New Drugs 2016
Tom Frank, Pharm.D., BCPS Director of Research and Education UAMS Northeast . I have no conflicts of interest to report
Entresto® (Sacubitril/valsartan) Novartis Sacubitril/valsartan Pharmacology • Indicated for reduced risk of cardiovascular death and hospitalization related to heart failure • Patients with chronic heart failure and reduced ejection fraction • Sacubitril is a neprilysin inhibitor, this inhibition increases levels of natriuretic peptides as well as bradykinin and adrenomedullin • Valsartan blocks the angiotensin II type 1 receptor
Sacubitril/valsartan Pharmacokinetics • The initial form (LCZ696) dissociates into sacubitril and valsartan; Sacubitril converted to LBQ657 by esterases • Higher bioavailability of this form of valsartan • Food does not influence absorption • All highly protein bound • Half life: Sacubitril 1.4hrs, LBQ657 11.5hrs, valsartan 9.9hrs. • Drug interactions: avoid concurrent ACEI/ARB; potassium increases, NSAID’s, lithium; avoid aliskirin in diabetic patients Sacubitril/valsartan Clinical Trials
• LCZ696 compared to enalapril in randomized, double-blind trial of patients with systolic dysfunction • ACEI or ARB plus beta blocker for at least four weeks • Sequential run-in receiving enalapril 10mg bid for 4 weeks then LCZ696 100mg bid for four weeks • Then randomized to LCZ696 200mg twice daily or enalapril 10mg twice daily Sacubitril/valsartan Clinical Trials
• Primary end point of evaluation: cardiovascular death or hospitalization for heart failure • Median follow up 27 months • Trial stopped by DSMB at third pre-specified end point • End point reached 21.8% on LCZ696, 26.5% enalapril • CV death 9% vs 10.9% respectively • All cause mortality 17% vs 19.8% respectively Sacubitril/valsartan Adverse Effects • Hypotension • Hyperkalemia • Cough • Dizziness • Renal failure • Orthostasis • Angioedema Sacubitril/valsartan Dosing • Already on >enalapril 10mg/day: hold ACEI 36hrs then start LQZ696 49/51mg twice daily; if
Praluent® (alirocumab) Regeneron Alirocumab Pharmacology • Inhibitor antibody of Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) • Indicated as adjunct to diet and maximally tolerated statin therapy • Heterozygous familial hypercholesterolemia • ASCVD patients who require additional lowering of LDL-C • Antibody binds to PCSK9 enzyme • Enzyme does not bind to LDL-C receptor • Receptor avoids degradation and get recycled to surface of hepatocyte
Alirocumab Pharmacokinetics • Bioavailability 85% • Peak concentration 3-7 days after injection • Steady state after 2-3 doses • Only distributed to circulatory system • Elimination by proteolytic pathways • Half life 17-20 days, 12 days when taken with statin • Drug interactions: none detected with statins Alirocumab Clinical Trials
• Alirocumab 150mg SQ every two weeks compared to placebo, double-blind, randomized, parallel group over 78 weeks • Patients with heterozygous FH, CHD or CHD equivalent • All received maximal dose statins • All with baseline LDL-C greater than 70mg/dl • Primary end point: change in LDL-C from baseline to week 24 • Results: treatment group 61% decrease, placebo group 0.8% decrease • Mean absolute change from baseline was -74mg/dl to level of 48mg/dl • Post-hoc cardiac outcomes rate 1.7% vs 3.3% Alirocumab Adverse Effects • Injection site reactions • Myalgia • Muscle spasms • Confusion • Musculoskeletal pain • Diarrhea • Cough Alirocumab Dosing • 75mg subcutaneously every two weeks • If response inadequate can increase to 150mg every two weeks Most awkward moment: The director of my play asked the audience to “turn off their phones and vibrators” instead of setting phones to vibrate
