FORMULATION MATTERS: OPTIMIZING TREATMENT FOR ADHD Learning Objectives

• Explore available treatment strategies for patients with ADHD

• Implement treatment strategies aimed at fulfilling the specific needs of the patient with ADHD Number of Preparations? Number of Stimulant Compounds? Decision Process:

• Compound • Form of administration • Duration of action • Delivery system/technology • Dosing • Patient preference • Insurance allowances • Copay cost Stimulant Compounds

• • Racemic (D=L) Evekeo • D-amph (just D) Dexedrine, Vyvanse • Mixed amph salts (3D:1L) • Desoxyn

• • Racemic Methylphenidate • D-methylphenidate Focalin ADHD Medication Sequencing

MAS Methylphenidate

D-MPH D-Amph Efficacy Familiarity Training Experience ©David W. Goodman, M.D. Decision Process: Medication

• Compound • Form of administration • Duration of action • Delivery system/technology • Dosing • Patient preference • Insurance allowances • Copay cost Form of Administration The form doesn’t convey duration of action • Liquid • Capsule • Procentra (d-amph) short-acting • Evekeo (amph) intermediate- • Dyanavel (d-amph) long-acting acting • Adderall XR (MAS) long-acting • Tablet • MPH (short-acting) • Patch • Concerta (long-acting) • Daytrana (MPH) • Dissolvable tablets • Chewable • Cotempla (MPH) • Methylin chewable short- • Adzenys (d-amph) acting • Sprinkles • Quillichew (MPH) long-acting • Methylin (short acting MPH) • Vyvanse chew (long acting • Jornay (delayed release MPH) AMPH) Reasons to Consider Formulations

• Individuals who experience difficulties swallowing • Individuals with autism or other developmental disabilities who may have tactile issues that preclude the use of tablets, capsules, or even sprinkled preparations • Chewing or crushing pills to ease ingestion may alter the pharmacokinetics of the and is inadvisable for some • Alternative oral dosage forms such as liquid, transdermal, ODT, and chewable, especially those in long-acting formulations with reduced dosing frequencies, may ease medication delivery and improve outcomes for patients Cutler AJ, Mattingly GW. CNS Spectr 2017;22(6):463-74; Beck MH et al. Clin Pediatr (Phila) 2005;44(6):515-26; Mccarthy S. Patient Prefer Adherence 2014;8:1317-27. Decision Process: Medication

• Compound • Form of administration • Duration of action • Delivery system/technology • Dosing • Patient preference • Insurance allowances • Copay cost International Adult ADHD Treatment Guidelines Consensus

• ADHD International Consensus Statement ADHD World Federation (2020) • Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA) 2018 • National Institute for Health and Clinical Excellence (NICE) UK (2018) • European Consensus by the European Network of Adult ADHD (2019) • No U.S. guidelines established ADHD Medication Sequencing

Efficacy Familiarity MAS Methylphenidate Amphetamine

D-MPH D-Amph Delivery System Technology

Duration / Side Effects

©David W. Goodman, M.D. Choice of Duration

• Short-acting (2–4 hours) • Dexedrine (d-amph), Ritalin (methylphenidate) • Intermediate-acting (4–6 hours) • Adderall (MAS), Ritalin SR (MPH) • Long-acting (8–10 hours) • Adderall XR (MAS), Concerta (methylphenidate) • “Ultra” long-acting (10–14 hours) • Mydayis (MAS), Adhansia (methylphenidate) • Delayed-release long-acting • Jornay (methylphenidate) Duration and Delivery System

• Delivery technology replicates PK curves of immediate release multi-daily dosing • Concerta mimics MPH-IR tid dosing • Adderall XR mimics Adderall bid dosing • Mydayis mimics Adderall XR + Adderall 3rd dose OROS-MPH IR:ER 22%:78%

Orifice/Exit Port

Drug Drug Overcoat Compartment #1 Water

Rate- Drug Controlled Compartment #2 Membrane

Water Push Compartment

Before Operation During Operation

Greenhill LL et al. J Am Acad Child Adolesc Psychiatry 2002;41(2 Suppl):26S-49S. OROS Tablet PK Curve: OROS-MPH and MPH IR

