Age and Pharmacokinetics Pediatric and Geriatric Considerations M

Age and Pharmacokinetics Pediatric and Geriatric Considerations M. E. Blair Holbein, Ph. D. Clinical Pharmacologist Presbyterian Hospital of Dallas

Pediatric Pharmacology - History v Some of the most disastrous therapeutic misadventures occurred in pediatrics. n n v Thalidomide 1957 Chloramphenicol 1959 Directly led to the “modern era” of pharmaceutical regulation with Kefauver-Harris Drug Amendments of 1962 n Requirement for demonstrated efficacy and safety for FDA approval and USA marketing.

Pediatric pharmacology - What’s unique? v Continuous development from embryo to adolescent n n v v “Perpetual pharmacologic moving target” Pharmacodynamics and pharmacokinetics change with time The most profound differences occur in the first weeks through first year of life. Descriptive pharmacology (especially for new drugs) in pediatric patients is often lacking n n Children are not “miniature adults” • Dosing based on “rule” (Young’s, Clark’s) or scaling (by body weight or body surface area) not always predictable for a given drug. Animal studies not always predictive. Clinical studies in children fraught with ethical and financial hurdles. Administration of drug can also be problematic.

Pediatric pharmacology - Approved drugs v v v Children are “therapeutic orphans” Only 20 -30% of approved drugs have pediatric labeling FDA has encouraged pediatric studies • Financial incentive to conduct studies • Orphan and off-patent drugs - no incentive to do studies • Increased studies resulted in new labeling for 40 drugs. • For approval of selective number of new drugs pediatric studies have been required. v Resources n n Center for Drug Evaluation and Research at FDA - www. fda. gov/cder/pediatric/ Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies. JAMA. 2003; 290: 905 -911.

The “Moving Target” - Developmental Changes v v v Body composition Organ function Drug metabolizing enzymes n v v Unique metabolic pathways Renal function Receptor response Unique disorders Extremely small margin of error for the most fragile patients n n Errors can be devastating Individual variance unpredictable

Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents Kearns, G. L. et al. N Engl J Med 2003; 349: 1157 -1167

Developmental Pharmacology - Absorption - GI v Gastric acid - approaches adult values ~ 3 mo in fullterm infants. n n v Bioavailability increased for acid-labile drugs (some penicillin derivatives) Decreased for drugs requiring acid to be absorbed. Digestive enzymes including pancreatic enzymes are low in newborns. n Colonization of the gut occurs rapidly after birth but is highly variable and unpredictable.

Developmental Pharmacology - Absorption - GI v Gastric emptying n v GI motility n n n v Delayed and unpredictable in newborns - adult values ~ 6 mo. Slow in newborns; may be increased in children. Usually affects the rate but not the fraction of drug absorbed. The absorptive surface area/BSA is > infants and children vs. adults The impact on absorption is usually minimal but is unpredictable

Developmental Pharmacology - Absorption - Skin v Percutanous absorption n v Premature infant has a significantly less effective skin barrier to absorption of drugs and toxins n v Directly related to the degree of skin hydration. Inversely related to the thickness of the stratum corneum. • Thinnest in premature neonate Greater extent of cutaneous perfusion Ex. Hexachlorophene toxic to immature infants Newborn skin surface area : body weight is 3 X > adult

Other Routes of Drug Administration v Intramuscular n n v Rectal n n v v Lipid solubility favors distribution from site into circulation (rate) Water soluble at physiologic p. H to prevent precipitation Highly susceptible to variance in absorption due to blood flow and relative muscle mass • Dispersion driven by muscle contraction (low in neonates and immobility) • Reduced skeletal-muscle blood flow in neonate Can be extremely painful, cause hemorrhage, nerve damage, abscess, necrosis, fibrosis, and CPK Absorption is excellent for some agents Less first pass effect due to decreased hepatic clearance Pulmonary for site specific agents Unintentional n n Breast milk Transplacental

Developmental Pharmacology - Absorption PK Pathway Premature Neonates Neonatal < 1 mo. Early infant Mid-Infant 3– 5 mo. Late infant -toddler 6 – 24 mo. Older child , , Dermal Lung Absorptio n Oral