Repatha® (evolocumab) Amgen Evolocumab Pharmacology • Inhibitor antibody of Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) • Indicated as adjunct to diet and maximally tolerated statin therapy • Patients with heterozygous FH, clinical ASCVD who require additional lowering of LDL-C, homozygous FH who require additional lowering of LDL-C Evolocumab Pharmacokinetics • Bioavailability 72% • Maximum suppression of unbound PCSK9 by 4 hours after dosing • Half-life 11-17 days • Drug interactions: none clinically meaningful Evolocumab Clinical Trials • Open-labeled, randomized trials enrolled patients who had previously been in phase 2 or 3 trials • Received either evolocumab 420mg SQ once monthly or 140mg SQ every two weeks plus standard therapy vs. standard therapy • Median LDL-C before randomization 120mg/dl • Evolocumab group had 61% LDL-C reduction to median of 48mg/dl • Pre-specified exploratory outcome of cardiovascular event rates at one year 0.98% vs. 2.18% Evolocumab Adverse Effects • Upper respiratory tract infection • Influenza • Back pain • Injection site reaction • Myalgia • Musculoskeletal pain • Neurocognitive events Evolocumab Dosing • Heterozygous FH or primary hyperlipidemia with CVD risk: 140mg subcutaneously every two weeks or 420mg one monthly (3 injections of 140mg) • Homozygous FH: 420mg subcutaneously once monthly • Check LDL-C 4-6 weeks after starting • Do not rub injection site • Store in refrigerator Most awkward moment: I was looking for clip on sunglasses to go over my prescription glasses. Asked the pharmacist At CVS if they sold “strap ons”.
Addyi® (flibanserin) Sprout Flibanserin Pharmacology • Indicated for hypoactive sexual desire disorder (HSDD) in premenopausal women • 5HT1A agonist and 5HT2A antagonist in the prefrontal cortex • Thought to reduce glutamate transmission in brainstem resulting in disinhibition of ascending dopamine and norepinephrine neurons plus inhibition of ascending serotonin neurons Flibanserin Pharmacokinetics • Bioavailability 33% • Increased absorption when taken with high fat meal or grapefruit juice • Metabolism predominantly by CYP 3A4 • Half life 11 hours • Drug interactions: CYP 3A4 inhibitors, CYP 3A4 inducers, digoxin; avoid alcohol while taking (hypotension) Flibanserin Clinical Trials • Flibanserin 100mg daily compared to placebo over 24 weeks • Premenopausal women with primary diagnosis HSDD • Co-primary end points: number of Satisfying Sexual Experiences (SSE) and Female Sexual Function Index – Sexual Desire Domain (FSFI-Desire) • After 24 weeks: SSE 2.5 per month for flibanserin, 1.5 for placebo change from baseline; FSFI-Desire improved by 1.0 in the flibanserin group and 0.7 in placebo group Female Sexual Function Index (Desire Segment) . 1. Over the past 4 weeks, how often did you feel sexual desire or interest? • Almost always or always • Most times (more than half the time) • Sometimes (about half the time) • A few times (less than half the time) • Almost never or never • (answer scores from five points down to one point) Female Sexual Function Index (Desire Segment) . 2. Over the past 4 weeks, how would you rate your level of sexual desire or interest? • Very high • High • Moderate • Low • Very low or none at all • (answer scores from five points down to one point) • Total answers 1 and 2, multiply by 0.6 to get FSFI-Desire Score that ranges from 1.2-6 Efficacy and Safety of Flibanserin in HSDD- Systematic Review and Meta-Analysis . 5 published and 3 unpublished studies (n=5914) . Pooled mean differences for Satisfying Sexual Events: 0.49 per four weeks (for published studies difference was 0.54) . For FSFI-Desire- mean difference was 0.27 points
Doi:10.1001/jamaintmed.2015.8565 Flibanserin Adverse Effects • Dizziness • Somnolence • Fatigue • Nausea • Insomnia • Dry mouth Flibanserin Dosing • 100mg at bedtime daily • Evaluate efficacy after 8 weeks • REMS must be reviewed Most awkward moment Got into the passenger seat of the wrong car outside of Starbucks. The driver waited until I finished my call to tell me.
