Metformin In Healthy Volunteers Research Articles

In vitro study of the drug–drug interaction potential of cetagliptin and clinical study of pharmacokinetic interaction of cetagliptin and metformin in healthy volunteers

Cetagliptin is an oral, potent, and newly developed selective inhibitor of dipeptidyl peptidase-4 (DPP-4). We evaluated the in vitro drug–drug interaction (DDI) potential of cetagliptin, as well as the pharmacokinetics of cetagliptin and metformin and the interaction between cetagliptin and metformin. Cetagliptin did not inhibit CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, only has a moderate inhibitory effect on CYP2D6, and did not induce CYP1A2, CYP2B6, and CYP3A4. Plasma protein binding of cetagliptin didn’t have species differences or concentration dependence. Cetagliptin was a substrate for P-glycoprotein (P-gp). The 34 healthy subjects enrolled were randomly divided into two sequences (A and B) with 17 subjects in each sequence. Coadministration with metformin had no effect on cetagliptin AUC0–120 (GMR, 99.25%; 90% CI, 95.96%–102.65%). There was a slightly increase in cetagliptin C max (GMR, 117.33%; 90% CI, 102.54%–134.25%). Coadministration with cetagliptin did not affect the metformin’s AUC0–24 (GMR, 108.54%; 90% CI, 101.41%–116.17%) or C max (GMR, 97.67%; 90% CI, 90.96%–104.89%). Based on in vitro study results, cetagliptin is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. Coadministration of cetagliptin and metformin had no clinically meaningful effect on the pharmacokinetics of each drug. There was no drug–drug interaction between cetagliptin and metformin. Both monotherapies and combination therapy were well tolerated. No serious AEs and hypoglycaemia was reported.

A drug\u2013drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers

PurposePeficitinib is an oral pan-Janus kinase inhibitor for the treatment of rheumatoid arthritis. Co-administration of peficitinib with metformin, a type 2 diabetes therapy, can occur in clinical practice. Hepatic and renal uptake of metformin is mediated by organic cation transporter 1 (OCT1) and OCT2, respectively, and its renal excretion by multidrug and toxin extrusion 1 (MATE1) and MATE2-K. This study investigated the effect of peficitinib on metformin pharmacokinetics in vitro and in healthy volunteers.MethodsInhibitory effects of peficitinib and its metabolite H2 on metformin uptake into human OCT1/2- and MATE1/2-K-expressing cells were assessed in vitro. In an open-label, drug–drug interaction study, 24 healthy volunteers received a single dose of metformin 750 mg on Days 1 and 10, and a single dose of peficitinib 150 mg on Days 3 and 5–11. Blood and urine samples were collected pre-dose on Days 1 and 10, and at intervals ≤ 48 h post-dose. Metformin concentration was determined by liquid chromatography–tandem mass spectrometry and its pharmacokinetic parameters calculated.ResultsPeficitinib, but not H2, inhibited metformin uptake into OCT1- and MATE1/2-K-expressing cells. Repeated-dose administration of peficitinib reduced metformin area under the concentration–time curve from 0 h extrapolated to infinity (AUCinf) by 17.4%, maximum plasma concentration (Cmax) by 17.0%, and renal clearance (CLR) by 12.9%. Co-administration of peficitinib with metformin was generally well tolerated.ConclusionSlight changes in AUCinf, Cmax and CLR of metformin were observed when co-administered with peficitinib; however, these changes were considered not clinically relevant.

A validated LC-MS/MS method for simultaneous determination of linagliptin and metformin in spiked human plasma coupled with solid phase extraction: Application to a pharmacokinetic study in healthy volunteers

Combination therapy has a pivotal role in type II diabetes mellitus management in patients unable to maintain normal glycemic level using metformin alone. Addition of linagliptin, dipeptidyl peptidase-IV inhibitor, to metformin improves glycemic control. This study is concerned with the development of an HPLC-MS/MS method for simultaneous quantification of linagliptin and metformin in spiked human plasma. The method was applied to evaluate the potential pharmacokinetic interactions between the cited drugs in healthy volunteers. Solid phase extraction was applied using Strata™ X cartridge. Separation was carried out on Symmetry® C18 column using methanol: 10 mM ammonium formate buffer (containing 0.2% formic acid) in a ratio of (95: 5, v/v) as mobile phase at flow rate 0.25 mL min−1. Quantification was performed with multiple reaction monitoring in positive ionization mode. The monitored transitions were set at m/z 473.24 → 419.94, 130.14 → 60.18 and 340.27 → 116.07 for linagliptin, metformin and alogliptin (internal standard), respectively. The method was validated according to FDA guidelines. The method showed excellent linearity over concentration ranges 0.25–10 and 25–2000 ng mL−1 for linagliptin and metformin, respectively. The validated HPLC-MS/MS method was successfully applied to pharmacokinetic study of linagliptin and metformin in healthy volunteers after oral administration of Jentadueto® tablets.

