Pediatric Pharmacology

Transcription

1 1 Pediatric Pharmacology Teri Moser Woo PhD, CPNP, CNL, FAANP October 12, 2012 Speaker Disclosure I have no financial relationships to disclose. AND I will not discuss off label use other than to define what off-label prescribing is and/or investigational use of individual drugs in my presentation. Session Objectives At the end of this session participants will understand pediatric developmental pharmacology and how it impacts prescribing for children. At the end of this session participants will be able to understand how current federal regulations impact pediatric drug development and labeling. At the end of this session participants will be aware of recent pediatric drug labeling changes that affect their prescribing for children. At the end of this session participants will be able to analyze issues around off-label prescribing for children 1

2 Pediatric Drug Legislation FDA Modernization Act of 1997 Best Pharmaceuticals for Children Act passed in 2002 BPCA 2007 Extends patent for on-patent drugs studied in children Expert panel develops a priority list of needs in pediatric therapeutics Will sunset Oct 1, 2012 Pediatric Research Equity Act Requires pediatric studies of drug applications for: new active ingredients, new indications, new dosage forms, new dosing regimens, new routes of administration Also due to sunset Oct 1, 2012 The Outcome So Far 405 completed pediatric studies from 9/2007 to 6/ % included Efficacy & Safety studies 15.8% were PK & Safety studies Total Approved Drugs Granted Exclusivity = 188 (2/12) Total label changes based on new pediatric studies= 413 (9/12) tresources/ucm htm 2

3 Labeling Changes Moxeza oph soln (moxifloxacin) Approved for patients 4 mo and older Vyvanse (lisdexamfetamin) Extends indication to include adolescents yrs Approved for age 6 to 17 yrs Ofirmev injection (acetaminophen) Approved for treatment of pain and fever in children 2 yrs and older Labeling information on younger infants: PK data in infants and neonates suggest that dose reductions of 33% in infants 1 month to < 2 years of age, and 50% in neonates up to 28 days, with a minimum dosing interval of 6 hours Labeling Changes Dulera Inhalation Aerosol (mometasone furoate and formoterol fumarate) Safety and effectiveness have been established in patients >12 years Safety and efficacy have not been established in children <12 years Data from clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients Label Changes Nasonex (mometasone) New indication in pediatric patients 2 years and older for nasal allergies Zymaxid (gatifloxacin) Approved for > 1 year of age Safety and effectiveness not established in infants < 1 year 3

4 Labeling Changes Topamax (topiramate) Safety and effectiveness not demonstrated for pediatric migraine Effectiveness for partial seizures not demonstrated in 2 RTCs of 1 to 24 mo olds New ADRs in 1 to 24 mo olds added 2011 change Expanded age range down to 2 years; previously approved for monotherapy for partial onset or primary generalized tonic-clonic seizures in patients 10 years and older " Information on weight based dosing in 2 to < 10 years 2011 Labeling Changes Kytril Injection (granisetron) Safety and efficacy have not been established in pediatric patients for the prevention of postoperative nausea and vomiting Nexium IV (esomeprazole) Extended indication from adults to pediatric patients 1 month to 17 years 2011 Label Changes Intuniv (guanfacine) Approved for use as adjunctive therapy with stimulants for the treatment of ADHD in pediatric patients 6 years and older Natroba (spinosad) Safety and effectiveness have been established in pediatric patients 4 years of age and older Safety in pediatric patients < 4 years has not been established Not recommended in pediatric patients< 6 months because of the potential for increased systemic absorption 2 4

5 2012 Label Changes Keppra (levetiracetam) Expanded indication to include pediatric patients from 1 month - <4 years; previously approved for use in 4 years and older In pediatric patients 1 month - < 4 years of age, 17% experienced psychotic symptoms compared to 5% on placebo Irritability was reported in 11.7% of the Keppratreated patients compared to 0% of placebo patients 2011 Label Changes Maxalt and Maxalt-MLT (rizatriptan) Expanded indication to include pediatric patients from 6-17 years. Efficacy and safety of treatment with more than one dose of Maxalt within 24 hours in patients 6 to 17 years of age have not been established Maxalt should not be prescribed to propranololtreated pediatric patients who weigh < 40 kg (88 lb) Hallucination, abnormal coordination, disturbance in attention, and presyncope occurred infrequently in pediatric patients in the clinical trial 2012 Label Changes Sklice (ivermectin) topical Safety and effectiveness in children 6 months and older have been established QNASL (beclomethasone dipropionate) nasal Safety and effectiveness in children 12 years and older have been established Safety and effectiveness in <12 years have not been established 5

