Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment.

AIMS: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being investigated for the treatment of type 2 diabetes mellitus (T2DM). METHODS: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50 mg dose of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR). RESULTS: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under the empagliflozin concentration-time curve (AUC0 -∞ ) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate, severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed to decreased renal clearance (CLR ). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased eGFR and CLR . Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment. CONCLUSIONS: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50 mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment.

Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment.

AIMS: This open-label, parallel-group study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics, safety and tolerability of the sodium glucose cotransporter 2 inhibitor empagliflozin. METHODS: Thirty-six subjects [8 each with mild, moderate or severe hepatic impairment (Child-Pugh classification), and 12 matched controls with normal hepatic function] received a single 50 mg dose of empagliflozin. RESULTS: Empagliflozin was rapidly absorbed. After reaching peak levels, plasma drug concentrations declined in a biphasic fashion. Compared with subjects with normal hepatic function, geometric mean ratios (90% confidence interval) of AUC(0-∞) and C(max) were 123.15% (98.89-153.36) and 103.81% (82.29-130.95), respectively, in patients with mild hepatic impairment, 146.97% (118.02-183.02) and 123.31% (97.74-155.55), respectively, in patients with moderate hepatic impairment, and 174.70% (140.29-217.55) and 148.41% (117.65-187.23), respectively, in patients with severe hepatic impairment. Adverse events, all mild or moderate in intensity, were reported in three subjects with moderate hepatic impairment, two subjects with severe hepatic impairment and six subjects with normal hepatic function. CONCLUSIONS: Empagliflozin was well tolerated in subjects with hepatic impairment. Increases in empagliflozin exposure were less than twofold in patients with hepatic impairment; therefore no dose adjustment of empagliflozin is required in patients with hepatic impairment.

Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers.

AIM: To investigate potential drug-drug interactions between empagliflozin and warfarin. METHODS: Healthy subjects (n = 18) received empagliflozin 25 mg qd for 5 days (treatment A), followed by empagliflozin 25 mg qd for 7 days (days 6-12) with a single 25 mg dose of warfarin on day 6 (treatment B), and a single 25 mg dose of warfarin alone (treatment C), in an open-label, crossover study. Subjects received treatments in sequence AB_C or C_AB with a washout period of ≥14 days between AB and C or C and AB. RESULTS: Warfarin had no effect on empagliflozin area under concentration-time curve or maximum plasma concentration at steady-state (AUC(τ,ss) or C(max,ss)): geometric mean ratios (GMRs) (90% confidence intervals [CI]) were 100.89% (96.86, 105.10) and 100.64% (89.79, 112.80), respectively. Empagliflozin had no effect on AUC from 0 h to infinity (AUC(0-∞)) or C(max) for R- or S-warfarin (GMRs [90% CI] for AUC(0-∞): 98.49% [95.29, 101.80] and 95.88% [93.40, 98.43], respectively; C(max): 97.89% [91.12, 105.15] and 98.88% [91.84, 106.47], respectively). Empagliflozin had no clinically relevant effects on warfarin's anticoagulant activity (international normalised ratio [INR]) (GMR [95% CI] for peak INR: 0.87 [0.73, 1.04]; area under the effect-time curve from 0 to 168 h: 0.88 [0.79, 0.98]. No drug-related adverse events were reported for empagliflozin after monotherapy or combined administration. The combination of empagliflozin and warfarin was well tolerated. CONCLUSIONS: No drug-drug interactions were observed between empagliflozin and warfarin, indicating that empagliflozin and warfarin can be co-administered without dosage adjustments of either drug.

Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses once daily over 28 days. METHODS: A total of 78 patients were assigned to empagliflozin 10 mg (n = 16), 25 mg (n = 16) or 100 mg (n = 30) or placebo (n = 16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints. RESULTS: Empagliflozin exposure increased dose-proportionally over the dose range 10-100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%). CONCLUSIONS: Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes.

Silver cluster interferences in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of nonpolar polymers.

Potential difficulties associated with background silver salt clusters during matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) of nonpolar polymers are reported. Silver salt cluster ions were observed from m/z 1500 to 7000 when acidic, polar matrices, such as 2,5-dihydroxybenzoic acid (DHB), all-trans-retinoic acid (RTA) or 2-(4-hydroxyphenylazo)benzoic acid (HABA), were used for the analysis of nonpolar polymers. These background signals could be greatly reduced or eliminated by the use of nonpolar matrices such as anthracene or pyrene. Representative examples of these background interferences are demonstrated during the analysis of low molecular weight nonpolar polymers including polybutadiene and polystyrene. Nonpolar polymers analyzed with acidic, polar matrices (e.g., RTA) and silver cationization reagents can yield lower quality mass spectral results when interferences due to silver clusters are present. Replacing the polar matrices with nonpolar matrices or the silver salts with copper salts substantially improved the quality of the analytical results. In addition, it was found that silver contamination cannot be completely removed from standard stainless steel sample plates, although the presence of silver contamination was greatly reduced after thorough cleaning of the sample plate with aluminum oxide grit. Carry-over silver may cationize polymer samples and complicate the interpretation of data obtained using nonpolar matrices in the absence of added cationization reagents.