36 Adults, single dose, Concerta 18 mg po vs. MPH 5 mg tid Ritalin LA (MPH): Spheroidal Oral Drug Absorption System (SODAS) Ritalin LA SODAS Beads IR:ER 50:50

Error bars are standard deviations

Adjei A et al. J Child Adol Psychopharm 2014;4:560-78. Focalin XR Beads IR:ER 50:50

Dailymed.nim.nih.gov Cotempla XR-ODT (MPH): Microparticles Mixed Amphetamine Salts XR ph Dependent Beads Pulse-Delivery System

Immediate-Release Pellet Delayed-Release Pellet (ph dependent) Drug layer Drug layer

Overcoating Overcoating Release-delaying polymer Bead Overcoating 50% 50%

MAS XR Capsule

Adderall XR® (mixed amphetamine salts) capsules [package insert]. Wayne, Pa: Shire US Inc; 2006. Mixed Amph Salts XR vs. MAS IR

Single dose MAS XR 20 mg vs. MAS 10 mg bid (4 hours) I got it…but then... Jornay (MPH): Delayed-Release/Extended-Release Tablet

• No more than 5% of total drug is available within the first 10 hours after dosing • After the lag period, the absorption of methylphenidate occurs in a single

Jornay package insert peak with a median Tmax 14.0 hours Jornay 100mg vs MPH 30mg bid

CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209311Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) 2016 Decision Process: Medication

• Compound • Form of administration • Duration of action • Delivery system/technology • Dosing • Patient preference • Insurance allowances • Copay cost Delivery Technology Systems

•Beaded •OROS (osmotic-release) • dissolution timing IR:ER ratio • pH-dependent •Micro-particles • non-pH-dependent • liquids • dissolvable tabs • IR:ER ratio • chewables •Cutaneous Diffusion • patch Beaded Delivery Systems: Compound Ratio

• Double-beaded—immediate:extended • 50:50 Ritalin LA (MPH) • 50:50 Adderall XR (MAS) • 40:60 Aptensio XR (MPH) Different • 30:70 Metadate CD (MPH) dissolution • 20:80 Adhansia (MPH) timing • Delayed-release/extended-release • ??:?? Jornay (MPH)

• “Triple-beaded”—immediate:delayed:extended • 33:33:33 Mydayis (MAS) Methylphenidate Preparations

Preparation Duration of Action Generic methylphenidate 2–3 hrs tablet Methylin liquid 2–3 hrs liquid MPH SR 4 hrs wax matrix LA 8 hrs beaded (50:50) OROS MPH 12 hrs OROS MPH ER 6–8 hrs beaded MPH CD 8 hrs beaded (30:70) DexMPH 3 hrs tablet XR 10 hrs beaded Methylphenidate Preparations

Preparation Duration of Action MPH XR Peaks at 2 hrs then again at 8 hrs beaded (40:60) MPH XL liquid 12 hrs liquid MPH ER chewable 12 hrs chewable MPH-ODT ER 12 hrs dissolvable tab MPH transdermal patch 12 hrs patch MPH (“triple bead”) 16 hrs beaded (20:80) MPH DR/ER (PM dosing) 16 hrs beaded (25:80) Amphetamine Preparations

Preparation Duration of Action D-Amph sulfate 2–3 hrs liquid Dextrostat 2–3 hrs tablet Dextroamphetamine 4 hrs tablet spanules 6 hrs beaded

Amphetamine (racemic) 6 hrs tablet Amphetamine Preparations

Preparation Duration of Action Mixed AMPH salts 6 hrs tablet XR (double bead) Up to 12 hrs beaded (50:50) triple bead Up to 16 hrs beaded(33:33:33) d-Amphetamine-ODT ER 12 dissolvable tab d-Amphetamine XR 12 liquid Lisdexamfetamine 14 hrs prodrug capsule 14 hrs chewable Into the Lab… Coatings

•Differences in drug release depending on type of coating • Insoluble Concerta (MPH) • pH dependent Adderall XR (MAS) • Slowly erodible Jornay (MPH) • No coating Vyvanse (d-AMPH) prodrug

Lecomte F et al. Pharmaceut Res 2004;21(5):882-90. Diffusion Controlled-Release Systems