Developmental Pharmacology - Distribution v v Larger extracellular and total-body water spaces in neonate and young infants Adipose stores also have higher ratio of water to lipid n v Plasma proteins n n v RESULT: Lower plasma levels (relative to weight) for water soluble drugs. Effect on lipid soluble less Low in premies and neonates ( free fraction) Most important in displacement of bilirubin from albumin resulting in toxicity (kernicterus) Tissue transporters - P-glycoprotein ATP-binding cassette family of transporters n n May limit cellular uptake of xenobiotic substrates [blood-brain barrier, hepatocytes, renal tubular cells and enterocytes] Very limited data; premature infants probably most affected

Developmental Pharmacology - Distribution Sites

Developmental Pharmacology - Metabolism v Prior to birth the fetus is in a relatively protected environment n n v Maturation of drug metabolizing enzymes occurs longitudinally n n v The xenobiotic clearing processes of the mother prevent exposure of the fetus. The placenta also acts as a barrier. The very young have very low activity • Ex. Cardiovascular collapse in chloramphenicol associated “gray baby syndrome” Cause for caution for drugs that have wider therapeutic index in adults • Ex. Methylxanthines, nafcillin, 3 rd generation cephalosporins, captopril and morphine Distinct patterns for each class and isoform of drug metabolizing enzymes.

Development of Drug-Metabolizing Enzymes - Phases of Drug Metabolism v Phase I n n n Oxidation Reduction Hydrolysis v Phase II n Conjugation

Development of Drug-Metabolizing Enzymes - Phase I - Oxidation/Reduction/Hydrolysis v Predominant isoform (liver) CYP 3 A 7 in prenatal period n n v Peaks at birth, then declines rapidly to undetectable in adults Role to detoxify dehydroepiandrosterone sulfate, teratogenic derivatives of retinoic acid Within hours after birth other isoforms begin to appear. n n n Each has individual pattern of development. Most are at or above adult levels by 1 year. Examples • • Midazolam clearance changes 7 X in 3 months (1. 2 9 ml/min) Phenytoin T 1/2 in premies 75 20 hr in 1 wk old full term infant Carbamzepine clearance children > adults Methylxanthine demethylation exceeds adults by 4 months (and declines in puberty in sex-based divergence)

Development of Drug-Metabolizing Enzymes - Phase II - Conjugation Reactions v v Ontogeny less well characterized than Phase I reactions Glucouronosyltransferase (glucuronidation) is decreased in newborns and young children compared to adolescents and adults n n n v Present by 24 wk gestational age Morphine glucuronidation correlates with post-conceptional age Morphine conjugate more potent (premies require increased dose for equivalent analgesia) Clearance of most agents more efficient in prepubescent children than adults (relative to bodyweight)

JPET Vol. 300, Issue 2, 355 -360, February 2002 The Ontogeny of Human Drug-Metabolizing Enzymes: Phase I Oxidative Enzymes

Relative Half-lives of CYP 1 A 2 Substrates Ginsberg et al. Pediatrics 2004; 113: 973.

Relative Half-lives of CYP 3 A Substrates PEDIATRICS Vol. 113 No. 4 April 2004, pp. 973 -983

Developmental Pharmacology -Metabolism: Phase I PK Pathway Prematur Neonata e l Metabolism: Neonate < 1 mo. s Phase I Early infant Mid. Infant 3– 5 mo. Late infanttoddler 6 – 24 mo. Older child CYP 1 A 2 Scale BW 3/4 CYP 2 E 1 Scale BW 3/4 CYP A Scale BW 3/4 CYP 3 A 7 Other CYPs Scale BW 3/4 ADH Scale BW 3/4

Developmental Pharmacology - Metabolism: Phase II PK Pathway Prematur Neonata e l Neonate < 1 mo. Metabolism: s Phase Ii Early infant Mid. Infant 3– 5 mo. Late infanttoddler 6 – 24 mo. Older child Glucuonidation N-acetylation

Developmental Pharmacology - Renal Elimination v Maturation of renal function dynamic n n v Begins with fetal organogenesis (9 wk gestational age) Complete by early childhood GFR correlates with nephrogenesis and postnatal renal and intrarenal bloodflow.

Acquisition of Renal Function

Developmental Pharmacology - Renal Elimination v Therapeutic implications n v Estimation of renal function necessary for determining dose regimen for drugs with extensive renal clearance • Ex. Ceftazidime, famotidine, aminoglycosides. • Measurement of drug levels often necessary Some drugs also alter renal maturation or renal blood flow. n Ex betamethsone, indomethacin

Developmental Pharmacology - Pharmacodynamics v v Very little data; most accepted practices are based on observation Anecdotal evidence for altered response to n n Warfarin Cyclosporine Midazolam Erythromycin (intestinal motilin receptors)

Criteria for Using a Drug in a Child or Infant v Has there been documented efficacy for the medication for the disorder in newborn or older infants/children. n v Is the data from adequate clinical trials (randomized, controlled, size, power, similar age/maturity)? Has the safety been established for pediatric population?