Adlyxin® (lixisenatide) Sanofi Lixisenatide Pharmacology • GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus • Increases glucose-dependent insulin release, decreases glucagon secretion, slows gastric emptying Lixisenatide Pharmacokinetics • Peak concentration 1-3.5hrs after injection • Similar absorption thigh abdomen or arm • Eliminated by glomerular filtration and proteolytic degradation • No changes in kinetics based on age, body weight, gender or race; increased levels in decreased renal function • Drug interactions: related to delayed gastric emptying; APAP or antibiotics- give one hour before dosing; ocp’s one hour before or 11 hours after; no changes detected with atorvastatin, digoxin, warfarin, ramipril Lixisenatide Clinical Trials • Lixisenatide 20mcg compared to plabebo over 12 weeks: HgbA1c -0.83% vs. -0.18%; FGP change -15mg/dl vs. -1.4mg/dl • Lixisenatide 20mcg added to metformin compared to metformin plus placebo: HgbA1c -0.72% vs -0.26%; FPG change -16mg/dl vs. -7.2mg/dl • Lixisenatide 20mcg added to basal insulin plus metformin compared to basal insulin/metformin/placebo: HgbA1c -0.71% vs. -0.34% • Lixisenatide compared to liraglutide over 24 weeks, added to metformin; additional reduction in HgbA1c -1.21% for lixisenatide vs. -1.83% for liraglutide Lixisenatide Clinical Trials
. Cardiovascular safety has been examined in a double- blind, placebo controlled trial . T2DM with history of acute coronary syndrome in past six months (n=6068) . Received lixisenatide 20mcg daily or placebo plus standard diabetes medications . Median observation time 25 months . Primary composite CV endpoint reached in 13.4% in the lixisenatide group and 13.2% in the control group Lixisenatide Adverse Effects • Nausea • Vomiting • Headache • Diarrhea • Dizziness Lixisenatide Dosing • Initial dose 10mcg subcutaneously once daily for 14 days • On day 15, increase dose to 20mcg daily Most awkward moment: Pre PAP test my friend sprayed perfume on her lady garden. Doc says, “that’s festive.” It was her daughter’s glitter spray
Jardiance® (empagliflozin) Boehringer Ingelheim Empagliflozin Pharmacology • Inhibits the SGLT2 receptors in the proximal renal tubule, reduces reabsorption of filtered glucose from the filtered lumen • Lowers the renal threshold for glucose, increases urinary glucose excretion • Benefit in diabetes is as an adjunct to diet and exercise Empagliflozin Pharmacokinetics • Peak concentration in 1.5 hours • Protein binding 86% • Metabolism by glucuronidation but no major metabolites • Primarily excreted unchanged in urine and feces • Increased exposure in patients with renal or hepatic impairment • Drug interactions: none detected with metformin, glimeparide, pioglitazone, sitagliptin, warfarin, verapamil, ramipril, simvastatin, hydrochlorothiazide, digoxin, oral contraceptives Empagliflozin Clinical Trials • Double-blind, placebo controlled trial T2DM • Patients 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 respectively Empagliflozin Clinical Trials • Empagliflozin 10mg and 25mg daily compared to placebo when added to metformin • Baseline HgbA1c 7.9% • Difference in HgbA1c from metformin/placebo: empagliflozin 10mg/metformin -0.6%, empagliflozin 25/metformin -0.6% • Rates of HgbA1c < 7%: 38%, 29% and in the metformin/placebo group 13% Empagliflozin Clinical Trials • Empagliflozin has been as add-on therapy and compared to placebo in patients not adequately controlled with insulin or insulin plus oral agents over 78 weeks • Basal insulin with or without metformin and/ or sulfonylureas: added empagliflozin 10mg, 25mg or placebo • Change in HgbA1c after 78 weeks: -0.4%, -0.6% and +0.1% in the group that received placebo Empagliflozin Clinical Trials • EMPA-REG Outcome- T2DM patients with established cardiovascular disease • Compared empagliflozin to standard care over 3.1 years • All cause mortality 5.7% vs 8.3% (32% difference); difference not is nonfatal MI or strokes, mostly in decreased CV death • 35% decrease in hospitalization for HF • But why? Maybe osmotic diuresis and sodium loss, maybe improved blood pressure, endothelial function and cardiac function; maybe staying away from other negative drugs • Potential to change guidelines regarding second oral drug to be started
NEJM 2015; 373:2117-2128 Empagliflozin Adverse Effects • Urinary tract infection • Female genital mycotic infection • Upper respiratory infection • Increased urination • Dyslipidemia • Arthralgia • Male genital mycotic infection • Nausea • Increased serum creatinine Empagliflozin Dosing • 10mg once daily in the morning with or without food • Dose may be increased to 25mg once daily if necessary • Assess renal function before initiating, do not start is eGFR is < 45ml/min/1.73m2 • Discontinue is eGFR falls to < 45ml/min/1.73m2 Most awkward moment On a trip, saw some baby horses, could not think of the word foal, finally shouted “horse kittens” and pointed. Wife understood.