• Release rate of drugs is dependent on the diffusion of drug through an inert, water insoluble membrane barrier • Two types • Reservoir diffusion system • Matrix diffusion system • Used in beads and micro-particles • Capsules, sprinkles, liquids, chewables, dissolvable tablets Reservoir System

• Dissolution rate depends on stability and thickness of the coating

• Masks color, odor, taste thereby minimizing GI irritation

Slowly dissolving coating Drug Matrix System

• Dissolution controlled by • Altering porosity of tablet • Decreasing its wettability Slowly • Dissolving at slower rate dissolving polymer • First order drug release Soluble drug • Drug release determined by dissolution rate of the polymer Osmotic Controlled-Release Oral Delivery System (OROS)

Coating: Third drug, compartment: binders molecules that react with water

Semipermeable Second compartment: rigid membrane high concentration of drug First compartment: low concentration of drug

Opening

Stahl, Mignon. Stahl’s Illustrated Attention Deficit Hyperactivity Disorder 2009. Generic OROS-MPH

1. Actavis Labs FL 2. Alvogen Pine Brook 3. Amneal Pharms But not all generic 4. Ani Pharms Inc Concerta uses 5. Mylan Pharms Inc OROS technology 6. Osmotica 7. Lannett Co Inc 8. Specgx LLC

FDA 39th Edition 2019 Approved Drug Product List Ritalin LA (MPH): Spheroidal Oral Drug Absorption System (SODAS) Ritalin LA SODAS Beads IR:ER 50:50

Dose relationship to serum level for the individual patient

Adjei A et al. J Child Adol Psychopharm 2014;4:560-78. Ritalin LA SODAS Beads IR:ER 50:50

Single 80 mg dose

9-fold difference in serum level

Adjei A et al. J Child Adol Psychopharm 2014;4:560-78. Metadate CD (MPH) IR:ER 30:70 Different Release Mechanisms: PK Comparisons Mixed Amphetamine Salts XR pH Dependent Beads

• 4 amphetamine salts

• D-amph:L-amph ratio: 3:1 • amphetamine aspartate monohydrate 25% (12.5% levo; 12.5% dextro) • amphetamine sulfate 25% (12.5% levo; 12.5% dextro) • dextroamphetamine saccharate 25% (0% levo; 25% dextro) • dextroamphetamine sulfate 25%

Lecomte F et al. Pharmaceut Res 2004;21(5):882-90. Gastrointestinal Tract: ph Changes Mydayis “Triple Bead” Technology Transdermal Patch: Daytrana

Impermeable covering membrane Drug Adhesive

skin

Capillary

Stahl, Mignon. Stahl’s Illustrated Attention Deficit Hyperactivity Disorder 2009. Transdermal Formulations

Advantages Disadvantages • Avoids first-pass • Patches can be metabolism (may large/visible reduce side effects, increase efficacy) • Local skin irritation/rash • Steady plasma concentrations • Patches may inadvertently come • Longer duration of off action • Proper disposal

Muramatsu RS et al. Am J Geriatr Pharmacother 2010;8(2):98-114. Microparticles Liquid: Quillivant XR (MPH) IR:ER—20%:80%

Quillivant XR package insert Microparticles Dissolvable Tablet: Adzenys XR ODT (d-AMPH) IR:ER—25%:75% Prodrug: Lisdexamfetamine Metabolism

Dextroamphetamine pharmacokinetic parameters following administration of lisdexamfetamine dimesylate in adults exhibited low inter-subject (<25%) and intra-subject (<8%) variability

Ermer JC, et al. Clin Drug Investig 2016;36:341-56. Decision Process: Medication

• Compound • Form of administration • Duration of action • Delivery system/technology • Dosing • Patient preference • Insurance allowances • Copay cost Amphetamine Base Equivalents

Amphetamine base in marketed amphetamine medications

Amphetamine base in Amphetamine base equal doses Drug (percent) (30 mg dose) total dextro- levo- dextro- levo-

