new drugs 2011 · 2016. 11. 2. · 6/11/2013 1 tom frank, pharm.d., bcps no conflicts of interest...

6/11/2013

1

Tom Frank, Pharm.D., BCPS

No conflicts of interest to disclose

Assess new trends in drug development. Recognize indications, pharmacology, adverse effects and dosing of the products discussed. Determine the role these products will play in the participant’s practice. Evaluate the economic implications of these choices. Examine products in the short-term pipeline that will be important to the practice of the participants.

What does Scrabble® have to do with the discussion?

What role does dragon’s blood have in medical therapeutics?

• Indicated for reduction in risk of stroke and systemic embolism in non-valvular atrial fibrillation

• Blocks factor Xa, inhibits formation of thrombin

• Indirectly inhibits platelet aggregation

Apixaban

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Pharmacokinetics

Apixaban

• Bioavailability 50%

• Peak concentration 3-4 hours after dosing

• Protein binding 87%

• Hepatic metabolism by CYP 3A4

• Mostly renal elimination

• Drug interactions: ketoconazole, itraconazole ritonavir, diltiazem, naproxen (increased apixaban effects); rifampin (decreased apixaban effects)

Clinical Trials Apixaban

• Apixaban 5mg twice daily compared to warfarin, double- blind randomized trial

• Patients with atrial fibrillation and at least one other risk factor for stroke

• Primary end point: stroke or systemic embolism, major bleeding and death from any cause

• End point reached: 1.25% on apixaban, 1.6% on warfarin

• Major bleeding: 2.13% vs. 3.09%

• Death from any cause: 3.52% vs. 3.94%

Clinical Trials Apixaban

• Apixaban 5mg twice daily has been compared to aspirin 81-325mg daily in patients with atrial fibrillation who can not tolerate warfarin

• Primary end point: occurrence of stroke or systemic embolism

• Stopped early

• Apixaban group 1.6%/year, aspirin group: 4.4%/year

• Major bleeding rates: 1.4%/year vs. 1.2%/year

Adverse Effects Apixaban

• Major bleeding

• Non-major bleeding

• Hypersensitivity

• Syncope

Dosing Apixaban

• 5mg twice daily

• 2.5mg twice daily if age ≥ 80, Scr ≥ 1.5mg/dl or weight ≤ 60kg

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• Inhaled anticholinergic agent indicated for long term maintenance treatment of COPD

• Long acting anti-muscarinic agent

• M3 receptor blockade reduces smooth muscle bronchoconstriction

Aclidinium

Pharmacokinetics

Aclidinium

• Low bioavailability

• Plasma levels within 10 minutes of inhalation

• Quickly cleared by hydrolysis to inactive metabolites

• Half life 5-8 hours

• No dose adjustment based on geriatric status, hepatic or renal insufficiency

• Drug interactions: potential for additive effect when used with other anticholinergics

Clinical Trials Aclidinium

• Aclidinium 400mcg inhaled twice daily compared to placebo in patients with COPD

• Primary end point: morning pre-dose FEV1 after 12 weeks

• Baseline FEV1 ranged from 1.25-1.51L depending on which one of the three month studies

• After 12 weeks, FEV1 increased by 60-100ml in the treatment groups and decreased by 10-20ml in the placebo group

• In the six month study, the treatment group improved by 60ml and the placebo group decreased by 50ml

Adverse Effects Aclidinium

• Headache

• Nasopharyngitis

• Cough

• Precautions regarding paradoxical bronchospasm, worsening narrow angle glaucoma, worsening urinary retention

Dosing Aclidinium

• One oral inhalation twice daily

• Press and release green button

• Breathe out completely

• Place lips around mouthpiece and breathe in deeply through mouth

• Breathe in even after the “click” sound is heard to obtain the full dose

• Control window should have changed from green to red

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• Indicated for chronic weight management

• In conjunction with reduced calorie diet and increased exercise

• Patients should be obese or overweight with at least one weight related comorbidity

• Phentermine mediates release of catecholamines in the hypothalamus

• Topiramate mechanism not known

Phentermine/topiramate

Pharmacokinetics


• Phentermine peak concentration in 6 hours, topiramate peak concentration in 9 hours

• Phentermine metabolized by hydroxylation and oxidation using 3A4 pathway, most eliminated unchanged in the urine

• Topiramate eliminated mostly unchanged in urine

• Half life: phentermine 20 hours; topiramate 65 hours.