Toujeo® (insulin glargine) Sanofi-Aventis Insulin glargine Pharmacology • Long acting insulin analog indicated for adults with diabetes mellitus • Stimulates peripheral glucose uptake and inhibits hepatic glucose production • Soluble and buffered to pH of 4 • 300 unit/ml product has smaller surface area and 100 unit/ml • Redissolution is reduced • Prolonged and consistent effect Insulin glargine Pharmacokinetics • Onset of action 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 interactions: risk of hypoglycemia with drugs that are prone to cause; glucose lowering effect decreased with atypicals, diuretics, niacin, OCP’s, SNS mimetics Becker R.H.A. et al. Diabetes Care 2015;38:637-643 Insulin glargine Clinical Trials
• Gla-300 compared to Gla-100, patients with T2DM on ≥42 units/day plus oral agents • Six month study • Primary end point: change in HgbA1c, secondary end point: rates of hypoglycemia • HgbA1c changes: -0.57% vs -0.56% • 10% more units of Gla-300 on average • Less nocturnal hypoglycemia and severe hypoglycemia with Gla-300 Insulin glargine Clinical Trials
• Gla-300 compared to Gla-100, patients with T2DM using basal insulin ≥42 units/day plus mealtime insulin with or without metformin over 6 months • Doses titrated to preprandial 90-130mg/dl • Baseline HgbA1c 8.15% • Mean HgbA1c at end of study 7.25% with Gla-300 and 7.28% with Gla-100 • Insulin dose changes: Gla-300: 70 units/day to 103 units/day; Gla-100: 71 units/day to 94 units/day • Nocturnal hypoglycemia events: 36% vs. 46% respectively Insulin glargine Adverse Effects • Nasopharyngitis • Upper respiratory infection Insulin glargine Dosing • T1DM (insulin naïve): 0.2-0.4 units per Kg once daily • Maximum effect may take 5 days to manifest • May be insufficient effect in first 24 hours of use • T2DM (insulin naïve): 0.2 units per Kg once daily • T2DM already on insulin: • 1:1 conversion for patients on once-daily long acting insulin • When changing from twice daily NPH to Gla-300, give 80% of the total daily dose of NPH initially Most awkward moment A friend went and placed her order at the drive thru. She then heard ”Could you drive up to the speaker you are talking to the trash can?”