6 Where to Find Info The list of all drugs with label changes and specific changes can be found at this website Developmental Pharmacology Developmental differences in pharmacokinetics Absorption Distribution Metabolism Elimination Metabolism Drugs are metabolized by both metabolic and enzymatic reactions Phase I and Phase II enzymes Enzyme maturation occurs at varying rates Some enzymes are more active in the fetal/neonatal period Other enzymes become active in the third trimester or postnatally, with increased activity in first year or two of life Hines, 2008; van den Anker,

7 Phase I enzymes Cytochrome (CYP) P450 family of drug metabolizing enzymes account for majority of drug metabolism in humans The enzymes may be slowed (inhibited) or increased (induced) Concurrent therapy with an inhibitor or inducer may alter the metabolism of a medication Most common: 1A2, 2C9, 2C19, 2D6, 3A4 (3A3/4) Neonates Iso-enzyme specific ontogeny CYP3A7 is the most abundant CYP iso-enzyme at birth CYP3A4 is 5% activity at birth CYP2D6 0-5% activity at birth Allegaert et al, 2007 Fig. 4 Source: Journal of Allergy and Clinical Immunology 2000; 106:S128-S138 Copyright 2000 Mosby, Inc. Terms and Conditions 7

8 Polymorphorisms (CYP2D6) Age Iso-enzyme specific phenotypic activity Comobidity Environmental (maternal smoking, co-medication) Allegaert et al, 2007 Enzyme CYP 2D6 CYP2C9 Known Developmental Pattern of Phase I Enzymes (Kearns, 2000) Low to absent in fetal liver but present at 1 week of age; activity (ie, 20% of adult) by 1 month; adult competence by 3-5 years of age. Absent in fetal liver; low activity in first 2-4 weeks of life, adult activity reached by approximately 6 months; activity may exceed adult levels during childhood and decline to adult levels after puberty. CYP1A2 Not present fetal liver; adult levels reached by approximately 4 months and exceeded in children at 1-2 years of age; adult activity reached after puberty CYP3A7 CYP3A4 Fetal form of CYP3A that is functionally active during gestation; disappears by 1-4 weeks postnatal when CYP3A4 activity predominates, but remains present in approximately 5% of individuals. Extremely low activity at birth, reaches 30%-40% of adult activity by 1 month and full adult activity by 6 months; may exceed adult activity between 1-4 years of age, decreasing to 2 adult levels after puberty. 3 Enzyme Known Developmental Pattern of Phase II Enzymes (Kearns, 2000) NAT2 N-acetyltransferase-2 TPMT thiopurine methyltransferase Some fetal activity by 16 weeks gestation; poor activity between birth and 2 months of age; adult phenotype distribution reached by 4-6 months, with adult activity reached by 1-3 years Fetal levels approximately 30% of adult values; in newborns, activity is approximately 50% higher than adults with phenotype distribution, which approximates adults; exception is Korean children, where adult activity is seen by 7-9 years of age. UGT uridine-5 -diphosphategluc-uronosyltransferases Ontogeny is isoform specific; in general, adult activity is reached by 6-24 months of age. Sulfotransferase Ontogeny is isoform specific and appears more rapid than that for UGT; activity for some isoforms may exceed adult levels 2 during infancy and early childhood. 4 8

9 5 What this means for Prescribing Psychotropics SSRIs TCAs Fluvoxamine Anti-seizure medications Carbamazepine Dosing changes required Topiramate More ADRs in younger children Lamotrigene Children have higher clearance rates Drug Distribution Newborns have higher body water Higher doses of hydrophilic drugs Decreased V d for lipid soluble drugs Blood-brain barrier more permeable Infants < 6 months have decreased plasma proteins available for drug binding May account for increased ADRs in younger children Fig. 1 Source: Journal of Allergy and Clinical Immunology 2000; 106:S128-S138 Copyright 2000 Mosby, Inc. Terms and Conditions 9

10 Drug Elimination Decreased GFR for first 6 months Decreased active tubular secretion for first 12 months Adult values attained by 24 months Fig. 2 Source: Journal of Allergy and Clinical Immunology 2000; 106:S128-S138 Copyright 2000 Mosby, Inc. Terms and Conditions Pharmacogenetics Growing body of knowledge Impacts many areas of prescribing Anesthesia Disease specific genetic influences Racial differences in pharmacogentics 10

11 Pharmacogenetics and Cancer Genotypes may be linked to chemo drug resistance in ALL patients Polymorphism may lead to increased toxicity of chemotherapy in some patients Drug efficacy in children with genetic syndromes may vary Racial and ethnic variations in response to therapy There is growing evidence for genetic predictors of chemotherapy toxicity and response to treatment Bomgaars et al, 2005; Bhatia, 2011; Borst, et al, 2011; Pharmacogenetics and Asthma Growing body of knowledge about genetic differences in response to asthma medications Polymorphisms of the beta(2)-adrenergic receptor may influence airway responses to regular inhaled beta-agonist treatment Genetic variation may account for person-toperson variability in inhaled steroid response Tse et al, 2011 Obesity and Drug Pharmacokinetics Obesity may decrease CYP 3A activity by 20-40% Obese adult women have altered metabolism Diazepam Ibuprofen Methylprednisolone Increased clearance of norethindrone and ethinylestradiol in obese women 11