• Phentermine levels increased in moderate renal and hepatic dysfunction

Pharmacokinetics


• Drug interactions: concurrent phenytoin or carbamazepine decreases topiramate levels; valproic acid plus topiramate can cause hypothermia and encephalopathy; increased levels of phenytoin or amitriptyline when given with topiramate; decreased levels or decreased effects of pioglitazone, glyburide and the estrogen component of OCP’s

• Increased risk of acidosis and nephrolithiasis if used with carbonic anhydrase inhibitor

Clinical Trials Phentermine/topiramate

• First study: obese patients studied for 52 weeks, received either placebo, phentermine 3.75mg/topiramate 23mg daily or phentermine 15mg/topiramate 92mg daily

• Efficacy end points: (1) percent weight loss from baseline (2) at least 5% weight loss

• Baseline mean weight 115Kg

• Mean change in weight: -1.6Kg, -5.1Kg and -10.9Kg

• 5% weight loss threshold achieved: 17%, 45%, 67%

• Withdrawal rate 40%

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Clinical Trials Phentermine/topiramate

• Second study: both overweight with comorbid conditions) and obese patients

• Patients received: placebo, phentermine 7.5mg/topiramate 46mg daily or phentermine 15mg/topiramate 92mg daily

• Mean weight at baseline: 103Kg • Mean change in baseline weight: -1.2%, -7.8%

and -9.8% • 5% weight loss threshold achieved: 21%, 62%,

70% • Withdrawal rate: 31%

Adverse Effects Phentermine/topiramate

• Paresthesia • Constipation • Dry mouth • Low bicarbonate • Dizziness • Dysgeusia • Insomnia • Increased creatinine • Nephrolithiasis • Pregnancy test •

Dosing Phentermine/topiramate

• Start with phentermine 3.75mg/topiramate 23mg daily for 14 days

• Increase dose to phentermine 7.5mg/topiramate 46mg once daily

• Evaluate weight loss after 12 weeks • If not lost 3% from baseline weight, discontinue or

increase to phentermine 11.25mg/topiramate 69mg for 14 days then increase to phentermine 15mg/topiramate 92mg

• Evaluate results after 12 more weeks • If not lost 5%, discontinue • To discontinue, taper using every other day dosing

for at least a week

• Serotonin 2c agonist indicated for chronic weight management

• Adjunct to diet and exercise

• Obese patients and overweight patients with at least one co-morbid condition

• Promotes satiety by activating the 5HT2c receptors on the anorexigenic pro-opiomenalocortin neurons

Lorcaserin

Pharmacokinetics

Lorcaserin

• Presence of food does not influence absorption

• Metabolized to inactive metabolites

• Half life 11 hours

• Eliminated almost entirely in the urine

• Half life prolonged in patients with renal dysfunction

• Drug interactions: dextromethorphan; potential for serotonin syndrome with SSRI’s, SNRI’s, dextromethorphan, MAOI’s, tricyclic antidepressants, bupropion, lithium, tramadol, St. Johns wort

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Clinical Trials Lorcaserin

• Placebo-controlled trial evaluating lorcaserin 10mg twice daily over one year

• After one year, patients on placebo, remained on placebo, patients who started on lorcaserin were randomly assigned to continue lorcaserin or to start placebo

• Co-primary end points: proportion with 5% or more reduction from baseline and proportion with greater than 10% or more loss from baseline

• Primary safety end point was proportion with valvulopathy by week 52


• 5% or more weight loss after 52 weeks: 47.5% vs 20.3%

• 10% or more weight loss: 22.6% vs 7%

• Valvulopathy rates: 2.7% vs 2.3%

• Weight loss maintained during year two: 67.9% vs 50.3% on placebo

• Withdrawal rate from study: 50%


• Obese or overweight patients with inadequately controlled diabetes mellitus

• Lorcaserin 10mg twice daily or placebo over 52 weeks



• Withdrawal rate from study: 36%

Adverse Effects Lorcaserin

• Valvular regurgitation • Headache • Dizziness • Fatigue • Nausea • Dry mouth • Constipation • Cognitive impairment • Precautions regarding priapism, reduced heart

rate, prolactin elevation, pulmonary hypertension

Dosing Lorcaserin

• 10mg twice daily

• Can be taken with or without food

• Evaluate weight loss after 12 weeks

• If not lost at least 5% from baseline bodyweight, discontinue

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• Janus kinase inhibitor indicated for treatment of moderate to severe rheumatoid arthritis patients who are intolerant or have inadequate response to methotrexate