Tresiba® (insulin degludec) Novo Nordisk Insulin degludec Pharmacology • Ultra-long acting basal insulin • Indicated for use in both type 1 and type 2 diabetes • Based on two modifications to human insulin • Last amino acid on B-chain is omitted • Dicarboxylic fatty acid coupled by glutamic acid spacer to lysine a B29 • Forms stable multi-hexamers Insulin degludec Pharmacokinetics • Steady state after three days • Plasma profile insulin concentration is flat • Half life 25 hours, glucose lowering effect 42 hours • Drug interactions: usual suspects that influence changes in glucose: hypoglycemia with ACEI’s, hypoglycemia agents; decreased efficacy with atypicals, corticosteroids, niacin; enhanced effect with alcohol, lithium, beta blockers; blunt symptoms with beta blockers, clonidine Insulin degludec Clinical Trials • Insulin degludec compared to insulin glargine, open- label, treat-to-target, non-inferiority trial, type 1 diabetes over 52 weeks • Bolus insulin doses by algorithm • HgbA1c changes: -0.4% vs -0.39% • HgbA1c < 7%: 40% vs 43% • Hypoglycemia rates: 42 per pt. yr. vs 40 per pt. yr. • Nocturnal hypoglycemia: 4.41 per pt. yr. with degludec, 5.86 per pt. yr. with glargine Insulin degludec Clinical Trials • Insulin degludec compared to insulin glargine, open-label, randomized, treat-to-target; non- inferiority trial over 52 weeks • All had been on another insulin regimen with or without oral agents for at least 3 months • HgbA1c change after 52 weeks: -1.1% vs -1.2% • Hypoglycemia rates: 11.1 per pt. yr. vs 13.6 per pt. yr. Insulin degludec Adverse Effects • Hypoglycemia Insulin degludec Dosing • Total daily basal dose converted to degludec at 1:1 ratio • Dose once daily at any time of day • Hold needle in skin for 6 seconds to allow time for dose delivery Most awkward moment The most handsome man I’ve ever seen sat down next to me and said, “Hi.” I responded with “I’m eating a tootsie roll.” He left.
Daklinza® (daclatasvir) BMS Daclatasvir Pharmacology • NS5A replication complex inhibitor indicated for use with sofosbuvir for treatment of patients with chronic hepatitis C genotypes 1 and 3 • Direct acting agent against hepatitis C • Inhibits HCV nonstructural protein 5A Daclatasvir Pharmacokinetics • Bioavailability 67% • 99% protein bound, peak concentration in 2 hours • Hepatic metabolism by CYP 3A4 • Half-life 12-15 hours • No dosing adjustment necessary for decreased renal or hepatic function • Drug interactions: strong CYP 3A4 inhibitors; strong CYP 3A4 inducers- do not use; moderate CYP 3A4 inducers; dabigitran (avoid concurrent use in renal impairment); amiodarone- avoid due to bradycardia; digoxin, statins Daclatasvir Clinical Trials • Daclatasvir 60mg once daily plus sofosbuvir 400mg daily evaluated in open-label trial in patients with HCV genotype 3 • Divided into treatment naïve and treatment experienced • Treated for 12 weeks and monitored for 24 weeks • Primary end point was SVR 12 • End point reached in 90% of treatment naïve and 86% of treatment experienced • SVR12 in subgroup with cirrhosis: 58% for treatment naïve and 69% for treatment experienced Daclatasvir Clinical Trials • Combination of daclatasvir 60mg and sofosbuvir 400mg once daily evaluated in open-label trial HCV patients co-infected with HIV (stable) • Patients not previously treated got 8 weeks or 12 week, previously treated got 12 weeks • Primary end point was SVR12 • Genotype 1 patients: 8 weeks (untreated)- 75%, 12 weeks- 96%; previously treated who got 12 weeks 97% Daclatasvir Adverse Effects • Headache • Fatigue • Nausea • Diarrhea Daclatasvir Dosing • 60mg once daily with or without food in combination with sofosbuvir for 12 weeks • 30mg dose if on strong CYP3A inhibitors • 90mg dose if on moderate CYP 3A inducers Most awkward moment: I bought Preparation H for under eye bags. Told the clerk she didn’t need to bag it because I was going to use it in the car.
