New Drugs 2016

Tom Frank, Pharm.D., BCPSDirector of Research and Education

UAMS Northeast

I have no conflicts of interest to report

Entresto®(Sacubitril/valsartan)

Novartis

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

Sacubitril/valsartan

• 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

Clinical TrialsSacubitril/valsartan

• 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

Clinical TrialsSacubitril/valsartan

• 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

Adverse EffectsSacubitril/valsartan

• Hypotension

• Hyperkalemia

• Cough

• Dizziness

• Renal failure

• Orthostasis

• Angioedema

DosingSacubitril/valsartan

• Already on >enalapril 10mg/day: hold ACEI 36hrs then start LQZ696 49/51mg twice daily; if <enalapril 10mg/day, start LQZ696 24/26 twice daily

• Already on valsartan >160mg daily, start LCZ696 49/51mg twice daily; if < 160mg/day, start LCZ696 24/26mg twice daily

• If not currently on ACEI or ARB; start LCZ696 24/26mg twice daily

• Renal or hepatic impairment: start LCZ696 24/26mg twice daily

• Escalate dose up through available strengths every 2-4 weeks to target maintenance dose of 97/103mg twice daily

Most awkward moments:Airport cashier: “have a safe flight,” Me: “You too!”I CAN NEVER COME HERE AGAIN

Praluent®(alirocumab)Regeneron

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

Alirocumab

• 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

Clinical TrialsAlirocumab

• 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%

Adverse EffectsAlirocumab

• Injection site reactions

• Myalgia

• Muscle spasms

• Confusion

• Musculoskeletal pain

• Diarrhea

• Cough

DosingAlirocumab

• 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” insteadof setting phones to vibrate

Repatha®(evolocumab)

Amgen

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

Evolocumab

• Bioavailability 72%

• Maximum suppression of unbound PCSK9 by 4 hours after dosing

• Half-life 11-17 days

• Drug interactions: none clinically meaningful

Clinical TrialsEvolocumab

• 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%

Adverse EffectsEvolocumab

• Upper respiratory tract infection

• Influenza

• Back pain

• Injection site reaction

• Myalgia

• Musculoskeletal pain

• Neurocognitive events

DosingEvolocumab

• 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 goover my prescription glasses. Asked the pharmacistAt CVS if they sold “strap ons”.

Addyi®(flibanserin)

Sprout

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

Flibanserin

• 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)

Clinical TrialsFlibanserin

• 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

Adverse EffectsFlibanserin

• Dizziness

• Somnolence

• Fatigue

• Nausea

• Insomnia

• Dry mouth

DosingFlibanserin

• 100mg at bedtime daily

• Evaluate efficacy after 8 weeks

• REMS must be reviewed

Most awkward momentGot into the passenger seat of the wrong car outsideof Starbucks. The driver waited until I finished my call to tell me.

Adlyxin®(lixisenatide)

Sanofi

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

Lixisenatide

• 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

Clinical TrialsLixisenatide

• 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

Clinical TrialsLixisenatide

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

Adverse EffectsLixisenatide

• Nausea

• Vomiting

• Headache

• Diarrhea

• Dizziness

DosingLixisenatide

• 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

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

Empagliflozin

• 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

Clinical TrialsEmpagliflozin

• 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

Clinical TrialsEmpagliflozin

• Empagliflozin 10mg and 25mg daily compared to placebo when added to metformin

• Baseline HgbA1c 7.9%• Difference in HgbA1c from

metformin/placebo: empagliflozin10mg/metformin -0.6%, empagliflozin25/metformin -0.6%

• Rates of HgbA1c < 7%: 38%, 29% and in the metformin/placebo group 13%

Clinical TrialsEmpagliflozin

• 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 empagliflozin10mg, 25mg or placebo

• Change in HgbA1c after 78 weeks: -0.4%, -0.6% and +0.1% in the group that received placebo

Clinical TrialsEmpagliflozin

• 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

Adverse EffectsEmpagliflozin

• Urinary tract infection

• Female genital mycotic infection

• Upper respiratory infection

• Increased urination

• Dyslipidemia

• Arthralgia

• Male genital mycotic infection

• Nausea

• Increased serum creatinine

DosingEmpagliflozin

• 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 momentOn a trip, saw some baby horses, could not thinkof the word foal, finally shouted “horse kittens” and pointed. Wife understood.

