Prevalence. Historical Timeline. Objectives. ADHD Pharmacology in Children and Adolescents APN Pharmacology Conference March 27, 2015

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1 ADD Pharmacology in Children and Adolescents APN Pharmacology Conference March 27, 215 Richard S. Kingsley, M.D. Clinical Associate Professor of Pediatrics and Psychiatry, Sidney Kimmel Medical College Thomas Jefferson University Chief, Child and Adolescent Psychiatry and Co-Director, Division of Behavioral ealth Nemours A. I. dupont ospital for Children Psychiatrist, Center for Counseling and Student Development University of Delaware Richard S. Kingsley, MD None Objectives istorical Timeline istorical Perspective Diagnostic Criteria FDA approved ADD medications Adverse effects Prevalence ADD DSM-5 Essential Features Present for at least 6 months to an extent that is disruptive and/or inappropriate for the person s developmental level Several symptoms are present before age 12 years Not better explained by another disorder Clear evidence that symptoms interfere with, or reduce the quality of, social, school, or work functioning Evident in at least 2 settings (e.g., home, school)! 1

2 ! ADD Core Symptom Areas Inattention Impulsivity/yperactivity ADD: DSM-5 Criteria Inattention Six or more of the following for children < 16; Five or more for those > 17: Inattention to details/ makes careless mistakes Difficulty sustaining attention Seems not to listen Fails to finish tasks Difficulty organizing Avoids tasks requiring sustained mental effort Loses things Easily distracted Forgetful DSM-5 Impulsivity Blurts out answer before question is finished Difficulty awaiting turn Interrupts or intrudes on others ADD: DSM-5 Criteria Impulsivity/yperactivity Six or more of the following for children < 16; Five or more for those > 17: yperactivity Fidgets Unable to stay seated Inappropriate running/climbing (restlessness) Difficulty in engaging in leisure activities quietly On the go Talks excessively ADD: Course of the Disorder yperactivity Impulsivity Inattention Time What this means for children and young adults Repeated grades School suspensions igh school graduation College enrollment Work firings Acquaintances Close friends Social problems Obtaining credit Amount of debt Owe money ave a savings account Difficulties paying bills (Age 25) ADD Risks Dating partners Length of relationships Became parents Contracted STDs Smoking rate Smoking age of onset Difficulties quitting smoking Driving with suspended license Traffic violations it-and-run crashes Slower/variable driving reactions Steering variability Scrapes Crashes against barriers Traffic rule compliance ADD - Pharmacological Treatment Stimulants Methylphenidate! Dexedrine! Amphetamine compounds! Prodrug/amphetamine! Atomoxetine Antidepressants Bupropion! Tricyclic Antidepressants! Antihypertensives Clonidine! Clonidine Extended Release! Guanfacine! Guanfacine Extended Release! Arousal Agents Modafinil! Other Combination/polypharmacy!! 1 st Line 1 st Line 1 st Line 1 st Line 2

3 ! ADD Stimulant Medications In ADD Stimulants Found to Improve Of pharmacologic options available for ADD, stimulant medications are the Core Symptoms AND Most studied! Most commonly used! Most effective! Inattention Impulsivity yperactivity Noncompliance Impulsive aggression Social interactions Academic efficiency Academic accuracy ADD Practice Parameters. JAACAP 1997;36:85S. Spencer et al. JAACAP 1996;35:49. ADD Practice Parameters. JAACAP 1997;36:85S. Zametkin and Ernst. N Eng J Med 1999;34: Best Response (Percent) 2 ADD Response to Stimulants Meta-analysis of within-subject comparative trials evaluating response to stimulant medications 36% 26% 38% D-amphetamine Methylphenidate Equal response to either Greenhill et al. JAACAP 1996;35:134 stimulant Best Response (Percent) Differential Response to Stimulants Adderall 16 MP 41 Equal response to either stimulant Arnold J Atten Disorder 2; 3:2-211 Elia, Kingsley et al. Future Med. 213;73-2 3