Zepatier® (elbasvir/grazoprevir) Merck Elbasvir/grazoprevir Pharmacology • Indicated as a fixed dose combination for HCV genotypes 1 and 4, with and without ribavirin • Elbasvir is an inhibitor of NS5A • Grazoprevir is an inhibitor of NS3/4A • Inhibits proteolytic activity of genotypes 1a, 1b and 4 Elbasvir/grazoprevir Pharmacokinetics • Elbasvir peak in 3hrs., grazoprevir peak in 2 hrs. • Can be taken without regard to food • Both are extensively protein bound • Metabolism primarily by CYP 3A • Half life: elbasvir 24 hours, grazoprevir 31 hours • Eliminated in feces • Higher levels in female, geriatric and Asian population Elbasvir/grazoprevir Pharmacokinetics • Contraindicated in moderate or severe hepatic impairment • Drug interactions: contraindicated with phenytoin, carbamazepine, rifampin, St. Johns wort, efavirenz, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine Elbasvir/grazoprevir Clinical Trials • Placebo controlled trial evaluating elbasvir/grazoprevir once daily in patient with HCV genotypes 1 or 4, with or without cirrhosis • Placebo group received active drug in a deferred fashion • Patients treated for 12 weeks, therapeutic end point was SVR12 • End point reached in 95% • Similar rates for 1a and 1b, cirrhosis and non-cirrhosis Elbasvir/grazoprevir Clinical Trials • Double-blind, placebo controlled trial; patients with genotype 1 with and without cirrhosis • Patients with CKD stage 4 and 5 (including HD) • One tablet daily for 12 weeks • SVR 12 for the treatment group 95% • SVR in patients with cirrhosis 86% Elbasvir/grazoprevir Clinical Trials • Randomized, open-label trial compared elbasvir/grazoprevir once daily for 12 weeks to elbasvir/grazoprevir plus ribavirin for 16 weeks • Patient with genotype 1 or 4; with or without cirrhosis, with or without HCV/HIV1 coinfection • Patients had failed PegIFN plus RBV therapy previously • SVR12 for genotype 1 after 12 weeks of elbasvir/grazoprevir 94% • SVR12 after 16 weeks of elbasvir/grazoprevir plus RIB was 97% • 5% relapse rate in 12 week group Elbasvir/grazoprevir Adverse Effects • Fatigue • Headache • Nausea • Usual ribavirin concerns if added Elbasvir/grazoprevir Dosing • Genotype 1a, treatment naïve, PegIFN experienced without baseline polymorphism: one tablet daily for 12 weeks • Genotype 1a, treatment naïve, PegIFN experienced with baseline polymorphism: one tablet daily for 16 weeks • Genotype 1b, treatment naïve or PegIFN/RBV experienced: one tablet daily for 12 weeks • Genotype 1a or 1b: Peg/IFN/RBV/NS3/4A protease inhibitor experienced: elbasvir/grazoprevir plus ribavirin for 12 weeks • Genotype 4, treatment naïve: one tablet daily for 12 weeks • Genotype 4, PegIFN/RBV experienced: elbasvir/grazoprevir plus ribavirin for 16 weeks Most awkward moment: Pulled into gas station and was on wrong side of the pump for my gas cap. Drove around to the other side and did it again. Drove away.
Viberzi® (eluxadoline) Pantheon/Forest Eluxadoline Pharmacology • Mu-opioid receptor agonist indicated for treatment of irritable bowel syndrome in adults • Locally active, mu-opioid receptor agonist, delta-opioid receptor antagonist, kappa-opioid receptor agonist Eluxadoline Pharmacokinetics • Low oral bioavailability • Mechanism of metabolism not established • Half life 3-6 hours • Drug interactions: cyclosporine, strong CYP inhibitors, rosuvastatin, drugs that cause constipation, probenecid Eluxadoline Clinical Trials • Evaluated in randomized, double-blind trials, patients with IBS-D and WAP score > 3 prior to randomization • Received either eluxadoline 75mg or 100mg twice daily for placebo for 26 weeks • Primary end point of evaluation was an improvement in the WAP by ≥ 30% compared to baseline and a reduction in the Bristol Stool Score to < 5 on at least 50% of the days within a 12 week time interval. • Primary end point was reached in study 1 in 25%, 24% and 17% on 100mg, 75mg and placebo respectively and similarly in study 2: 30%, 29% and 16%. The rates of improved abdominal pain ≥30% were: 43%, 42% and 40mg for 100mg, 75mg and placebo in study 1 and similarly 51%, 48% and 45% in study 2 Eluxadoline Adverse Effects • Constipation • Nausea • Vomiting • Sphincter of Oddi spasm • Potential for increased risk pancreatitis • Avoid chronic or excessive alcohol Eluxadoline Dosing • 100mg twice daily with food, not high fat meals • Use 75mg twice daily for patients without a gallbladder, can’t tolerate larger dose, on OATP1B1 inhibitors, mild to moderate hepatic impairment Most awkward moment: I apologized to a woman I nearly bumped into in a record store. It was my reflection in the window. I just dyed my hair blond.