• Inhibits JAK type 1 and 3 enzymes

• Phosphorylation and activation of members of the STAT family is prevented

• Gene expression inhibited

• Dose dependent reduction in CD16/56 NKC’s

Tofacitinib

+ + + + - -

- - + + + +

+ - - - - -

- + + - + -

*Type II cytokine receptors such as those for IL-10, IL-19, IL-20, and IL-22 as well as gp130 subunit sharing receptors for IL-6 and IL-11 mainly signal through JAK1, but also associate with JAK2 and TYK2.2 †IL-10/IL-22 may have pro- or anti-inflammatory activities depending on the cellular environment and/or disease state.4

1. O’Sullivan LA, et al. Mol Immunol. 2007;44(10):2497-506; 2. Ghoreschi K, et al. Immunol Rev. 2009;228:273-287; 3. Ghoreschi K et al. Nat Immunol. 2009;10(4)356-360.

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JAK1 JAK3 JAK1 TYK2

TYK2*

JAK2 JAK1 JAK1 JAK2* JAK2 TYK2 JAK2 JAK2

JAK1 inhibitor

JAK2 inhibitor

JAK3 inhibitor

TYK2 inhibitor

Progenitor T helper (Thp) lymphocytes differentiate into different effector CD4+ T-cell lineages1,2:

T helper (Th) 1

Th2

Th17

Follicular Th (Tfh)

T regulatory (Treg) cells

Characterized by specific cytokine production and functions1

IL-6, IL-21

IL-23,TGFβ

Th17

IL-17 IL-22

Tissue inflammation Autoimmunity Clearance of extracellular bacteria

Tfh IL-21

B-cell help

Th2

IL-4 IL-5 IL-13

Humoral immunity Clearance of helminths Allergy

IL-4

Treg

IL-10 TGFβ IL-35

Tolerance Immune suppression

IL-2 TGFβ

DC Thp

Th1 IFNɣ

Cellular immunity Clearance of intracellular pathogens

IL-12 IFNγ

1. Kumar V, et al. Diseases of the immune system. In: Robbins and Cotran Pathologic Basis of Disease.

8th ed. Philadelphia, PA: Saunders Elsevier; 2009:1-15; 2. O’Shea JJ, et al. Science. 2010;327:1098.

Figure adapted from Chen Z, et al. Immunol Res. 2008.

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X tofacitinib

X

X

X X

X

X

X

Pharmacokinetics

Tofacitinib

• Oral bioavailability 74%

• Peak concentration 30-60 minutes after dosing


• Hepatic metabolism by CYP 3A4 and some CYP 2C19


• Reduce dose if moderate renal or hepatic impairment

• Drug interactions: ketoconazole, fluconazole, cyclosporine, rifampin

Clinical Trials Tofacitinib

• Tofacitinib 5mg and 10mg twice daily compared to placebo in RA patients with inadequate response to DMARD’s

• Some patients re-randomized to active treatment after three months of placebo

• End points of evaluation: ACR20, physical function (HAQ-DI), disease activity score

• ACR 20 reached in 59.8% on 5mg, 65.7% on 10mg and 26.7% receiving placebo

• HAQ-DI changes: -0.5pts, -0.57pts and -0.19pts respectively

• DAS28-4ESR score not distinguished from placebo

Clinical Trials Tofacitinib

• Tofacitinib 5mg twice daily, 10mg twice daily adalimumab 40mg Q2wks and placebo compared in RA patients on methotrexate

• End points: ACR20, HAQ-DI and DAS28-4ESR

• ACR20 reached in 51.5% on 5mg, 62.6% on 10mg, 47.2% on adalimumab and 28.3% on placebo

• Change in HAQ-DI: -0.55, -0.61, -0.49 and -0.25 respectively

• Threshold response in DAS28-4ESR reached in: 6.2%, 12.5%, 6.7% and 1.1% respectively

