious risks to patients’ health. Within this context, the development of bioanalytical methods for monitoring the therapeutic levels of antidiabetic drugs is notably useful to ensure patients’ safety. In the present work, a liquid chromatography–mass spectrometry method for the quantitation of pioglitazone, repaglinide, and nateglinide in human plasma is described. Sample preparation was performed by fabric phase sorptive extraction (FPSE), and hydrophilic interaction liquid chromatography (HILIC) was implemented for the chromatographic separation of the analytes, using a ZIC®-cHILIC analytical column (150 × 2.1 mm, 3 µm) under isocratic elution. The mobile phase consisted of 10 mM ammonium formate aqueous solution (pH = 6.5)/ acetonitrile, 10/90 v/v, and was pumped at a flow rate of 0.2 mL min⁻¹. Design of Experiments was used during the development of the sample preparation method to gain deeper insight into the effect of various experimental parameters on extraction efficiency, their potential interactions and to optimize the recovery rates of the analytes. The linearity of the assay was assessed over the ranges of 25 to 2000, 6.25 to 500, and 125 to 10000 ng mL⁻¹ for pioglitazone, repaglinide, and nateglinide, respectively. The presented method was fully validated and can be used for the therapeutic monitoring of the targeted analytes in human plasma samples.
Development and validation of RP-HPLC method for quantification of repaglinide in mPEG-PCL polymeric nanoparticles: QbD-driven optimization, force degradation study, and assessment of in vitro release mathematic modeling
2021, Microchemical Journal
Citation Excerpt :
Repaglinide is a conventional anti-diabetic drug approved by US-Food and Drug Administration (US-FDA) in 1998. It is rapidly absorbed from the gastrointestinal tract after oral administration and acts by inhibiting the ATP-sensitive potassium channel [3,4]. It differs from other anti-diabetic agents due to its structural activities, binding profile, duration of action, and mode of excretion.
Repaglinide (REP) an insulinotropic agent used in the treatment of type-2 diabetes. It belongs to meglitinides, which act by blocking the ATP sensitive potassium channels and stimulates the insulin release. REP is the first insulin secretagogue used to target postprandial hyperglycemia. In this study, a rapid, sensitive, and reproducible RP-HPLC method has been developed and validated using an analytical quality-by-design approach. Initially, the Ishikawa fishbone diagram provides the basis of variation in critical analytical attributes with various inputs. Additionally, Taguchi design was selected to screen the critical method parameters affecting method development. Further, systemic optimization of the RP-HPLC method was determined by using Box-Behnken design. The chromatography separation was achieved by acetonitrile and phosphate buffer (60:40) with isocratic flow system on waters Nova-pack C₁₈ column (3.9 × 150 mm, 4 μm) with 0.8 mL/min flow rate and the developed method was validated as per ICH guidelines. Moreover, the force degradation studies were also performed under different conditions (acidic, basic, oxidation and photolytic) to understand the degradation pathways and products. Furthermore, an amphiphilic di-block biodegradable polymer, i.e., polyethylene glycol-polycaprolactone (mPEG-PCL) was synthesized with different molecular weights to encapsulate REP and understand the release kinetics with mathematical modeling. In addition, the validated RP-HPLC method was effectively utilized to determine percent entrapment efficiency and loading efficiency of REP loaded nanoparticles. The developed method would also be applicable to quantify the REP from the biological matrix.
Molecular pharmacokinetic mechanism of the drug-drug interaction between genistein and repaglinide mediated by P-gp
2020, Biomedicine and Pharmacotherapy
Citation Excerpt :
With this in mind, our study investigated the inhibitory influence of genistein on P-gp found that genistein enhanced the intestinal absorption of repaglinide in rats, showing the possibility of the combination use of repaglinide and genistein to treat diabetes. The pharmacokinetic characteristics of repaglinide in humans have been reported, indicating its rapid absorption and elimination with Tmax and T1/2 in an hour after oral administration [27–29]. It will be helpful to efficacy to find a nontoxic candidate for co-administration with repaglinide to improve its bioavailability.
This study was devised to investigate if P-glycoprotein (P-gp) mediated the drug–drug interaction (DDI) between genistein and repaglinide. When genistein was added, the plasma concentrations of repaglinide in rats were increased. The maximum plasma concentration (Cmax) of repaglinide increased from 70.80 ± 7.98 ng/mL to 124.71 ± 9.02 ng/mL and the area under the plasma concentration-time curve (AUC) increased from 134.89 ± 13.65 μg·h/L to 245.95 ± 7.24 μg·h/L. Intestinal absorption of repaglinide was markedly enhanced by genistein or P-gp inhibitor verapamil (Ver), both in situ rat jejunal perfusion studies and in vitro transport assays using everted rat intestinal sac preparations. Furthermore, the accumulation of repaglinide in both Caco-2 cells and IEC-6 cells also increased significantly in the presence of genistein and Ver. The transepithelial transport rate of repaglinide from basolateral-to-apical in MDR1-MDCK cells was 3.6-fold higher than the apical-to-basolateral rate with a net efflux ratio of 1.92 compared with mock-MDCK cells, which was significantly decreased following co-administration with genistein or Ver. In an intracellular accumulation experiment using Rhodamine 123 as a P-gp substrate, genistein significantly increased the intracellular fluorescence of Rhodamine 123. These results indicated that genistein had an inhibitory effect on the efflux function of P-gp. Through molecular docking assays we further found that genistein could bind to the nucleotide-binding domains (NBD) in the cytoplasm of P-gp, thus affecting the functions of P-gp. In conclusion, genistein inhibited the efflux of repaglinide mediated by P-gp in rats and in vitro. The findings suggested that the DDI between genistein and repaglinide is mediated by P-gp, and a dosage adjustment may be needed when they are co-administered in a clinical setting.
