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New Drugs 2015 New Drugs 2015 Tom Frank, Pharm.D., BCPS Director of Research and Educaon UAMS Northeast • I have no conflicts of interest to report Afrezza® (insulin human inhalaon powder) Mannkind Insulin inhalaon Pharmacology • Rapid acCng inhaled insulin to improved glycemic control in adults with diabetes • SCmulates peripheral glucose uptake by skeletal muscle and fat • Inhibits hepac glucose producCon • Produced by recombinant DNA technology • Adsorbed to carrier parCcles Insulin inhalaon PharmacokineCcs • Peak concentraon reached in 12-15 minutes • Insulin levels back to baseline in 180 minutes • Peak glucose lowering at 53 minutes • Half life 28-39 minutes • Carrier parCcles are not metabolized, eliminated unchanged • Drug interacCons: albuterol (enhanced insulin effect); hyper and hypoglycemia associated drugs as with injected insulin; hypoglycemia symptom effects reduced when on sympatheCc inhibitors Insulin inhalaon Clinical Trials • Inhaled insulin compared to insulin aspart, both added to basal, both given at mealCme • Paents with type 1 diabetes, open label trial over 24 weeks • Pre-specified non-inferiority margin -0.4% HgbA1c • Change from baseline: -0.21% HgbA1c for inhaled and -0.4% HgbA1c for aspart • HgbA1c <7% rate: 13.8% vs 27.1% • FPG change from baseline: -25.3mg/dl vs. +10.2mg/dl Insulin inhalaon Clinical Trials • Paents with type 2 diabetes inadequately controlled on (a)meeormin only or (b)two or more oral anCdiabeCc agents • Compared inhaled insulin to inhaled placebo, randomized, double-blind over 24 weeks • HgbA1c reducCon -0.82% in the inhaled group, -0.42% in the placebo group • HgbA1c < 7%: 32% vs. 15% • FPG change: -11mg/dl vs. -3mg/dl Insulin inhaled Adverse Effects • Cough • Throat pain • Hypoglycemia • Acute bronchospasm (avoid in chronic lung disease) • Decline in FEV1 over me • Lung cancer – 2 cases in clinical trials • DiabeCc ketoacidosis • HypersensiCvity reacCons • Hypokalemia • Fluid retenCon/heart failure when used with TZD’s Inhaled insulin Dosing • Check baseline spirometry, repeat in 6 months and annually • Administer at beginning of a meal • Insulin naïve: inhale four units at each meal • Previous mealCme insulin: 8 units injected = 8 units inhaled • 24 units per dose inhaled is maximum • If previous pre-mixed: divided TDD by 2 then split that number into 3 mealCme doses • Stable 10 days at room temperature • Cartridge and inhaler at room temperature for 10 minutes before dose • Replace inhaler every 15 days Jardiance® (empagliflozin) Boehringer Ingelheim Empagliflozin Pharmacology • Inhibits the SGLT2 receptors in the proximal renal tubule, reduces reabsorpCon of filtered glucose from the filtered lumen • Lowers the renal threshold for glucose, increases urinary glucose excreCon • Benefit in diabetes is as an adjunct to diet and exercise Empagliflozin PharmacokineCcs • Peak concentraon in 1.5 hours • Protein binding 86% • Metabolism by glucuronidaon but no major metabolites • Primarily excreted unchanged in urine and feces • Increased exposure in paents with renal or hepac impairment • Drug interacCons: none detected with meeormin, glimeparide, pioglitazone, sitaglipCn, warfarin, verapamil, ramipril, simvastan, hydrochlorothiazide, digoxin, oral contracepCves Empagliflozin Clinical Trials • Double-blind, placebo controlled trial T2DM • Paents received empagliflozin 10mg or 25mg daily or placebo over 24 weeks • Baseline HgbA1c was 7.9% • Change from placebo in HbA1c: -0.7% and -0.9% • HgbA1c <7%: 35% on 10mg and 44% on 25mg • FPG change: -19mg/dl, -25mg/dl and +12mg/dl in the placebo group • Weight change: -2.5kg, -2.8kg and -0.4kg respecCvely Empagliflozin Clinical Trials • Empagliflozin 10mg and 25mg daily compared to placebo when added to meeormin • Baseline HgbA1c 7.9% • Difference in HgbA1c from meeormin/placebo: empagliflozin 10mg/meormin -0.6%, empagliflozin 25/meormin -0.6% • Rates of HgbA1c < 7%: 38%, 29% and in the meeormin/placebo group 13% Empagliflozin Clinical Trials • Empagliflozin has been as add-on therapy and compared to placebo in paents not adequately controlled with insulin or insulin plus oral agents over 78 weeks • Basal insulin with or without meeormin and/ or sulfonylureas: added empagliflozin 10mg, 25mg or placebo • Change in HgbA1c aer 78 weeks: -0.4%, -0.6% and +0.1% in the group that received placebo Empagliflozin Adverse Effects • Urinary tract infecCon • Female genital mycoc infecon • Upper respiratory infecCon • Increased urinaon • Dyslipidemia • Arthralgia • Male genital mycoc infecon • Nausea • Increased serum creanine Empagliflozin Dosing • 10mg once daily in the morning with or without food • Dose may be increased to 25mg one daily if necessary • Assess renal funcCon before iniCang, do not start is eGFR is < 45ml/min/1.73m2 • Disconnue