Age and PharmacokineticsPediatric and Geriatric ConsiderationsM. E. Blair Holbein, Ph.D.Clinical PharmacologistPresbyterian Hospital of Dallas

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

Pediatric pharmacology - Whats unique?Continuous development from embryo to adolescentPerpetual pharmacologic moving targetPharmacodynamics and pharmacokinetics change with timeThe most profound differences occur in the first weeks through first year of life.Descriptive pharmacology (especially for new drugs) in pediatric patients is often lackingChildren are not miniature adultsDosing based on rule (Youngs, Clarks) 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 Children are therapeutic orphans Only 20-30% of approved drugs have pediatric labelingFDA has encouraged pediatric studiesFinancial incentive to conduct studiesOrphan and off-patent drugs - no incentive to do studiesIncreased studies resulted in new labeling for 40 drugs.For approval of selective number of new drugs pediatric studies have been required.ResourcesCenter 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 ChangesBody composition Organ functionDrug metabolizing enzymesUnique metabolic pathwaysRenal functionReceptor responseUnique disordersExtremely small margin of error for the most fragile patientsErrors can be devastatingIndividual variance unpredictable

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

Developmental Pharmacology - Absorption - GIGastric acid - approaches adult values ~ 3 mo in full-term infants. 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.Colonization of the gut occurs rapidly after birth but is highly variable and unpredictable.

Developmental Pharmacology - Absorption - GIGastric emptying Delayed and unpredictable in newborns - adult values ~ 6 mo.GI motility 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. adultsThe impact on absorption is usually minimal but is unpredictable

Developmental Pharmacology - Absorption - SkinPercutanous absorptionDirectly related to the degree of skin hydration.Inversely related to the thickness of the stratum corneum.Thinnest in premature neonateGreater extent of cutaneous perfusionPremature infant has a significantly less effective skin barrier to absorption of drugs and toxinsEx. Hexachlorophene toxic to immature infantsNewborn skin surface area : body weight is 3X > adult

Other Routes of Drug AdministrationIntramuscular Lipid solubility favors distribution from site into circulation (rate)Water soluble at physiologic pH to prevent precipitationHighly susceptible to variance in absorption due to blood flow and relative muscle massDispersion driven by muscle contraction (low in neonates and immobility)Reduced skeletal-muscle blood flow in neonateCan be extremely painful, cause hemorrhage, nerve damage, abscess, necrosis, fibrosis, and CPKRectalAbsorption is excellent for some agentsLess first pass effect due to decreased hepatic clearancePulmonary for site specific agentsUnintentionalBreast milkTransplacental

Developmental Pharmacology - Absorption

Developmental Pharmacology - DistributionLarger extracellular and total-body water spaces in neonate and young infantsAdipose stores also have higher ratio of water to lipidRESULT: Lower plasma levels (relative to weight) for water soluble drugs. Effect on lipid soluble less Plasma proteinsLow 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 transportersMay 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 - MetabolismPrior to birth the fetus is in a relatively protected environmentThe xenobiotic clearing processes of the mother prevent exposure of the fetus. The placenta also acts as a barrier.Maturation of drug metabolizing enzymes occurs longitudinallyThe very young have very low activityEx. Cardiovascular collapse in chloramphenicol associated gray baby syndrome Cause for caution for drugs that have wider therapeutic index in adultsEx. Methylxanthines, nafcillin, 3rd generation cephalosporins, captopril and morphineDistinct patterns for each class and isoform of drug metabolizing enzymes.