Dextroamphetamine sulfate 73.38% 73.38% - 22.0 mg -

Amphetamine sulfate (racemic) 73.38% 36.69% 36.69% 11.0 mg 11.0 mg

Mixed amphetamine salts 62.57% 47.49% 15.08% 14.2 mg 4.5 mg 25% dextroamphetamine sulfate 73.38% 73.38% - 25% amphetamine sulfate 73.38% 36.69% 36.69% 25% dextroamphetamine saccharate 56.27% 56.27% - amphetamine aspartate 25% monohydrate 47.22% 23.61% 23.61%

Lisdexamfetamine dimesylate 29.68% 29.68% - 8.9 mg -

Amphetamine base suspension 100% 76.19% 23.81% 22.9 mg 7.1 mg FDA-Approved Medications: Adults ADHD DAILY Medication Child Adolescent Adult U.S. trials dosing dosing dosing (adult) 0.5 mg/kg (<70kg) 40mg 120 mg max 1.2 mg/kg (max 100 mg) max 100 mg XR 5 mg 10 mg 40 mg max 20 mg max 20 mg Triple bead mixed No 12.5 mg 12.5 mg 75 mg amphetamine salts indication Max 25 mg Max 50 mg Mixed amphetamine salts XR 10 mg 20 mg 60 mg max 30 mg max-none OROS Methylphenidate HCL 18 mg 18 mg 18 or 36 mg 108 mg max 54 mg max 72 mg max 72 mg Triple bead MPH 25 mg 25 mg 25 mg 100 mg max 70 mg max 70 mg max 85 mg OROS-MPH Adult Dosing

•Randomized, 7-week, double-blind, placebo- controlled, dose-escalation, parallel-group study •Dosing 36 to 108 mg/d •N = 226, age range 18–65 •Dosing didn’t increase if • AISRS decreased by >30% AND • CGI-I rated as “much” or “very much” improved

Adler L et al. J Clin Psychopharm 2009. 29:3;239-47. OROS-MPH Adult Trial Dosing

Daily 36 mg 54 mg 72 mg 90 mg 108 mg dose

Subjects 36 16 19 16 23 (32.7%) (14.5%) (17.3%) (14.5%) (20.9%)

35%

Adler L et al. J Clin Psychopharm 2009. 29:3;239-47. High-Dose OROS MPH

N=17; children, mean age 16; mean number of meds 2.23 Mean daily dose 169 ±31.2

MPH Levels # patients Mean=27.3 ± 10.0 ng/mL 10

8

6

4

2

0 10-19.9 20-29.9 30-39.9 40-49.9

MPH Serum Level (ng/mL)

Stevens JR et al. J Child Adolesc Psychopharmacol 2010;20(1):49-54. High-Dose OROS MPH

• High-dose OROS MPH, used in combination with other medications, was not associated with either unusual elevated plasma MPH concentrations or with clinically meaningful changes in vital signs • Study limitations include a single time-point sampling of MPH concentrations, a small sample size, and a lack of outcome measures to address treatment effectiveness

Stevens JR et al. J Child Adolesc Psychopharmacol 2010;20(1):49-54. Primary Considerations for Dosing Dosing in mgs for ADHD medication is primarily based on: Weight/ height No weight or height correlations for optimal dosing Pediatrics has weight guidelines but there is tremendous dose variability with patients Delivery system No delivery system is consistently better for all patients Symptom reduction Easily assessed clinically and with symptom rating scales Impairment reduction Impairment arises from both ADHD and executive symptoms Observer reports Helpful but only observed behavior that is context specific ADHD Medication Sequencing

Efficacy MAS Methylphenidate Amphetamine

D-MPH Duration/Side D-Amph effects Delivery System Technology Beaded (IR/ER ratio, double-/triple-beaded) (beads-pH dependent, non-pH dependent) OROS (osmotic-release) Microparticles (liquid/dissolvable tabs/chewables) Patch Monotherapy Guanfacine Atomoxetine Clonidine Adjunctive

©David W. Goodman, M.D. Atomoxetine

• No delivery mechanism • “Non-stimulant” because it doesn’t directly act on DA receptors • Acts on NE receptors in PFC with downstream effect on DA • Takes weeks to evaluate full cognitive effects • Therapeutic adult daily dose: 80–100 mg AM or PM • Clinical adult registration trial: max daily dose 120 mg • 2D6 substrate (2D6 inhibitors will increase atomoxetine levels) • Side Effects: nausea, dry mouth, decreased appetite, insomnia and fatigue. Pharmacotherapy of ADHD and Executive Function Deficits