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Adverse Effects Tofacitinib

• Serious infections

• Malignancy

• Upper respiratory tract infections

• Headache

• Diarrhea

• Increased creatinine

• Elevated ALT/AST

• Elevated lipids

Dosing Tofacitinib

• 5mg orally twice daily

• Reduce dose to once daily if moderate hepatic or renal insufficiency; inhibitors of CYP 3A4 or CYP 2C19

• Indicated for prevention of influenza types A and B in adults

• Culture derived influenza vaccine (CCIV)

• Prepared from MDCK cells rather than inoculated chicken eggs

• Virus strains produced separately and inactivated then pooled

• No preservatives, no antibiotics

Flucelvax®

Clinical Trials Flucelvax®

• CCIV compared to placebo and trivalent influenza vaccine (TIV)

• Randomized, observer-blinded study

• End point: comparison of each vaccine to placebo regarding confirmed influenza illness

• Influenza-like illness: CCIV 5%, TIV 7%, placebo 9%

• Vaccine efficacy against all circulating strains: 69.5% for CCIV, 63% for TIV

• Seroconversion rates: 51-78% for CCIV, 68-75% for TIV and 0% for placebo

Adverse Effects Flucelvax®

• Injection site pain

• Erythema

• Headache

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Dosing Flucelvax®

• Single 0.5ml IM injection annually

• Indicated for prevention of influenza A and B in persons 18-49y/o

• Contains recombinant hemagglutinin proteins

• Produced from insect cell line using baculovirus vector

• Resulting hemagglutinin proteins function as antigens to produce immune response

Influenza vaccine

Clinical Trials Influenza vaccine

• Randomized, observer-blind, placebo-controlled trial

• Primary end point- CDC defined ILI with positive culture for virus strain resembling strain in vaccine

• Virus isolated from 178 of 582 who were cultured • Only 2 isolates in vaccine group and 6 in placebo

identified for strains in vaccine • Efficacy against culture positive CDC-ILI regardless

of strain was 44.6% • Protective antibody levels in 99% for H1, 97% for

H3 and 96% for B

Adverse Effects Influenza vaccine

• Pain

• Headache

• Fatigue

• Muscle pain

Dosing Influenza vaccine

• 0.5ml IM x1

• 18-49 years of age

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• Indicated for treatment of overactive bladder

• Symptoms of urge urinary incontinence, urgency and urinary frequency

• Beta-3 adrenergic receptor agonist

• Relaxes detrusor muscle during bladder filling phase

Mirabegron

Pharmacokinetics

Mirabegron


• 71% protein bound

• Multiple metabolic routes to non-active metabolites

• Dual routes of excretion


• Higher concentration in females and Japanese patients, adjust dose if severe renal or moderate hepatic impairment

• Drug interactions: metoprolol, desipramine, ketoconazole

Clinical Trials Mirabegron

• Randomized, double-blind trial comparing placebo, mirabegron 50mg, 100mg and tolterodine SR 4mg/d

• Baseline average ≥8 micturitions/24 hours and at least 3 episodes of urgency, incontinence episodes 2.63-2.89/day

• After 24 weeks: incontinence episodes decreased by -1.13 placebo, -1.62 mirabegron 50mg, -1.51 mirabegron 100mg and -1.21 tolterodine 4mg

• Daily micturitions reduced by 1.37 placebo, 1.94 mirabegron 50mg, 1.75 mirabegron 100mg, 1.57 tolterodine 4mg

Adverse Effects Mirabegron

• Hypertension

• Nasopharyngitis

• Urinary tract infection

• Headache

• Precaution about increase in blood pressure and urinary retention in patients with bladder outlet obstruction

Dosing Mirabegron

• 25mg once daily with or without food

• Can be increased to 50mg once daily

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• Laxative indicated to treat chronic idiopathic constipation and IBS-C

• Peptide that binds and activates guanylate cyclase C receptor on intestinal epithelium

• Increased cGMP activates cystic fibrosis transmembrance regulator (CFTR)

• Secretion of chloride and bicarbonate into intestinal lumen

• Enhances intestinal transit

Linaclotide

Pharmacokinetics

Linaclotide

• Bioavailability 0.1%

• Minimal systemic absorption

• Metabolized by carboxypeptidases and proteases

• Half life 3 minutes

• Drug interactions:

Clinical Trials Linaclotide

• Randomized, double-blind trials comparing linaclotide 145mcg daily, 290mcg daily and placebo in chronic constipation

• Primary end point: three or more CSBM’s per week AND an increase of at least one CSBM per week from baseline

• After 12 weeks: with 145mcg/day- 21.1% and 16%; 290mcg/day- 19.4% and 21.3%; placebo- 3.3% and 6%

Clinical Trials Linaclotide

• Randomized, double-blind trial comparing linaclotide 266mcg/day and placebo

• Patient with constipation predominant IBS

• Primary end point: 30% reduction in abdominal pain, three or more CSBM per week AND increase of at least one CSBM per week

• End point reached in 12.1% vs 5.1%

Adverse Effects Linaclotide

• Diarrhea

• Flatulence

• Abdominal pain

• Abdominal distension

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Dosing Linaclotide

• Chronic constipation: 145mcg once daily on empty stomach

• IBS-C: 290mcg once daily on empty stomach

• Protect from moisture

• Botanical product derived from the sap of the Croton lechleri

• Indicated for the treatment of diarrhea associated with HIV/AIDS antiretroviral therapy

• Blocks two chloride channels in the gut- the CFTR and the CaCC

• Blocks chloride secretion

Crofelemer

Pharmacokinetics

Crofelemer

• Minimal systemic absorption

• No metabolism has been identified

• Excreted with the stool

Clinical Trials Crofelemer

• Randomized, double-blind, placebo-controlled trial

• HIV positive patients on stable ART with history of diarrhea x 1month or longer

• Crofelemer 125mg, 250mg or 500mg twice daily or placebo

• End point: ≤ 2 loose bowel movements per week during two of the four weeks of the placebo controlled study

• End point reached 17.6% vs 8% on placebo

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Adverse Effects Crofelemer

• Rule out infectious cause

• Upper respiratory infection

• Bronchitis

• Cough

• Flatulence

• Increased bilirubin

Dosing Crofelemer

• 125mg twice daily with or without food

• Approved for head lice infestations in patients 6 months of age and older

• Binds to glutamate-gated chloride channels

• Increased permeability to chloride ions produces hyperpolarization in nerve and muscle cell

Ivermectin

Pharmacokinetics

Ivermectin

• Mean plasma level in children 0.24ng/ml

Clinical Trials Ivermectin

• Ivermectin lotion compared to placebo in single dose, 10 minute application

• End point of evaluation: louse free on day 2 extending through days 8 and 15

• Two trials: ivermectin effective in 76% and 71%, vehicle effective in 16% and 18%

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Adverse Effects Ivermectin

• Conjunctivitis

• Ocular hyperemia

• Eye irritation

• Dandruff

• Dry skin

• Burning sensation of the skin

Dosing Ivermectin

• Apply to dry hair sufficient to thoroughly coat hair and scalp

• Leave on for 10 minutes, rinse off with water

• Second treatment not necessary

• Indicated for the topical treatment of actinic keratosis

• Active ingredient from the sap of Euphorbia peplus

• Induces cell death by activation of protein kinase C delta

• Includes neutrophil-mediated oxidative burst

Ingenol

Pharmacokinetics

Ingenol

• Systemic absorption after topical application below level of detection

Clinical Trials Ingenol

• Ingenol 0.015% has been compared to vehicle control in two double-blind trials

• Actinic keratosis of face or scalp

• Applied once daily for three consecutive days

• Efficacy assessed on day 57

• Complete clearance in 42% vs. 3.7%

• Trunk and extremities clearance rate: 34% vs. 4.7%

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Adverse Effects Ingenol

• Erythema

• Flaking/scaling

• Crusting

• Swelling

• Vesiculation/pustulation

• Erosion/ulceration

Dosing Ingenol

• Face and scalp: apply 0.015% gel to affected area for three consecutive days

• Trunk and extremities: apply 0.05% gel to affected areas for two consecutive days

• Ethyl ester of eicosapentaenoic acid derived from fish oil

• Labeled indication as adjunct to diet to reduce triglyceride levels in severe hypertriglyceridemia (≥500mg/dl)