4 Understanding Dopamine (DA) Neurotransmission in ADD Effect of Stimulants on Dopamine (DA) Neurons Presynaptic Neuron 1. DA is released into the synapse 2. DA temporarily attaches to receptors Postsynaptic Neuron Vesicles containing DA DA transporters DA receptors 3. DA in the synapse is reabsorbed (reuptake) Adapted from: Barkley RA. Sci Am. 1998;279: Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35: Barkley RA. Sci Am. 1998;279: Dougherty DD et al. Lancet. 1999;354: AMP inhibits MAO and VMAT- 2 which increases intracellular DA release Presynaptic Neuron Dopamine (DA) Postsynaptic Neuron Mitochondrion containing MAO (which breaks down DA) DA receptors Vesicles containing DA VMAT-2 (similar to DAT but on surface of vesicles) DA transporters (DAT) MP binds to DAT & inhibits reuptake AMP inhibits reuptake and reverses direction of DAT MP in ADD: Optimizing Dosing Medication Starting Dose FDA Max Rec Daily Dose d, l MP (Ritalin, Methylin) Focalin (d-mp) 5mg QD/BID/ TID 2.5mg QD/BID/ TID 6mg/day 2mg/day Focalin XR 5mg QD 4mg/day; (3mg < 18y) Concerta (MP Oros) 18mg QD 72mg/day; (54mg < 13y) Maximum Dose* Lesser of 2mg/kg/day or mg/day Lesser of 1mg/kg/day or 5mg/day Lesser of 1mg/kg/day or 5mg/day Lesser of 2mg/kg/day or 8mg/day Duration 3-4 hrs 4-5 hrs 8- hrs 12 hrs Quillivant XR 5-mg 6mg/day -12 hrs (5mg/ml liquid) Metadate CD -2mg QD 6mg/day Lesser of 2mg/kg/day or mg/day Ritalin LA 2mg QD 6mg/day Lesser of 2mg/kg/day or mg/day Daytrana (skin mg QD patch) 3mg/day (9 hr wear time) 8 hrs 8 hrs MP = Methylphenidate QD = Daily BID = Twice Daily *May exceed FDA approved dose Adapted from Wilensand Spencer, Psych Clin N AM, 2:9; Adapted from Wilens at AACAP AnnualMtg, Toronto, 25; AACAP PP hrs (9 hr wear time) AMP in ADD: Optimizing Dosing Medication Starting Dose FDA Max Rec Daily Dose Adderall (mixed amphetamine salts) Adderall XR Dexedrine (dextroampheta mine) Procentra (1mg/ml liquid d-amph) Dexedrine Spansule 2.5 to 5mg BID to TID 5mg to mg QD 2.5 to 5mg BID to TID 2.5mg to 5mg BID to TID 5mg QD to BID 4mg/day ADD (6mg/day narcolepsy) 3mg/day 4mg/day ADD (6mg/ day narcolepsy) 4mg/day ADD (6mg/ day narcolepsy) 4mg/day ADD (6mg/day narcolepsy) Maximum Dose* Lesser of 1.5mg/kg/day or 6mg/day Lesser of 1.5mg/kg/day or 6mg/day Lesser of 1.5mg/kg/day or 6mg/day Lesser of 1.5mg/kg/day or 6mg/day Duration 4-6 hrs 12 hrs 3-5 hrs 4-6 hrs 6 hrs Vyvanse 2 to 3mg QD 7mg/day 12 hrs *May exceed FDA approved dose AMP = Twice daily = amphetamine QD = daily BID Wilens and Spencer, Psych Clin N AM, 2:9; Adapted from Wilens at AACAP Annual Mtg, Toronto, 25; AACAP PP 27 Variable C max T max T 1/2 Pharmacokinetics 1 Definition Maximum drug concentration measured in blood plasma Time to reach maximum drug concentration Time taken for the plasma concentration to reduce by half Methylphenidate Low bioavailability (~2 to 25%) Typical therapeutic doses provide Tmax = 1.5 to 2.5 hrs! Cmax = 6 to 15 ng/ml! T ½ = 2 to 3.5 hrs! Primarily de-esterified extrahepatic metabolism (plasma based) Prominent metabolism (L-MP) in intestinal wall Stereoisometric metabolism (L>D) Linear PK at moderate doses No PK drug interactions Wilens and Spencer. Child AdolescPsychiatrClin N Am 2:9; Patrick and Markowitz. um PsychopharmacolClin Exp 1997:12:

5 Amphetamines igh bioavailability (~75%) Typical therapeutic doses of d-amphetamine provide Tmax = 2 to 3 hrs! Cmax = 4 to 7 ng/ml! T ½ = 7 hrs! Linear PK Redundant hepatic metabolism No PK drug interactions Wilens and Spencer. Child AdolescPsychiatrClin N Am 2:9; Patrick and Markowitz. um PsychopharmacolClin Exp 1997:12: Long Acting Oral Stimulant Formulations Adderall XR Mixed amphetamines formulated for 12 hour dosing! Bimodal delivery with 5% immediate and 5% delayed release! Vyvanse Prodrug! d-amphetamine! Rate limited hydrolysis provides for extended 12 hour duration! Concerta d, l-methylphenidate formulated for 12 hour dosing! OROS osmotic pressured delivery at an increasing concentration! Focalin XR d-methylphenidate formulated to last 8 to 9 hours! Bimodal delivery with 5% immediate and 5% delayed release! Metadate CD d, l-methylphenidate formulated to last 8 to 9 hours! Biphasic release with delivery of 3% as an initial rapid release followed by the remaining 7% as a continuous release! Ritalin LA d, l-methylphenidate formulated to last 8 to 9 hours! Bimodal delivery with 5% immediate and 5% delayed release! Quillivant XR! d, l-methylphenidate liquid formulated to last up to 12 hours! Biphasic with 2% immediate release with the remaining 8% continuous release! MP LONG-ACTING AGENTS DIFFERENCES IMMEDIATE RELEASE / EXTENDED RELEASE RATIOS METADATE: 3/7 RITALIN LA: 5/5 CONCERTA: 22/88 FOCALIN XR: 5/5 DAYTRANA: absorbed throughout day Quillivant XR: 2/8 CONCERTA TABLET: UNBREAKABLE DIFFICULTY SWALLOWING PILLS METYLIN LIQUID; Quillivant XR LIQUID BEADED PREPARATONS SPRINKLE ON FOOD DAYTRANA PATC GI ABSORPTION DAYTRANA PATC Adderall XR (mixed amphetamine salts) Immediate-Release Bead Bead Core Drug Layer Overcoating Pulse-Delivery System 5% 5% Delayed-Release Bead Bead Core Release-Delaying Polymer Overcoating Drug Layer Overcoating 5,, 15, 2, 25, and 3 mg Caps Bioequivalence of ADDERALL XR 2 mg QD to Adderall mg BID Mean dextro and levoamphetamine concentration (ng/ml plasma) Adderall XR (mixed amphetamine salts) dextroamphetamine levoamphetamine Adderall mg BID Adderall XR 2 mg QD TIME (OURS) Vyvanse - Prodrug Technology A prodrug is a precursor of a drug that, following administration, undergoes chemical conversion by metabolic processes to an active pharmacologic agent 1,2 (examples: levodopa, fosphenytoin) Why are prodrugs developed? To 1,3 Improve bioavailability! Improve or create site specificity! Decrease toxicity! Increase patient compliance or acceptance! 1. an K, Amidon GL. AAPS Pharmsci. 2;2(1):E6; 2. Dorland s Illustrated Medical Dictionary. 29th ed. 2;1463;

6 Vyvanse (lisdexamfetamine) A long-acting, prodrug stimulant Once-daily dose Capsules available in multiple dosage strengths, 2, 3, 4, 5, 6, 7 mg! Lower drug-liking effect compared with d- amphetamine at equivalent doses Suggests reduced potential for abuse!! ow Does Vyvanse Work? Vyvanseis a prodrug that is therapeutically inactive until it is converted to active d-amphetamine in the body 2 N N2 O C N Lisdexamfetamine (Prodrug) 3 Site of cleavage Rate-limited ydrolysis 2 N N 2 l-lysine O O C + 2 N 3 d-amphetamine (active) Vyvanse (lisdexamfetamine) Plasma Concentration vs. Time Concerta - OROS (d, l methylphenidate) Capsule-Shaped Tablet Mean Concentration (ng/ml) d-amphetamine after 75 m LDX Lisdexamfetamine after 75 mg LDX Time (h) MP Drug Overcoat -22% Total dose Rate Controlled Membrane Laser Drilled ole/exit Port MP Drug Compartment #1 MP Drug Compartment #2 Push Compartment Water Water Before Operation During Operation Concerta - OROS (d, l methylphenidate) 18 mg tab consists of 4mg IR! 14mg sustained release! 18mg Concerta equivalent to 2.5 to 5mg IR MP BID/TID Available as 18, 27, 36, and 54mg tablets Metadate CD (d,l methylphenidate) Capsules Once-daily methylphenidate combines immediate-release (IR) and extendedrelease (ER) forms in 1 Diffucaps capsule 3% of dose is rapidly released (IR)! 7% of dose is continuously released to extend coverage, eliminate midday dose (ER)! Available in, 2, 3, 4, 5, and 6mg capsules! 3% of dose rapidly released Core Methylphenidate CI Protective Coating 7% of dose continuously released Core Methylphenidate CI Protective Coating Release-control Membrane Beads shown not actual color 6