Criteria for Using a Drug in a Child or Infant v v Has the pathway of drug clearance been established in children/infants? Is that pathway established in the child/infant you are treating (based on maturity or physical state)? Is there reason to believe that pathway may be compromised in the specific child/infant (genetics, disease state, concomitant therapy)? Have the pharmacokinetics been established in similarly aged children?

Criteria for Using a Drug in a Child or Infant v v v Is there a safe route to administer the drug? (intact GI tract, central access, intact skin, nontoxic solvent) Is displacement an issue for albumin binding or bilirubin displacement? Are there technical issues surrounding administration, e. g. solvents, preservatives, volume? Is there an established dose and interval appropriate for age and disease state of the child? Have a plan for monitoring for appropriate response to the agent. Look for adverse effects of the agent.

Criteria for Using a Drug in a Child or Infant v The very small doses required in the most immature patients and the immature clearance pathways leave very little margin of error.

Developing Age-specific Dosing Regimens v v v Official prescribing information usually does not have pediatric dosing regimens. Developmental status adjusted regimens are highly specific for a given agent. Use of established compendia and published guidelines provide the most reliable method of selecting an appropriate therapeutic agent and adjusting dose.

Geriatric Pharmacology - What’s unique? Physiology v Changes in underlying physiology occurs over time. n n n v v Even “healthy” elderly have diminished capacities. Aging is a continuum and the aged are stratified by degree of age. n n n v Altered, usually diminished, receptor sensitivity and responsiveness The ability to mount a compensatory physiologic response is diminished. Normal homeostatic mechanisms are blunted and sometimes produce inappropriate responses. Young old is 65 – 75 years Old – 75 – 85 years Old old – age > 85 years As age progresses so do the exceptional considerations.

Geriatric Pharmacology - What’s unique? Physiology v Body composition n v CNS n n v total body water, lean body mass, body fat; serum albumin, -1 acid glycoprotein weight and volume of the brain sensitivity to depressant drugs: ethanol, anticholinergic effects, antipsychotic agents. CNS effects and side effects are exaggerated Delirium and dementia complicate therapy. ANS n n Responsiveness and appropriate reflex effects are diminished. Orthostatic hypotension - frequent side effect due to diminished capacity for response to agents with any degree of sympathetic blockade.

Geriatric Pharmacology - What’s unique? Physiology v Cardiovascular n n n v -adr receptor activity, baroreceptor activity Cardiac output is generally fairly well maintained Cardiac disease and reserve capacity diminish with age. Adrenergic receptor sensitivity is altered. Any pro-arrhythmic side effect can be accentuated. Endocrine n n n Atrophy of thyroid incidence of diabetes mellitus Menopause, andropause

Geriatric Pharmacology - What’s unique? Physiology v Digestive tract n v gastric emptying time, GI blood flow; gastric p. H, intestinal transit time. Hepatic n n liver size, hepatic blood flow. Some hepatic functions are better preserved than others. • albumin • Alcohol use, gallstones, cholangitis, fatty liver (NASH), heart failure, and conditions requiring concomitant drugs can affect metabolism.

Geriatric Pharmacology - What’s unique? Physiology v Renal n n v Pulmonary n v GFR, renal blood flow, tubular function Renal function and size diminishes with age. respiratory muscle strength, chest wall compliance, total alveolar surface Most systems are more affected by disease than age alone.

Geriatric Pharmacology - What’s unique? Disease v The elderly accumulate diseases.

Geriatric Pharmacology - What’s unique? Polypharmacy v With the accumulation of disease these is an accumulation of treatments n n n v Disproportionate use of drugs in the elderly. n n v “Polypharmacy” Multiple medications for multiple chronic diseases Multiple physicians Self-medication 12% of population receive 30% of all prescriptions. 2/3 use 1 or more drugs daily. • Ave 5 - 12 drugs daily • < 5% use no drugs. • 1/3 use 1 or more psychotropic drugs each year. It is often difficult to distinguish between disease and adverse drug events.