• Increased beta oxidation, inhibition of DGAT, decreased hepatic lipogenesis, increased lipoprotein lipase activity

Icosapent ethyl

Pharmacokinetics

Icosapent ethyl

• De-esterified during absorption process and absorbed as EPA

• Highly protein bound

• Metabolized by beta oxidation


• Drug interactions: none detected

Clinical Trials Icosapent ethyl

• Icosapent ethyl 2gm/day and 4gm/day compared to placebo; double-blind, randomized trial

• Patients with severe hypertriglyceridemia

• After 12 weeks, placebo-corrected mean change from baseline: -19.7% in 2gm group; -33% in the 4gm/day group

• Minimal change in LDL

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• Patients on stable doses of statin and triglycerides 200-500mg/dl

• After 12 weeks, median placebo-adjusted change from baseline: -10.1% in the 2gm/day group and -21.5% in the 4gm/day group

Adverse Effects Icosapent ethyl

• Arthralgia

Dosing Icosapent ethyl

• 2 capsules (1gm each) twice daily with food

• DPP-4 inhibitor indicated as an adjunct to diet and exercise in patients with type 2 diabetes

• Inhibits degradation of glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)

• Binds to DPP-4 but not DPP-8 or DPP-9

Alogliptin

Pharmacokinetics

Alogliptin



• Peak inhibition of DPP-4 at 2-3 hours

• Primarily renal elimination, limited CYP 2D6 or 3A4 metabolism


• Reduce dose for moderate or severe renal impairment

• Drug interactions: none detected

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Clinical Trials Alogliptin

• Alogliptin 12.5mg and 25mg once daily compared to placebo

• Double-blind trial of patients with inadequate control with diet and exercise

• After 26 weeks, change from baseline HgbA1c -0.6% in 25mg group and -0% in the placebo group

• FBS change: -16mg/dl vs. +11mg/dl respectively


• Alogliptin 25mg once daily, pioglitazone 30mg once daily, alogliptin 12.5mg/pioglitazone 30mg once daily and alogliptin 25mg/ pioglitazone 30mg once daily

• After 26 weeks, the HgbA1c reductions were: -1% alogliptin 25mg, -1.2% pioglitazone 30mg, -1.7% alogliptin 25mg/pioglitazone 30mg


• Alogliptin 12.5mg once daily, alogliptin 25mg once daily or placebo added to metformin

• After 26 weeks, HgbA1c reductions were: -0.6% alogliptin 25mg plus metformin, -0.1% metformin plus placebo

Adverse Effects Alogliptin

• Nasopharyngitis

• Headache

• Upper respiratory infection

Dosing Alogliptin

• 25mg once daily

• 12.5mg once daily if CrCl 30-60ml/min

• 6.25mg once daily if CrCl < 30ml/min

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• Estrogen receptor agonist/antagonist indicated for treatment of dyspareunia associated with menopause

• Binds to estrogen receptors without steroid moiety

• Agonist at vaginal epithelium, bone and vasculature

• Antagonist at breast tissue

• Weak antagonist at endometrial lining

Ospemifene

Pharmacokinetics

Ospemifene

• Peak concentration in 2 hours

• Food increased bioavailability

• 99% protein bound

• Hepatic metabolism by CYP 3A4, 2C9 and 2C19


• No dose adjustments based on age, geriatric status, renal status or mild-moderate hepatic dysfunction

• Drug interactions: fluconazole, ketoconazole, rifampin; estrogens

Clinical Trials Ospemifene

• Double-blind, placebo-controlled trial compared ospemifene 30mg, 60mg and placebo over 12 weeks

• Post-menopausal women with ≤5% superficial cells, pH >5 and at least one symptom consistent with vulvovaginal atrophy

• Dyspareunia score fell from 2.7 to 1.31 vs placebo 2.7 to 1.81

• Second study similar design: dyspareunia score fell from 2.7 to 1.15 vs. placebo 2.7 to 1.41

• Significant increase in superficial cells and reduction in pH

Adverse Effects Ospenifene

• Thromboembolic stroke

• Hemorrhagic stroke

• Deep vein thrombosis

• Hot flush

• Vaginal discharge

• Genital discharge

• Muscle spasms

• Hyperhidrosis

Dosing Ospemifene

• One tablet once daily with food

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• Indicated for treatment of pseudobulbar affect (PBA)