7 Ritalin LA (d,l, methylphenidate) Bimodal Release Mean MP Concentration-Time Profile: Metadate CD 2 mg Capsule 7 Methylphenidate (ng/ml) 6 Metadate capsule Time (hrs), 2, 3, and 4mg capsules Pentikis S et al. J Am Acad Child Adolesc Psychiatry. 22;41: Ritalin LA - Pharmacokinetic Profile 2 Mean d,lmethylphenidate plasma levels (ng/ml) Ritalin LA: 4 mg QD (n=17) Ritalin: 2 mg BID (n=16) Focalin XR (d-methylphenidate) Use of the purified d-isomer allows lower dosage, eliminates unnecessary metabolism of l-isomer, and reduces circulation of controlled substances?reduced side effect liability? 2 Same bimodal release system as N Ritalin LA C3OOC 2 Ph 5,, 15, 2, 25, 3, 35 and 4 mg caps d-methylphenidate 15 Time (hours) Daytrana (d,l methylphenidate) Utilizes Advanced DOT Matrix Transdermal Technology Bioavailability of Daytrana Transdermal administration of MP exhibits much less first-pass effect than oral administration Methylphenidate is mixed with adhesive Clear, thin, and easy to apply Oral bioavailability of MP is approximately 3%1!, 15, 2, and 3mg patch strengths A much lower total daily dose of Daytrana on a mg/kg basis compared to oral doses may still produce higher exposures of dmp with transdermal administration compared to oral administration Oral MP Daytrana DOT Matrix is a diffusion-based transdermal system 1. Patrick and Markowitz. um Psychopharmacol Clin Exp 1997;12:527. 7

8 Methylphenidate Pharmacokinetics with Daytrana 5 4 Mean Plasma 3 d-mp Conc (ng/ 2 ml) Mean Plasma Concentration of d-methylphenidate mg Daytrana 2 mg Daytrana 3 mg Daytrana Quillivant XR (liquid methylphenidate) 5mg mph/ml 2% immediate-release and 8% extended-release methylphenidate Dose range to 6mg/day Time post-dose (hr) Patch applied Patch removed Lower limit of quantification.25 ng/ml. Pierce et al. Poster presented at the AACAP Annual Meeting. Toronto. October 2, 25. ADD: Stimulant Adverse Effects AMP, MP: Similar Side Effect Profiles Decreased Appetite! Insomnia! Upset Stomach! eadache! Irritability/rebound phenomena! Rates of these AE s may be high prior to any medical intervention; baseline levels should always be obtained Use of side effects scale helpful! Ref: Klein 1992; Wilens 1992; Pelham 199 Rates of Sudden Death On and Off Stimulant Medication for ADD Assessment of the Risks and Benefits of Medications for the Treatment of ADD Variable Sudden death associated with MP, AMP, and atomoxetine Sudden death expected in those <18 yr of age Risk or Benefit.2 to.5 per, patientyears 1.3 to 8.5 per, patientyears The total patient-years is a summation of each patient's duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc. Rappley, et al N Engl J Med (21): Cardiovascular effects Minor changes in blood pressure and heart rate with both MP, AMP Large scale studies suggest only mild and clinically insignificant increases in blood pressure and negligible increases in pulse Greatest predictor of developing hypertension is high blood pressure at baseline AA Guidelines Medical history (essentially screening of sudden death risk) Personal congenital or acquired cardiac disease Palpitations, chest pain, syncope, seizures, post-exercise symptoms Family history of premature cardiac disease (<3 years of age) Other meds (including those that prolong the QTc) Routine medical history Physical Examination BP/R initially and during the course of treatment ECG NOT necessary! It is reasonable for a physician to consider obtaining an ECG as part of the evaluation of children being considered for stimulant drug therapy, but this should be at the physician s judgment, and it is not mandatory to obtain one! Safety of Stimulants Experience spanning 5 to 7 years Over 2 studies with stimulants Randomized, long-term, follow-up data for thousands of individuals Data available on children and adults Balance with risks of not treating 8