Toujeo®(insulin glargine)

Sanofi-Aventis

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

Insulin glargine

• 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

Clinical TrialsInsulin glargine

• 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

Clinical TrialsInsulin glargine

• 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

Adverse EffectsInsulin glargine

• Nasopharyngitis

• Upper respiratory infection

DosingInsulin glargine

• 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 momentA 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

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

Insulin degludec

• 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

Clinical TrialsInsulin degludec

• 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

Clinical TrialsInsulin degludec

• 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.

Adverse EffectsInsulin degludec

• Hypoglycemia

DosingInsulin degludec

• 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 momentThe most handsome man I’ve ever seen sat down nextto me and said, “Hi.” I responded with “I’m eating a tootsie roll.” He left.

Daklinza®(daclatasvir)

BMS

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

Daclatasvir

• 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

Clinical TrialsDaclatasvir

• 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

Clinical TrialsDaclatasvir

• Combination of daclatasvir 60mg and sofosbuvir400mg 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%

Adverse EffectsDaclatasvir

• Headache

• Fatigue

• Nausea

• Diarrhea

DosingDaclatasvir

• 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 clerkshe didn’t need to bag it because I was going to use itin the car.

Zepatier®(elbasvir/grazoprevir)

Merck

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/grazoprevir

• 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

Pharmacokinetics

Elbasvir/grazoprevir

• Contraindicated in moderate or severe hepatic impairment

• Drug interactions: contraindicated with phenytoin, carbamazepine, rifampin, St. Johns wort, efavirenz, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine

Clinical TrialsElbasvir/grazoprevir

• 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

Clinical TrialsElbasvir/grazoprevir

• 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%

Clinical TrialsElbasvir/grazoprevir

• Randomized, open-label trial compared elbasvir/grazoprevironce 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

Adverse EffectsElbasvir/grazoprevir

• Fatigue

• Headache

• Nausea

• Usual ribavirin concerns if added

DosingElbasvir/grazoprevir

• 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

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-opioidreceptor agonist

Eluxadoline

Pharmacokinetics

Eluxadoline

• 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

Clinical TrialsEluxadoline

• 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

Adverse EffectsEluxadoline

• Constipation

• Nausea

• Vomiting

• Sphincter of Oddi spasm

• Potential for increased risk pancreatitis

• Avoid chronic or excessive alcohol

DosingEluxadoline

• 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

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

Brexpiprazole

• 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

Clinical TrialsBrexpiprazole

• 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)

Clinical TrialsBrexpiprazole

• 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

Adverse EffectsBrexpiprazole

• 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

DosingBrexpiprazole

• 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

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

Naloxegol

• 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

Clinical TrialsNaloxegol

• 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

Adverse EffectsNaloxegol

• Do not use if GI obstruction present

• Abdominal pain

• Diarrhea

• Nausea

DosingNaloxegol

• 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

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

Idarucizumab

• 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

Clinical TrialsIdarucizumab

• 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

Adverse EffectsIdarucizumab

• Hypokalemia

• Delirium

• Constipation

• Pyrexia

• Pneumonia

DosingIdarucizumab

• 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

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 TrialsMeningococcal Group B Vaccine

• 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%

Adverse EffectsMeningococcal Group B Vaccine

• Pain

• Erythema

• Induration

• Fatigue

• Headache

• Nausea

• Arthralgia

DosingMeningococcal Group B Vaccine

• 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)

Key Takeaways Key Takeaway #1

• The high expense of these products will necessitate a strong focus on value-based evaluations

Key Takeaway #2• PBM’s, ACO’s and other third party payors will look for multiple

avenues to spread the financial burden of these new products Key Takeaway #3

• Innovations presented may necessitate updating of guidelines that are already a part of quality metrics

Instructions for Key Takeaway Sli