Rexulti® (brexpiprazole) Otsuka Brexpiprazole Pharmacology • Atypical antipsychotic indicated for schizophrenia and adjunctive treatment of major depressive disorder
• Partial agonist at 5HT1A and D2 receptors; antagonist at 5HT2A receptors Brexpiprazole Pharmacokinetics • Bioavailability 95% • Protein binding 99%, peak concentration at 4 hours • Can be given with or without food • Metabolism by CYP 3A4 and 2D6 • Half life 91 hours • Drug interactions: strong CYP 3A4 inhibitors; strong CYP 3A4 inducers Brexpiprazole Clinical Trials • Efficacy evaluated in two randomized, double- blind, placebo-controlled trials over 6 weeks • Patients with schizophrenia • Treatment group started at 1mg daily and escalated to clinical trial dose • Primary end point- PANSS score • Placebo-subtracted difference -8.7 and -3.1 for 2mg dose and -7.6 and -6.5 for the 4mg group (study 1 and study 2) Brexpiprazole Clinical Trials • Evaluated as adjunctive treatment in MDD; two 6-week double-blind, placebo-controlled trials, patients with inadequate response to prior antidepressant therapy • Study 1 randomized to brexpiprazole 2mg or placebo; study 2 brexpiprazole 1mg or 3mg or placebo • Primary end point change from baseline to week 6 in MADRS (baseline score 27 out of 60) • Placebo subtracted difference at 6 weeks: -1.3 for 1mg, -3.2 for 2mg and -2.0 for 3mg Brexpiprazole Adverse Effects • Class black box warning regarding: increased risk of death in elderly dementia with psychosis • Class black box regarding increased risk of suicidal thoughts in 24y/o and younger • Akathisia • Headache • Weight increased • Somnolence Brexpiprazole Dosing • Adjunctive treatment MDD: 0.5mg or 1mg daily initially, escalate to target of 2mg at weekly intervals (maximum 3mg per day) • Schizophrenia: 1mg daily initially, target dose 2-4mg per day (maximum 4mg daily); escalate at weekly intervals • Reduce or increase dose appropriately for presence of CYP 3A4 and 2D6 interaction status; reduce dose for renal or hepatic impairment Most awkward moment: An elderly man presented his discount card to me and I said "you're getting ready to expire!" I could not recover.
Movantik® (naloxegol) Astra Zeneca Naloxegol Pharmacology • Mu receptor opioid antagonist indicated for treatment of opioid induced constipation in adults • PEGylated derivative of naloxone • PEG moiety reduces passive permeability so does not reach CNS • Peripheral antagonist activity Naloxegol Pharmacokinetics • Low protein binding • Peak concentration in 2 hours • High fat meal increases absorption • Metabolized by CYP 3A • Fecal excretion • Half life 6-11 hours • Reduce dose for impaired renal function • Drug interaction: ketoconazole, diltiazem, quinidine Naloxegol Clinical Trials
• Patients on chronic opioids with <3 SBM’s per week • Randomized to naloxegol 12.5mg 25mg or placebo once daily for 12 weeks • Primary end point: ≥ 3 SBM’s per week and a change of ≥1 SBM for at least 9 of the 12 study weeks and 3 out of last 4 weeks • End point reached: 41%, 42% and 29% first study; 35%, 40% and 29% second study Naloxegol Adverse Effects • Do not use if GI obstruction present • Abdominal pain • Diarrhea • Nausea Naloxegol Dosing • Discontinue maintenance laxatives • 25mg tablet swallowed whole on empty stomach in the morning • Reduce dose to 12.5mg if unable to tolerate or CrCl < 60ml/min • Avoid consumption of grapefruit • Discontinue the is medication if opioid discontinued Most awkward moment: I texted my boss at the end of my FIRST DAY on the new job: “Heading out. Love you”, intended for my boyfriend.