9 Management of Common Stimulant- Induced Adverse Effects Anorexia, nausea, weight loss Administer with meals! Use caloric supplements! Discourage forcing meals! Add appetite stimulant (nortriptyline, periactin)! Consider shorter acting formulation! Change to alternative stimulant or non-stimulant! Insomnia Administer early in day! Change to shorter acting formulation! Discontinue late dosing! Consider adjunctive treatment (e.g., melatonin, antihistamines, clonidine, mirtazapine, atomoxetine)! Management of Common Stimulant- Induced Adverse Effects Dizziness Change to long acting formulation! Monitor blood pressure! Encourage fluid intake! Refer to PCP/Specialist if sudden onset/ disappearance! Rebound phenomena Change to long acting preparation or combine! Overlap stimulant dosing! Consider adjunctive or alternative treatment (e.g., atomoxetine, clonidine, guanfacine, antidepressant)! Management of Common Stimulant- Induced Adverse Effects Irritability Assess timing (during peak or withdrawal phase)! Evaluate for comorbid disorders! Change to alternative stimulant! Consider adjunctive or alternative treatment (e.g., atomoxetine, clonidine, guanfacine, lithium, antidepressants, anticonvulsants)! Dysphoria Evaluate for comorbid disorders (e.g., mood disorder)! Change to long acting preparation! Change to alternative stimulant! Consider adjunctive or alternative treatment (e.g. atomoxetine, bupropion, TCA, anticonvulsants, lithium)! Management of Common Stimulant- Induced Adverse Effects Growth impairment May see 6 to 12 months of no weight gain! Attempt weekend and/or vacation holidays! If severe consider nonstimulant treatment (~3% of cases)! Add caloric supplements and/or appetite stimulants! Seizure history Monitor EEG! Use with antiseizure medication! Pre-existing hypertension and heart disease Should be controlled prior to initiating stimulant treatment! Consider nonstimulants! Why Non-Stimulant Treatments For ADD? Problems with the stimulants! Scheduled II drugs (abuse liability, diversion, medico-legal concerns) 3% do not adequately respond or cannot tolerate stimulant treatment Rebound effects Short duration of action if short acting preparations used (compliance, embarrassment) Side effect profile Concerns about growth suppression and tic development Strattera (atomoxetine) Appropriate first line agent Mechanism of action Selectively blocks NE transporter which inhibits NE reuptake! 24 hour duration 3 to 6 weeks for onset of action Once daily (morning or evening) or twice daily dosing May be helpful with sleep onset insomnia! Plasma alf-life: 5 hours in CYP2D6 extensive metabolizers! 9 hours in poor metabolizers (7% of population)! Increase dose every 4 to 7 days Starting at a lower dose with less aggressive titration reduces GI side effects! Some suggest more useful in stimulant naïve patients May be useful as adjunctive 1 J. Witcher, et al JAACAP agent 24 to stimulants Available in, 18, 25, 4, 6, 8, and mg caps 9

10 Medication Strattera Strattera (atomoxetine) Starting Dose.5 mg/kg/day or, 18 or 25 mg QD or divided BID with meals FDA Max Rec Daily Dose Lesser of mg/day or 1.2 to 1.4 mg/kg/ day Maximum Dose* Lesser of mg/day or mg/ kg/day Duration 24hr Reduce dose to.5 mg/kg/day if using known inhibitors of cytochrome P45 (e.g., paroxetine, fluoxetine, ketoconazole) Consider serum levels to help navigate with dosing No drug interactions with stimulants In combination with stimulant may provide effect greater than stimulant or Strattera alone igher doses (1.8 to 2. mg/kg/day) increasingly suggested *May exceed FDA approved dose Strattera (atomoxetine) Adverse Effects Somnolence Insomnia GI: nausea/gi upset/dyspepsia, vomiting Liver hepatitis Appetite suppression Suicidal ideation Blood pressure/pulse (adults) Sexual dysfunction (adults) Intuniv (Extended Release Guanfacine) Appropriate first line nonstimulant agent Mechanism of action: alpha-2 a receptor agonist May provide up to 24 hour duration 3 weeks for onset of action but may begin to see effects sooner Once daily dosing Generally administered in the morning! Possibility of evening administration or twice daily dosing! Increase dose every 7 days May be useful as adjunctive agent to stimulants Available in 1, 2, 3, and 4 mg tabs Be aware of incorrect pharmacy substitutions Medication Intuniv (Extended release guanfacine) Intuniv (Extended Release Guanfacine) Starting Dose 1 mg daily in am FDA Max Rec Daily Dose (ages 6 to 17) Lesser of 4mg/ day or.12mg/ kg/day Maximum Dose* Not yet known Duration 24hr Start at 1mg in the morning Increase by 1mg/week! Initial target dose is.5 to.8mg/kg/day Average dose is 2 (2%), 3 (33%), or 4 (25%) mg/day No drug interactions with stimulants May increase concentration of valproic acid Intuniv (Extended Release Guanfacine) Adverse Effects Kapvay (Extended Release Clonidine) First line nonstimulant agent Mechanism of action: alpha-2 receptor agonist May provide up to 12 hours duration BID dosing up to.4mg/day Increase dose every 7 days May be useful as adjunctive agent to stimulants

11 Kapvay (Extended Release Clonidine) Mean concentration with once daily administration ADD Summary ADD affects millions of people of both genders! persists through adolescence and adulthood in a high percentage of cases! can have negative impact on multiple areas of functioning! Effective available treatments 11