Ocular pharmacokinetics of cephalosporins using microdialysis.

The purpose of this study was to delineate the ocular pharmacokinetics of cephalosporins and investigate the presence of peptide transporters in the retina. New Zealand albino rabbits were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous chamber and linear probe across the cornea in the aqueous humor. Isotonic phosphate buffer saline was perfused through the probes, and samples were collected every 20 min over a period of 10 hr. A 500 microg dose of cephalexin, cephazolin, and cephalothin was administered intravitreally. Inhibition experiments were carried out in vivo, using gly-pro and gly-sar. The vitreal half-lives of cephalexin, cefazolin, and cephalothin were 185.38 +/- 27.25 min, 111.40 +/- 17.17 min, and 146.68 +/- 47.52 min, respectively. Cephalexin generated higher aqueous humor concentrations compared to cefazolin. The pharmacokinetic parameters of cephalexin in the presence of gly-pro, i.e., AUC (44452.06 +/- 3326.55 microg x min/ml), clearance (0.0013 +/- 0.0004 ml/min) and vitreal half-life (825.12 +/- 499.95 min) were different from that of the control (14612.83 +/- 4036.47 microg x min/ml, 0.0036 +/- 0.0011 ml/min, and 187.96 +/- 65.12 min, respectively). Gly-pro did not inhibit cefazolin, and gly-sar showed no effect on the pharmacokinetics of both drugs. These studies indicate the involvement of a peptide carrier in the transport of cephalosporins across the retina. Although gly-pro inhibited the elimination of cephalexin from the vitreous, the effect of an alpha-amino group on peptide carriers was not clearly evident.

Ocular pharmacokinetics in rabbits using a novel dual probe microdialysis technique.

Ocular infections involve delicate internal structures of the eye that often require treatment with antimicrobial agents. A major constraint to the study of ocular drug absorption from systemic administration is the inaccessibility of the vitreous for continuous serial sampling. A novel dual probe microdialysis technique has been employed in our laboratory, which will enable the delineation of complete ocular pharmacokinetics of a drug. New Zealand albino rabbits weighing 2--2.5 kg were used. The animals were kept under anesthesia throughout the experiment. A concentric probe was implanted in the vitreous chamber about 3 mm below the corneal scleral limbus. Simultaneously a linear probe was implanted in the anterior chamber across the cornea. Intraocular pressure (IOP) was measured using Schiotz tonometer. The total protein concentrations in the aqueous and vitreous humors were determined using the Bio-Rad protein assay method. The aqueous and vitreous elimination kinetics of fluorescein were studied after intravitreal and systemic administrations over a period of 10 hr. Microdialysis technique was also compared to the conventional direct sampling technique by determining the intravitreal kinetics of fluorescein. Results suggest that IOP reverted to normal within 2 hr after the implantation of the probes. The increase in the vitreal total protein concentration was not significantly different from the baseline. The increase in the aqueous total protein concentration was less than five times the basal concentration throughout the experiment. The blood-aqueous and blood-retinal barrier integrity was delineated by determining the permeability index for fluorescein and were found to be 9.48 +/- 4.25% and 1.99 +/- 0.66% for the anterior and vitreous chamber, respectively. The rate constant of penetration of fluorescein into the anterior chamber was found to be 8.48 +/- 1.33 x 10(-2) min(-1), which was significantly higher than into the vitreous i.e. 4.34 +/- 2.82 x 10(-2) min(-1). The terminal elimination rate constant of fluorescein from the anterior chamber (1.48 +/- 0.79 x 10(-2) min(-1)) was found to be similar to that of the plasma terminal elimination rate constant (1.57 +/- 0.25 x 10(-2) min(-1)), but significantly higher than from the vitreous (3.0 +/- 0.7 x 10(-3) min(-1)). The terminal vitreal elimination rate constant of fluorescein after intravitreal administration was found to be similar by both microdialysis (3.98 +/- 0.6 x 10(-3) min(-1)) and direct sampling (4.38 +/- 1.4 x 10(-3) min(-1)) techniques. In case of direct sampling technique the area under the vitreous concentration-time curve was higher compared to that obtained by the microdialysis technique. There was no breakdown of the blood ocular barriers as shown by a very small change in the intraocular fluid protein concentrations. This was also confirmed by the fluorescein kinetics, which were in accordance with the previous studies. IOP data suggests that the intraocular fluid dynamics were not affected and the animals stabilized within 2 hr after the implantation of the probes. Fluorescein data suggests that the vitreous compartment is surrounded by a tighter barrier compared to the anterior chamber. This technique appears to be more sensitive, reproducible and requires only one animal for the determination of entire ocular pharmacokinetic profile.