Praxbind® (idarucizumab) Boehringer Ingelheim Idarucizumab Pharmacology • Monoclonal antibody indicated for reversing effects of dabigatran • Emergency surgery situations or life threatening or uncontrolled bleeding • Binds to dabigatran and its metabolites with greater binding affinity than the binding affinity toward thrombin Idarucizumab Pharmacokinetics • Initial half-life 47 minutes, terminal half-life 10 hours • Antibodies metabolized by protein catabolism • Plasma levels of unbound dabigatran reduced immediately • Limited number of patients had return of elevated PT or ECT between 12-24 hours • Option to redose in clinically relevant bleeding return Idarucizumab Clinical Trials
• Interim analysis published (n=90) • Patients with serious bleeding or need for urgent procedure • Serial blood samples checked for dilute thrombin time and ECT • Received 2 boluses of 2.5gm each • Dilute thrombin time normalized in 98% of group A and 93% of group B at the first check (10 minutes) • 9 deaths in group A and 9 deaths in group B, total of 5 fatal bleeding events Idarucizumab Adverse Effects • Hypokalemia • Delirium • Constipation • Pyrexia • Pneumonia Idarucizumab Dosing • 5gm as bolus or infusion (2x2.5gm) • Resume anti-thrombotic therapy as soon as medically appropriate Most awkward moment: Sandwich shop cashier: “What’s your name?” Me: “Uh, I have a boyfriend.” Cashier: “For the sandwich.”
Bexsero® (meningococcal group B vaccine) Novartis Meningococcal Group B Vaccine Pharmacology • Indicated to prevent invasive disease caused by Neisseria meningitidis serogroup B • Contains three recombinant proteins- Nad A, FHbp, NHBA plus outer membrane protein Por A P1.4 Meningococcal Group B Vaccine Pharmacokinetics Meningococcal Group B Vaccine Clinical Trials • Immunogenicity has been evaluated in two trials • Two doses in individuals 11-24 years of age • Measured endpoint of serum bactericidal activity using human complement (hSBA) for each of the three antigens • ≥4 fold increased reached for FHBP in 78-98%, Nad A 64-99%, Por A P1.4 39-67% measured one months after completed regimen • Composite hSBA response after 11 months 88% and 66% Meningococcal Group B Vaccine Adverse Effects • Pain • Erythema • Induration • Fatigue • Headache • Nausea • Arthralgia Meningococcal Group B Vaccine Dosing • Two 0.5ml doses IM at least one month apart Most awkward moment: After flunking job interview, got up, shook everyone’s hands and walked into the coat closet. Self-Assessment Question 1 . The onset of effect for Praxbind® to reverse the anticoagulant effect of Pradaxa® is: • Immediate • 15 minutes • One hour • Depends on patient’s body size
Answer: A. (immediate) Self-Assessment Question 2 . The size of the expected reduction in LDL-C in patients with Familial Combined Hypercholesterolemia receiving PCSK9 inhibitors is: • 20% • 40% • 60% • 80%
Answer: C. (60%) Self-Assessment Question 3 . Which of the following diabetes drugs has shown a reduction in mortality in patients with cardiovascular disease? • Insulin glargine (Toujeo®) • Insulin degludec (Tresiba®) • Empagliflozin (Jardiance®) • Glyburide (Micronase®)
Answer: Empagliflozin (Jardiance®) Self-Assessment Question 4 . Controversy is being generated regarding the impact of sacubitril on maintenance of beta amyloid levels. Which two body systems are being discussed in the controversy? • Heart and lungs • Skin and hair • Eyes and brain • Bone marrow and ears
Answer: C. (eyes and brain) I n s t Key Takeaways r u . Key Takeaway #1 c t • The high expense of these products will necessitate a strong i o focus on value-based evaluations n . Key Takeaway #2 s f • PBM’s, ACO’s and other third party payors will look for multiple o r avenues to spread the financial burden of these new products K . e Key Takeaway #3 y • Innovations presented may necessitate updating of guidelines T a that are already a part of quality metrics k e a w a y S l i