A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study.

BackgroundThe aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers.MethodsA total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated.ResultsThe plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms.ConclusionsThis study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin.Trial registrationClinicalTrials.gov NCT02712619

The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin

Pharmacokinetic outcomes of transporter-mediated drug-drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multidrug and toxin extrusion protein 1 (MATE1), using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers. Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1µM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50% inhibition (IC50) 0.25µM]. Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically [i.e. maximum unbound plasma drug concentration (C max,u)/IC50 >0.1]. Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (p<0.005). Interestingly, famotidine increased the estimated bioavailability of metformin [cumulative amount of unchanged drug excreted in urine from time zero to infinity (A e∞)/dose; p<0.005] without affecting its systemic exposure [area under the plasma concentration-time curve (AUC) or maximum concentration in plasma (C max)] as a result of a counteracting increase in metformin renal clearance. Moreover, metformin-famotidine co-therapy caused a transient effect on oral glucose tolerance tests [area under the glucose plasma concentration-time curve between time zero and 0.5h (AUCglu,0.5); p<0.005]. These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin.

The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers.

In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H(+)/organic cation antiporters, multidrug and toxin extrusion (MATE) 1 and MATE2K. Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects. Strategic cell-based screening of 71 US Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study. In healthy volunteers, the MATE2K-selective inhibitor nizatidine significantly increased the apparent volume of distribution, half-life, and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (concentration of drug producing 50% inhibition [IC50]) of MATE2K-mediated transport, nizatidine did not affect the renal clearance (CLR) or net secretory clearance of metformin. This study demonstrates that a selective inhibition of MATE2K by nizatidine affected the apparent volume of distribution, tissue concentrations, and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the CLR of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with metformin.

Steady-state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers

The aim of the study was to determine the steady-state pharmacokinetics of metformin in healthy volunteers with different numbers of reduced-function alleles in the organic cation transporter 1 gene (OCT1). The study was conducted as part of a randomized cross-over trial. Thirty-four healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9 with two reduced-function alleles) were included. In one of the study periods, they were titrated to steady-state with 1 g metformin twice daily. Neither AUC(0-12), C(max) nor Cl(renal) were statistically significantly affected by the number of reduced-function alleles (0, 1 or 2) in OCT1: (AUC(0-12): 0, 1, 2: 14, 13 and 14 h ng/L (P = 0.61)); (C(max): 0, 1, 2: 2192, 1934 and 2233 ng/mL, (P = 0.26)) and (Cl(renal): 0, 1, 2: 31, 28 and 30 L/h (P = 0.57)) CONCLUSIONS: In a cohort of healthy volunteers, we found no impact of different OCT1 genotypes on metformin steady-state pharmacokinetics.

Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers.

The organic cation transporter 1 (OCT1) plays a key role in the cellular transport of metformin and its subsequent glucose-lowering effect. A recent non-clinical study reported that metformin uptake into hepatocytes is regulated via OCT1, and that uptake was strongly inhibited by verapamil. Therefore, we investigated the effects of verapamil co-administration on the pharmacokinetics and pharmacodynamics of metformin in humans. We evaluated the pharmacokinetics and the anti-hyperglycaemic effects of metformin using an oral glucose tolerance test (OGTT) in 12 healthy participants, before (day 1) and after metformin treatment (day 2), and again on days 15 and 16 after co-administration with verapamil. Verapamil inhibited the ability of metformin to reduce maximum blood glucose concentrations (ΔGmax ) by 62.5% (P = 0.008) and decreased the area under the glucose concentration-time curve (ΔAUCgluc ) by 238% (P = 0.015). However, verapamil did not significantly alter the Cmax and the AUC of metformin, nor its renal clearance. Our results suggest that verapamil remarkably decreases the glucose-lowering effect of metformin, possibly by acting as a competitive inhibitor of OCT1.