• Effects of Stimulant on Neuropsychological Tests - Examined neuropsychological test results in group of transitional adults (15–25 years)

• Atomoxetine Treatment of Executive Function Deficits - Examined effects on executive function during 6- month trial of atomoxetine via Brown Adult Attention Deficit Scale - Results: Improvement in all measures of executive functioning

65 Welsh MC, Pennington BF. Dev Neuropsychol 1988;4(3):199-230; Biederman et al. J Clin Psychiat 2008;69(7):1150-56; Brown et al. (In Press) Alpha Agonists Guanfacine XR Formulation

Guanfacine XT package insert Guanfacine XR Plus Stimulants in the Treatment of Child ADHD

Multisite, controlled 9 week trial, n=455, age 6–17 years

Design: 5-week optimization then 3-week dose maintenance period (visits 7–10) Dosing: 1–4 mg daily; mean of 3.2 mg (0.1 mg/kg) Inclusion: Stimulant partial responders Primary outcome: ADHD-RS IV (Investigator)

Wilens et al. J Am Acad Child Adolesc Psychiatry 2012. Guanfacine XR Plus Stimulant for ADHD

Wilens et al. J Am Acad Child Adolesc Psychiatry 2012. Guanfacine XR and Lisdexamfetamine Kinetics

Guanfacine XR Guanfacine XR

Adults

Roasch B et al. Drugs R D 2013;13:119–28. Guanfacine XR and Lisdexamfetamine Kinetics

Vyvanse Vyvanse

Adults

Roasch B et al. Drugs R D 2013;13:119–28. CYP450 Inhibitory Effects of ADHD Medications

Cytochrome P450 Isoenzymes Medication 1A2 2C9 2C19 2D6 3A4 Amphetamine 0 0 0 0 0 Methylphenidate 0 0 0 0 0 Atomoxetine 0 0 0 0* 0 ? ? ? +++ ? 0 0 0 0 0

Goodman D. In: ADHD Across the Life Span: From Research to Clinical Practice—An Evidence-Based Understanding 2006; Biederman J, ed. Hasbrouck Heights, NJ: Veritas Institute for Medical Education, Inc.; Devane L et al. Poster presented at the 156th Annual Meeting of the APA; San Francisco: May 17-22, 2003. Drugs in Development

• SPN 812 ER (Supernus) • 4 studies from Phase 3 in child/adolescents • Pooled data analysis • Daily Dosing: 400 mg

Utilizes Microtrol® beaded technology to make it extended-release

Nasser A et al. A Pooled Analysis of Four Phase 3 RCT trials in child/adol with ADHD. Presented at APSARD Jan 2020. Drugs in Development

• Centanafadine SR (Otsuka) • Two adult trials:

1. Single-blind, flexible dose, n=41 • Significant change on ADHD RS IV at week 4

2. RCT, crossover, n=85 • Significant change ADHD RS IV at week 3 with effect size 0.66 Decision Process: Medication

• Compound • Form of administration • Duration of action • Delivery system/technology • Dosing • Patient preference • “The Dance of the Tiers”—Insurance allowances • Copay cost Summary

• Too many stimulant formulations to keep track of! • Clinicians need to consider several factors, including compound and delivery system, when planning a pharmacologic algorithm • Delivery systems will provide unique effects both intra- patient and inter-patient • Unique characteristic of a patient (i.e., age, comorbidities, medications) will influence compound and technology choices Posttest Question 1

How many FDA-approved stimulant preparations for ADHD exist?

1. 6 2. 13 3. 17 4. 29 5. 32 Posttest Question 2

Dosing in mgs for ADHD medication is primarily based on:

1. Weight 2. Height 3. Delivery system 4. Symptom reduction 5. Impairment reduction 6. Observer reports Posttest Question 3

Methylphenidate serum level can be approximated on the basis of:

1. Total daily dose 2. Height 3. Weight 4. Delivery preparation 5. Mg/kg 6. None of the above