Geriatric Pharmacokinetics - Absorption v Age related changes are small. n n n v v v Gastric/intestinal motility Surface area and blood flow Net negligible change in absorption Less significant than disease-specific changes. Effects of age on absorption for delayed and sustained release formulations have not been well-documented. A diminished first-pass effect results in an increased bioavailability.

Geriatric Pharmacokinetics - Distribution v Lean body mass and body water n n n v Increased fat serves as a repository for fat soluble drugs n v v Vd (volume of distribution) for water soluble drugs Water soluble drug - conc. • Ex. ethanol Fat soluble drugs conc. Ex. Amiodarone, desipramine, diazepam, haloperidol, digitoxin Impact on drug therapy in general is not great. Protein binding to albumin and -1 acid glycoprotein is more affected by disease than age. n Decreased albumin can result in increased free fraction of drugs. • Increased delivery to receptor • Increased drug interactions

Volume of Distribution by Age

Geriatric Pharmacokinetics - Metabolism v Phase II reactions are better preserved than Phase I. n v v Note on syllabus. Disease and environmental factors have a greater impact on hepatic drug metabolism than age. High extraction drugs may have decreased clearance attributable to diminished hepatic blood flow.

Antipyrine Clearance

Geriatric Pharmacokinetics - Elimination v v v Renal Elimination Cl and t 1/2 for renally cleared drugs and metabolites. The age-related change in renal clearance is the most consistent and predictable change in pharmacokinetics. The dose of most drugs that are renally cleared should be adjusted for renal function. The adjustment method most frequently used is the Cockroft-Gault equation to estimate renal clearance. This method is not without problems, but is simple and readily applicable in most situations.

Estimating Renal Function v v v Cockcroft Gault estimation Assumes steady state production of creatinine. Very limited utility in critically ill, clinically unstable, malnourished or wasted patients. n n Measure creatinine clearance or use extrinsic marker if critically important. Other formulas may be more accurate in special populations. CLCr (ml/min) = (140 – age) (lean weight in kg) 72 (serum creatinine in mg/d. L) (multiply by 0. 85 for women)

Geriatric Pharmacokinetics - Renal Function v Drugs with predominantly renal elimination and potentially serious toxic effects should have dosing adjusted based on renal function.

Geriatric Pharmacokinetics – Drug Elimination v Drug dosing requires adjustment for changed pharmacokinetic parameters. 0. 693 X Vd t 1/2 = Clearance Vd is smaller for water soluble drugs Clearance is usually diminished with age

Geriatric Pharmacodynamics v Receptor alteration with age best documented for adrenergic receptors and autonomic nervous system. n n n v Increased sensitivity to sedation. Increased sensitivity to hypotensive (side) effects due to decreased baroreceptor function. Diminished adaptive capacity most manifested as increased occurrence of adverse events with medications. Treatment of elderly patients can be very complex because of multiple diseases and drug therapies that can produce adverse drug reactions.

Appropriate Prescribing for Geriatric Patients v v v Obtain a complete drug history Avoid prescribing before a diagnosis is made Review medications regularly and before prescribing a new medication Know the actions, adverse effects, and toxicity profiles of he medications you prescribe Start low dose and titrate dose based on tolerability and response Geriatric dictum: “Start low and go slow”

Appropriate Prescribing for Geriatric Patients v v v Educate patient and/or caregiver about each medication Avoid using one drug to treat the side effects of another Attempt to use one drug to treat two or more conditions Use combination products cautiously Communicate with other prescribers Avoid using drugs from the same class or with similar actions

How do you adjust drug therapy for special populations?

Drug Information v On-line decision support n n v Institutional: CPOE (Computerized Physician Order Entry) Guidelines, rules, protocols Text-based (online and print) n Secialized information • Johns Hopkins: The Harriet Lane Handbook: A Manual for Pediatric House Officers, 16 th ed © 2002 Mosby, Inc. • Geriatrics At Your Fingertips, 2005 by D Reuben, and Others. The American Geriatrics Society (AGS) n v Literature (Medline, full-text, etc) Exceptions n n n Investigational drugs • NME (New Molecular Entity) • Indication not labeled • Literature, FDA, Sponsors Unusual patients (age, disease, indications) International patients (online resources, Pharmaceutical regulatory agencies)

Drug Information Age-specific v v FDA, Government and professional organizations web sites Medical departments of Pharmaceutical Manufacturers n n Most have available physicians who have specialized knowledge of products Different constraints on information sharing when physician-tophysician