A single-dose, crossover study comparing the pharmacokinetics and pharmacodynamics of 2 formulations of metformin in healthy volunteers

To compare pharmacokinetics and pharmacodynamics of two formulations of metformin in healthy male volunteers under fasting conditions. This was a randomized, 3-treatment, 6-sequence, 3-period, crossover study in healthy Korean volunteers. Subjects received a placebo or a single oral dose of reference formulation (500-mg metformin hydrochloride) or a test formulation (571-mg metformin acetate). The pharmacodynamic profile was assessed according to the blood glucose level. A total of 30 healthy male volunteers were included, although 2 of them withdrew consent before drug administration. For the test formulation, the mean (SD) pharmacokinetic parameters of Cmax and AUC(0-24) were 1,691 (476.7) μg/ ml and 11,081 (2,804.5) mg×h/ml, respectively. For the reference formulation, the mean (SD) pharmacokinetic parameters of C(max) and AUC(0-24) were 1,749 (494.4) mg/ml and 11,814 (3,344.2) mg×h/ml, respectively. The 90% CIs for the test:reference ratio were 86.6 - 103.5 for logarithm-transformed AUClast and 87.9 - 107.4 for logarithm-transformed C(max), respectively. In pharmacodynamic analysis, the average blood glucose levels were obtained in the first 4 hours and 5 - 8 hours after drug administration. The 90% CIs for the test:reference ratio of the average blood glucose level were 96.5 - 101.8 for the intervals up to 4 hours during continued fasting and 99.3 - 106.8 for 5 - 8 hours after drug administration, respectively. The data suggests that the test and reference formulations meet the regulatory criteria for the pharmacokinetic equivalence in fasting healthy Korean male volunteers. The pharmacodynamic profile was similar between the test and reference formulations. Both metformin formulations appeared to be generally well-tolerated.

Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin

The goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin. The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G, and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [14 homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited to this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both the groups. We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics was characterized in 23 healthy volunteers of Caucasian and African-American ancestries. We observed that the renal clearance (CL(R)) and the net secretion (SrCL(R)) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (P<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CL(R) and SrCL(R) of metformin (P<0.01). We conclude that genetic variation in OCT2 plays an important role in the CL(R) and SrCL(R) of metformin in healthy volunteers.

Clinical pharmacokinetics of metformin.

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Considerable renewal of interest in this drug has been observed in recent years. Metformin can be determined in biological fluids by various methods, mainly using high performance liquid chromatography, which allows pharmacokinetic studies in healthy volunteers and diabetic patients. Metformin disposition is apparently unaffected by the presence of diabetes and only slightly affected by the use of different oral formulations. Metformin has an absolute oral bioavailability of 40 to 60%, and gastrointestinal absorption is apparently complete within 6 hours of ingestion. An inverse relationship was observed between the dose ingested and the relative absorption with therapeutic doses ranging from 0.5 to 1.5 g, suggesting the involvement of an active, saturable absorption process. Metformin is rapidly distributed following absorption and does not bind to plasma proteins. No metabolites or conjugates of metformin have been identified. The absence of liver metabolism clearly differentiates the pharmacokinetics of metformin from that of other biguanides, such as phenformin. Metformin undergoes renal excretion and has a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 hours. This elimination is prolonged in patients with renal impairment and correlates with creatinine clearance. There are only scarce data on the relationship between plasma metformin concentrations and metabolic effects. Therapeutic levels may be 0.5 to 1.0 mg/L in the fasting state and 1 to 2 mg/L after a meal, but monitoring has little clinical value except when lactic acidosis is suspected or present. Indeed, when lactic acidosis occurs in metformin-treated patients, early determination of the metformin plasma concentration appears to be the best criterion for assessing the involvement of the drug in this acute condition. After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or haemodialysis, both of which favour rapid elimination of the drug. Although serious, lactic acidosis due to metformin is rare and may be minimised by strict adherence to prescribing guidelines and contraindications, particularly the presence of renal failure. Finally, only very few drug interactions have been described with metformin in healthy volunteers. Plasma levels may be reduced by guar gum and alpha-glucosidase inhibitors and increased by cimetidine, but no data are yet available in the diabetic population.