• Studied in patient with ALS and MS

• Dextromethorphan is agonist at sigma-1 receptor and NMDA antagonist

• Glutamate effects inhibited

• Quinidine inhibits CYP P450 2D6 blocking biotransformation of dextromethorphan

Neudexta®

Pharmacokinetics

Neudexta®

• Dextromethorphan (alone) bioavailability 1-2%, with quinidine get 20x increase in dextromethorphan systemic exposure

• Peak concentration reached 3-4 hours after dosing

• Quinidine levels 1-3% of concentration necessary for antiarrhythmic effect

• Dextromethorphan metabolism CYP 2D6, quinidine metabolism CYP 3A4

Clinical Trials Neudexta

• Randomized, placebo-controlled trial over 12 weeks comparing three groups: dextromethorphan 20mg/quinidine 10mg twice daily, dextromethorphan 30mg/quinidine 10mg twice daily and placebo

• PBA patients with underlying ALS or MS

• Primary end point: change in crying and laughing episodes

• DM 30 group not different from DM 20 and not approved

Clinical Trials Neudexta

• 49% reduction in PBA episode rate in the DM 20mg group vs. placebo

• Mean change in Center for Neurologic Study- Lability Scale: -8.2 points for treatment group, -5.7 points for placebo group

• Proportion of episode-free days greater in treatment group

• Subgroup analysis showed greater benefit in ALS patients than MS patients

Adverse Effects Neudexta

• Diarrhea

• Dizziness

• Cough

• Vomiting

Dosing Neudexta

• Starting dose: one capsule daily for 7 days

• Maintenance dose: one capsule every 12 hours

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• Sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as adjunct to diet and exercise in adults with type 2 diabetes

• Inhibits SGLT2 receptor in renal tubule

• Lowers the renal threshold for glucose excretion

• Reduces reabsorption of filtered glucose

Canagliflozin

Pharmacokinetics

Canagliflozin



• Metabolized by glucuronidation


• Adjust dose for moderate renal dysfunction; avoid use if eGFR < 45ml/min

• Drug interactions: digoxin; enzyme inducers; no interaction detected with cyclosporin, ocp, hydrochlorothiazide, metformin, probenecid, APAP, simvastatin, warfarin

Clinical Trials Canagliflozin

• Placebo compared to canagliflozin 100mg and 300mg daily over 26 weeks

• Patients with T2DM not adequately controlled with diet and exercise

• End point: change in HgbA1c: +0.14% placebo, -0.77% with 100mg, -1.03% with 300mg

• Patients with HgbA1c < 7%: 21%, 45% and 62% respectively

Clinical Trials Canagliflozin

• T2DM patients inadequately controlled on metformin

• Treatments added to metformin were: placebo, canagliflozin 100mg, canagliflozin 300mg or active comparator sitagliptin 100mg over 26 weeks

• Change from baseline in HgbA1c: placebo/metformin -0.17%, canagliflozin 100mg/metformin -0.79%, canagliflozin 300mg/metformin -0.94%

• Rates of HgbA1c less than 7%: 30%, 48% and 58% respectively



• Patients on stable doses of statin and triglycerides 200-500mg/dl

• After 12 weeks, median placebo-adjusted change from baseline: -10.1% in the 2gm/day group and -21.5% in the 4gm/day group

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Adverse Effects Canagliflozin

• Female genital mycotic infections • Urinary tract infections • Increased urination • Male genital mycotic infections • Vulvovaginal itching • Thirst • Symptomatic hypotension • Increased creatinine • Hyperkalemia • Hypoglycemia • LDL increased

Dosing Canagloflozin

• 100mg once daily before first meal of the day

• eGFR 45-49ml/min: 100mg maximal daily dose

• eGFR > 60ml/min, dose can be increased to 300mg daily

• Do not use if eGFR < 45ml/min

Re: Scrabble®

• If Xeljanz® could be played it would be worth 30 points (no double or triple letter value)

• If Fulyzaq® could be played, it would be worth 31 points (no double or triple letter value)

• A new tool for drug naming is born

new drugs 2011 · 2016. 11. 2. · 6/11/2013 1 tom frank, pharm.d., bcps no conflicts of interest...

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