LY2963016 Insulin Glargine and Insulin Glargine (Lantus) Produce Comparable Pharmacokinetics and Pharmacodynamics at Two Dose Levels.

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products with identical amino acid sequences. This was a phase 1 single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period crossover study to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY IGlar and IGlar at 2 different doses. Fasted healthy subjects were randomly assigned to receive 2 single doses of LY IGlar and IGlar (0.3 and 0.6 U/kg for each product). Blood samples were collected up to 24 hours postdose to assess PK, and a euglycemic clamp lasting up to 24 hours postdose was conducted to assess PD. Twenty-four healthy subjects aged 23 to 52 years participated in the study. The primary PK parameters (area under the concentration versus time curve from 0 to 24 hours [AUC0-24 ] and maximum observed drug concentration [Cmax ]) and PD parameters (total amount of glucose infused during the clamp [Gtot ] and maximum glucose infusion rate [Rmax ]) were not statistically different between LY IGlar and IGlar at either dose. No safety concerns were noted with either drug. The study demonstrated that the PK and PD parameters for LY IGlar and IGlar were comparable following single doses at both 0.3 and 0.6 U/kg.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.

AIM: The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. METHODS: This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. RESULTS: All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. CONCLUSION: A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS.

The pharmacokinetics of linezolid are not affected by concomitant intake of the antioxidant vitamins C and E.

In vitro metabolism experiments have suggested a possible role for endogenous reactive oxygen species (ROS) in the in vivo clearance of linezolid, a synthetic antibiotic of the oxazolidinone class. This observation has resulted in the hypothesis that dietary antioxidant supplements might disturb the balance of ROS in vivo and thereby lower the clearance of linezolid. The purpose of this open-label, two-group parallel design study was to investigate whether continuous intake of widely used vitamin C or vitamin E will affect the pharmacokinetics of linezolid. A total of 28 healthy volunteers (27 male and 1 female), including 22 of Chinese origin, were administered a single oral dose of 600 mg linezolid on days 1 and 8. Half of the subjects received daily oral doses of 1000 mg vitamin C on days 2 through 9, whereas the other half were administered daily oral doses of 800 IU vitamin E during the same time period. Serial blood samples for assessment of the pharmacokinetic parameters of linezolid and its two inactive metabolites were collected on days 1 and 8, whereas vitamin concentrations were measured prior to and after the vitamin intake on these days. Urine was collected on days 1 and 8 to assess the fraction of dose excreted as linezolid and its major metabolites. All linezolid samples were analyzed according to validated HPLC/MS/MS methods. Linezolid was well tolerated in both groups with no reported clinically significant adverse events. No significant changes were found between the day 1 and day 8 AUC0- infinity and Cmax values of linezolid in either the vitamin C treatment group (p = 0.55 and p = 0.64, respectively) or the vitamin E treatment group (p = 0.06 and p = 0.49, respectively). Assessment of other pharmacokinetic parameters did not imply any change across the study groups. In conclusion, linezolid pharmacokinetics are not affected by concomitant administration with vitamins C and E. Therefore, no dose adjustment is necessary in patients taking vitamin C or vitamin E. These no-effect drug interaction data are in accord with current literature indicating that antioxidant vitamins have only subtle effects on overall ROS balance in vivo.