Case Study - 1 v NICU, 32 week infant; 1 wk p delivery, wt 1800 gm Apparent pneumonia, worried about sepsis; blood culture growing MRSA; intermediate vancomycin sensitivities Is Linezolid a therapeutic alternative in this patient? v What information do you need to gather? v v

Case 1 v Has there been documented efficacy for the medication for the disorder in newborn or older infants/children? n n n Is the drug approved for pediatric use? Is the drug approved for this indication? Is it approved for this indication in pediatrics? • Look in the Official Product Information • On-line sources: Manufacturer, FDA • Other compendia: Micro. Medex, Epocrates • Note: The FDA may be revising OPI format. • See FDA announcement: •

OPI

Official Product Insert (Approved labeling) v v Description Clinical Pharmacology n n n v v v Pharmacokinetics • Absorption, Distribution, Metabolism, Excretion • Special populations: Geriatric, pediatric, gender, renal insufficiency, hepatic insufficiency Drug-drug interactions Special: Antibiotics|Microbiology Indications and Usage Contraindications (do not use) Warnings (use with caution) Precautions (during therapy) Information for patients

Labeling, cont’d. v Interactions n n v Use in special populations or extraordinary considerations n n n v Drug-drug Drug-laboratory Pediatric, geriatric Carcinogenesis, mutagenesis, impairment of fertility Pregnancy; teratogenesis, lactation Other pharmacology n Animal studies

Labeling, cont’d. v Adverse Reactions n n v v Signs, symptoms, laboratory changes, etc Post-marketing experience Toxicity and Overdose Abuse and dependence Dosage and Administration How supplied Clinical Studies References

Case 1. Cont’d. v Recognized text books either hard print or online sources n n v Ex. Johns Hopkins: The Harriet Lane Handbook, The Sanford guide to antimicrobial therapy Official guidelines Is the data from adequate clinical trials (randomized, controlled, size, power, similar age/maturity)? • • Approved labeling Official guidelines (www. guidelines. gov) Some compendia will list sources Medline or other primary literature resources

Case 1, cont’d v v Have the pharmacokinetics been established in similarly aged children? Has the pathway of drug clearance been established in children/infants? Is that pathway established in the child/infant you are treating (based on maturity or physical state)? Is there reason to believe that pathway may be compromised in the specific child/infant (genetics, disease state, concomitant therapy)? n n n Official compendia Secondary sources Primary literature (animal studies are not reliable for most metabolic data)

Metabolism

Metabolism

Pediatric kinetics

Elderly NO

Case 1, cont’d v v v Is there a safe route to administer the drug? (intact GI tract, central access, intact skin, nontoxic solvent) Is displacement an issue for albumin binding or bilirubin displacement? Are there technical issues surrounding administration, e. g. solvents, preservatives, volume?

If there is no “Approved labeling” v v Official compendia, professional organizations, published guidelines, adequate clinical trials, “standard of care”, etc. are usually sufficient. In dire circumstances in the absence of published information extraordinary resources may be necessary. n n n Manufacturer’s Medical Department Investigators International sources

Summary: Pediatric pharmacology v v v Children and infants, especially neonates, have different pharmacokinetic parameters than adults Appropriate drug therapy cannot be assumed to identical to adults, even when adjusted for weight or body surface area. Each agent is unique and requires adequate clinical studies before a drug can safely be used in children.

Summary - Geriatric pharmacology v v Normal homeostatic mechanisms are blunted and sometimes produce inappropriate responses. Metabolism and renal elimination are most often impacted • Phase II drug metabolizing reactions are better preserved than Phase I. • The dose of most drugs that are renally cleared should be adjusted for renal function. • Cockroft-Gault equation is frequently used to estimate renal function.

Summary - Geriatric pharmacology cont’d v v v Disease and environmental factors have a greater impact on hepatic drug metabolism than age. Therapeutic plan should include only agents with established efficacy. Most drugs should started at lower doses and titrated more slowly. Frequent review of the complete therapeutic plan to minimize interactions and side effects. Adverse drug effects can mimic disease and should be included in the evaluation of a patient. “Drugs are the great imitator of disease” C. R. C. Wyndham, MD

Questions? v Blair Holbein, Ph. D. • Presbyterian Hospital of Dallas v v Email: bholbein@hcin. net Website: http: //phdres. caregate. net Annotated bibliography Slides n n April 29 : • Age and Pharmacokinetics: Pediatric and Geriatric Considerations May 2: • Drug Interactions