12 Obesity and Drug Pharmacokinetics in Children Doxorubicinol clearance is decreased in children with >30% body fat Altered gentamycin peaks and troughs in obese children Altered vancomycin troughs if dosed every 12 hrs Obese children may require higher than adults dosing of enoxaparin for therapeutic effect Choi et al, 2011; Moffit et al, 2011; Miller et al, 2011; Lewis et al, 2011 Off Label Prescribing Legal Decision is based on Understanding the medication being prescribed Rational scientific principles Expert medical opinion (the literature) Controlled clinical trials Keep current on label changes! Summary 1. It is essential to keep up to date on pediatric drug studies and label changes 2. Young infants (< 6 months) are at greatest risk for ADRs due to developmental pharmacokinetics 3. Pharmacogenetics and obesity may play a significant role in prescribing in the future 12

13 3 7 Questions? wootm@plu.edu References Allegaert, K, van den Anker, J.N., Naulaers, G. & de Hoon, J. (2007). Determinants of drug metabolism in early neonatal life. Current Clinical Pharmacology, 2, Bhatia, S. (2011) Disparities in cancer outcomes: lessons learned from children with cancer. Pediatric Blood & Cancer, 56(6), Bomgaars, L., & HL, M. (2005). Pharmacogenetics and pediatric cancer. Cancer Journal,11(4), Borst, L. Wallerek, S., Dalhoff, K., Rasmussen, K., Wesenberg, F., Wehner, P. & Schmiegelow, K. (2011). The impact of CYP3A5*3 on risk of prognosis in childhood acute lymphoblastic leukemia. European Journal of Haematology, 86(6), Choi et al 2011 de Wildt, S., & Knibbe, C. (2009). Knowledge of developmental pharmacology and modeling approaches should be used to avoid useless trials in children. European Journal Of Clinical Pharmacology, 65(8), 849. Gaedigk, A., Isidoro-García, M., Pearce, R., Sánchez, S., García-Solaesa, V., Lorenzo-Romo, C., &... Corey, S. (2010). Discovery of the nonfunctional CYP2D6 31 allele in Spanish, Puerto Rican, and US Hispanic populations. European Journal Of Clinical Pharmacology, 66(9), Gupta, S., & Awasthi, S. (2010). Pharmacogenomics of pediatric asthma. Indian Journal Of Human Genetics, 16(3), Hanley, M., Abernethy, D., & Greenblatt, D. (2010). Effect of obesity on the pharmacokinetics of drugs in humans. Clinical Pharmacokinetics, 49(2), Kearns, G.L. (2000). Impact of developmental pharmacology on pediatric study design: Overcoming the challenges. Journal of Allergy and Clinical Immunology, 105(3), S128- S138. Landau, R., Ballag, L. & Kraft, J. (2012). Pharmacogenetics and anaeshesia: the value of genetic profiling. Anaesthesia, 67(2), Lewis, TV, Johnson, PN, Nebbia, AM & Dunlap, M. (2011). Eincreased enoxaparin dosing is required for obese children. Pediatrics, 127(3), e Meurer, J. R., Lustig, J. V., & Jacob, H. J. (2006). Genetic Aspects of the Etiology and Treatment of Asthma. Pediatric Clinics of North America, 53(4), Miller, M, Miller, J, Hagemann, T., Harrison, D, Chavez-Bueno, S, & Johnson, P (2011). Vancomycin dosage in overweight and obese children American Journal of Health-System Pharmacy: AJHP: Official Journal of he American Society of Health- System,Pharmacists. 68(21), Thompson, P., Rosner, G., Matthay, K., Moore, T., Bomgaars, L., Ellis, K., &... Berg, S. (2009). Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study. Cancer Chemotherapy and Pharmacology, 64(2), Tse, S., Tantisira, K. & Weiss, S. (2011). The pharmacogenetics and pharmacogenomics of asthma therapy. The PharmacogenomicsJournal, 11(6), van den Anker, J. (2010). Developmental pharmacology. Developmental Disabilities Research Reviews, 16(3), Weschler, M. (2006). Managing asthma in the 21st century: role of pharmacogenetics. Pediatric Annals, 35(9), , Yuen, E., Gueorguieva, I., Wise, S., Soon, D., & Aarons, L. (2010). Ethnic differences in the population pharmacokinetics and pharmacodynamics of warfarin. Journal Of Pharmacokinetics And Pharmacodynamics, 37(1),