Analysis of the variability of the pharmacokinetics of multiple drugs in young adult and elderly subjects and its implications for acceptable daily exposures and cleaning validation limits
2017, International Journal of Hygiene and Environmental Health
The elderly constitute a significant, potentially sensitive, subpopulation within the general population, which must be taken into account when performing risk assessments including determining an acceptable daily exposure (ADE) for the purpose of a cleaning validation. Known differences in the pharmacokinetics of drugs between young adults (who are typically the subjects recruited into clinical trials) and the elderly are potential contributors affecting the interindividual uncertainty factor (UF_H) component of the ADE calculation. The UF_H values were calculated for 206 drugs for young adult and elderly groups separately and combined (with the elderly assumed to be a sensitive subpopulation) from published studies where the pharmacokinetics of the young adult and elderly groups were directly compared. Based on the analysis presented here, it is recommended to use a default UF_H value of 10 for worker populations (which are assumed to be approximately equivalent to the young adult groups) where no supporting pharmacokinetic data exist, while it is recommended to use a default UF_H value of 15 for the general population, to take the elderly into consideration when calculating ADE values. The underlying reasons for the large differences between the exposures in the young adult and elderly subjects for the 10 compounds which show the greatest separation are different in almost every case, involving the OCT2 transporter, glucuronidation, hydrolysis, CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP3A4 or CYP3A5. Therefore, there is no consistent underlying mechanism which appears responsible for the largest differences in pharmacokinetic parameters between young adult and elderly subjects.
Comparative Bioavailability and Tolerability of a Single 2-mg Dose of 2 Repaglinide Tablet Formulations in Fasting, Healthy Chinese Male Volunteers: An Open-Label, Randomized-Sequence, 2-Period Crossover Study
2013, Current Therapeutic Research - Clinical and Experimental
Citation Excerpt :
During short- and long-term administration repaglinide has been well tolerated and few patients have withdrawn from treatment because of adverse effects.3,4 The pharmacokinetic profile of repaglinide has been reported in humans.5–7 Cmax is reached 30 to 60 minutes after administration.
Repaglinide, an oral insulin secretagogue, was the first meglitinide analogue to be approved for use in patients with type 2 diabetes mellitus.
In our study, the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of repaglinide 2 mg were compared in a fasting, healthy Chinese male population.
This 2-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in 22 healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 2-mg dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. After an overnight fast, subjects received a single oral dose of repaglinide (2 mg). Blood samples were drawn at predetermined time points (0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 6.0 hours). All plasma concentrations of repaglinide were measured by LC-MS/MS. The observed C_max, T_max, t_1/2, and AUC were assessed. The formulations were to be considered bioequivalent if the ln-transformed ratios of C_max and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration of the People’s Republic of China. Tolerability was assessed throughout the study via subject interview, vital signs, and blood sampling.
The mean (SD) age of the subjects was 24.2 (2.3) years; their mean (SD) weight was 62.6 (5.8) kg, their mean (SD) height was 172 (5.7) cm, and their mean (SD) body mass index was 21.0 (1.1). The mean (SD) C_max for repaglinide with the test and reference formulations were 20.0 (5.1) and 18.7 (8.7) ng/mL. The AUC_0–t for the test formulation was 46.3 (15.1) and AUC_0–∞ was 47.9 (16.5) ng^•h/mL. With the reference formulation, the corresponding values were 46.4 (26.1) and 49.0 (31.3) ng^•h/mL. The mean (SD) T_max values with the test and reference formulations were 1.2 (0.7) hours and 1.5 (0.8) hours and the mean (SD) values t_1/2 values were 1.0 (0.3), and 0.9 (0.3) hours, respectively. The ln-transformed ratios of C_max, AUC_0–t, and AUC_0–∞ were 113.6:1, 105.6:1, and 104.7:1. The corresponding 90% CIs were 99.8 to 129.2, 93.4 to 119.5, and 91.8 to 119.5, respectively.
This single-dose study found that the test and reference formulations of repaglinide met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. ClinicalTrials.gov identifier: 2012L01684.

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New drugRepaglinide pharmacokinetics in healthy young adult and elderly subjects

Abstract

Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults

The pharmacological treatment of hyperglycemia in NIDDM

Diabetes Care

Non-insulin-dependent diabetes mellitus in the elderly

Bailliere's Clin Endocrinol Metab

Oral antihyperglycaemics. Considerations in older patients with non-insulin-dependent diabetes mellitus

Drugs Aging

Hypoglycemia and type II diabetes: Sulfonylureas

Management of non-insulin-dependent diabetes mellitus in Europe: A consensus view

Diabetic Med

Physician's Guide to Non-Insulin-Dependent (Type II) Diabetes: Diagnosis and Treatment

New drug
Repaglinide pharmacokinetics in healthy young adult and elderly subjects