is eGFR falls to < 45ml/min/1.73m2 Tanzeum® (albigluCde) GSK AlbigluCde Pharmacology • A glucagon-like pepCde (GLP-1) agonist indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes • GLP1 agonist that augments glucose dependent insulin secreCon • Two repeats of GLP-1 fused to recombinant human albumin • Amino acid subsCtuCon to resist DPP-4 AlbigluCde PharmacokineCcs • Peak concentraon in 3-5 days • Metabolism as with nave human albumin • Half life 5 days • No pharmacokineCc differences based on age, gender, race, body weight, mild or moderate renal or hepac impairment • Increased drug exposure in severe renal impairment • Drug interacCon: simvastan AlbigluCde Clinical Trials • AlbigluCde 30mg and 50mg weekly compared to placebo in a 52 week randomized, double- blind trial of paents with type 2 diabetes inadequately controlled with diet and exercise • Change from baseline in HgbA1c: +0.2% with placebo, -0.7% with 30mg and -0.9% with 50mg • Changes in FBS from baseline: +18mg/dl, -16mg/dl and -25mg/dl AlbigluCde Clinical Trials • AlbigluCde has been evaluated in a 104 week randomized, double-blind trial of paents with type 2 diabetes inadequately controlled with meeormin • Paents assigned to: meeormin/placebo, meormin/albigluCde, meormin/sitaglipCn or meormin/glimepiride • Change from baseline in HgbA1c was: meeormin/ placebo +0.3%, meeormin/albigluCde -0.6%, meormin/sitaglipCn -0.3% and meeormin/ glimeparide -0.4% • The proporCon achieving an HgbA1c < 7% was 16%, 39%, 32% and 31% respecCvely AlbigluCde Clinical Trials • AlbigluCde given weekly has been compared to liragluCde given daily in a randomized, open-label non-inferiority trial over 32 weeks • Not controlled on monotherapy or combinaon of oral agents previously • Change in HgbA1c was -0.8% for albigluCde and -1% for liragluCde • ProporCon with HgbA1c < 7%: 42% vs 52% • Change in body weight: -0.6kg vs -2.2kg AlbigluCde Adverse Effects • Upper respiratory infecCon • Diarrhea • Nausea • InjecCon site reacCon • Cough • Back pain • Arthralgia • Sinusis • Influenza AlbigluCde Dosing • 30mg subcutaneous injecCon once weekly • Dose can be increased to 50mg if inadequate response • Separate current dose from last dose by at least 4 days • If miss dose, give within three days of scheduled dose • Allow 15 minutes aer mixing steps for product to dissolve Trulicity® (dulagluCde) Lilly DulagluCde Pharmacology • GLP-1 receptor agonist indicated as adjunct to diet and exercise for glycemic control in type 2 diabetes mellitus • 90% amino acid homology to endogenous human GLP-1 • Fusion protein with 2 chains containing N- terminal sequence linked to immunoglobulin G4 heavy chain • Increases insulin release, decreases glucagon, slows gastric emptying DulagluCde PharmacokineCcs • Time to peak 24-72 hours • Steady state concentraon reached in 2-4 weeks • Bioavailability: 0.75mg- 65%, 1.5mg- 47% • Metabolized by protein catabolism pathways • Half life 5 days • Drug interacCons: none detected DulagluCde Clinical Trials • DulagluCde compared to meormin in paents inadequately controlled on one oral agent • Received dulagluCde 0.75mg, 1.5mg or meormin 1500-2000mg/d • Aqer 52 weeks: HgbA1c changes: -0.7%, -0.8%, -0.6%; FBG changes: -26mg/dl, -29mg/dl, -24mg/dl DulagluCde Clinical Trials • Add-on study to paents already on meormin in placebo-controlled study • Received either dulagluCde 0.75mg, 1.5mg or sitaglipCn 100mg over 104 weeks • Changes in HgbA1c: -0.1%, -1%, -1.2% and -0.6% for the sitaglipCn group • Rates of HgbA1c < 7%: 22%, 56%, 62% and 39% DulagluCde Clinical Trials • Paents previously treated with one or two daily doses of insulin • Stabilized over 7 week stabilizaon period • Randomized to dulagluCde 0.75mg, 1.5mg or insulin glargine • All got pre-prandial insulin lispro • Aqer 26weeks, HgbA1c changes: -1.6%, -1.6% and -1.4% respecCvely DulagluCde Adverse Effects • Nausea • Diarrhea • Voming • Abdominal pain • Decreased appeCte • Dyspepsia • PancreaCs DulagluCde Dosing • 0.75mg subcutaneously once weekly • May increased to 1.5mg once weekly for increased glycemic control • No dose adjustment needed for paents with renal impairment Toujeo® (insulin glargine) Sanofi-AvenCs Insulin glargine Pharmacology • Long acCng insulin analog indicated for adults with diabetes mellitus • SCmulates peripheral glucose uptake and inhibits hepac glucose producCon • Soluble and buffered to pH of 4 • 300 unit/ml product has smaller surface area and 100 unit/ml • RedissoluCon is reduced • Prolonged and consistent effect Insulin glargine PharmacokineCcs • Onset of acCon over 6 hours • Takes 12-16 hours to reach peak effect • Half life 19 hours • Intersubject variability at steady state: 21% • Insulin exposure similar with lower and higher doses • Drug interacCons: risk of hypoglycemia with
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