Development of Drug-Metabolizing Enzymes - Phases of Drug Metabolism Phase IOxidationReductionHydrolysis

Phase IIConjugation

Development of Drug-Metabolizing Enzymes - Phase I - Oxidation/Reduction/HydrolysisPredominant isoform (liver) CYP3A7 in prenatal periodPeaks at birth, then declines rapidly to undetectable in adultsRole to detoxify dehydroepiandrosterone sulfate, teratogenic derivatives of retinoic acidWithin hours after birth other isoforms begin to appear. Each has individual pattern of development.Most are at or above adult levels by 1 year.ExamplesMidazolam clearance changes 7X in 3 months (1.2 9 ml/min)Phenytoin T 1/2 in premies 75 20 hr in 1 wk old full term infantCarbamzepine clearance children > adultsMethylxanthine demethylation exceeds adults by 4 months (and declines in puberty in sex-based divergence)

Development of Drug-Metabolizing Enzymes - Phase II - Conjugation ReactionsOntogeny less well characterized than Phase I reactionsGlucouronosyltransferase (glucuronidation) is decreased in newborns and young children compared to adolescents and adultsPresent by 24 wk gestational ageMorphine glucuronidation correlates with post-conceptional ageMorphine 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 CYP1A2 SubstratesGinsberg et al. Pediatrics 2004; 113: 973.

Relative Half-lives of CYP3A SubstratesPEDIATRICS Vol. 113 No. 4 April 2004, pp. 973-983

Developmental Pharmacology -Metabolism:Phase I

Developmental Pharmacology - Metabolism:Phase II

Developmental Pharmacology - Renal EliminationMaturation of renal function dynamicBegins with fetal organogenesis (9 wk gestational age)Complete by early childhoodGFR correlates with nephrogenesis and postnatal renal and intrarenal bloodflow.

Acquisition of Renal Function

Developmental Pharmacology - Renal EliminationTherapeutic implicationsEstimation of renal function necessary for determining dose regimen for drugs with extensive renal clearanceEx. Ceftazidime, famotidine, aminoglycosides.Measurement of drug levels often necessarySome drugs also alter renal maturation or renal blood flow.Ex betamethsone, indomethacin

Developmental Pharmacology - PharmacodynamicsVery little data; most accepted practices are based on observationAnecdotal evidence for altered response toWarfarinCyclosporineMidazolamErythromycin (intestinal motilin receptors)

Criteria for Using a Drug in a Child or InfantHas there been documented efficacy for the medication for the disorder in newborn or older infants/children.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 InfantHas 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 InfantIs 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 InfantThe very small doses required in the most immature patients and the immature clearance pathways leave very little margin of error.

Developing Age-specific Dosing RegimensOfficial 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 - Whats unique?Physiology Changes in underlying physiology occurs over time. 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.Even healthy elderly have diminished capacities. Aging is a continuum and the aged are stratified by degree of age. Young old is 65 75 yearsOld 75 85 yearsOld old age > 85 years As age progresses so do the exceptional considerations.

Geriatric Pharmacology - Whats unique?Physiology Body composition total body water, lean body mass, body fat; serum albumin, -1 acid glycoproteinCNS 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 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 - Whats unique?Physiology Cardiovascular -adr receptor activity, baroreceptor activityCardiac 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 Atrophy of thyroid incidence of diabetes mellitusMenopause, andropause

Geriatric Pharmacology - Whats unique?PhysiologyDigestive tract gastric emptying time, GI blood flow; gastric pH, intestinal transit time.Hepatic liver size, hepatic blood flow.Some hepatic functions are better preserved than others. albuminAlcohol use, gallstones, cholangitis, fatty liver (NASH), heart failure, and conditions requiring concomitant drugs can affect metabolism.

Geriatric Pharmacology - Whats unique?PhysiologyRenal GFR, renal blood flow, tubular functionRenal function and size diminishes with age. Pulmonary respiratory muscle strength, chest wall compliance, total alveolar surfaceMost systems are more affected by disease than age alone.

Geriatric Pharmacology - Whats unique?Disease The elderly accumulate diseases.

Geriatric Pharmacology - Whats unique?PolypharmacyWith the accumulation of disease these is an accumulation of treatmentsPolypharmacy Multiple medications for multiple chronic diseasesMultiple physiciansSelf-medicationDisproportionate use of drugs in the elderly. 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 - AbsorptionAge related changes are small. Gastric/intestinal motility Surface area and blood flow Net negligible change in absorptionLess 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 - DistributionLean body mass and body water Vd (volume of distribution) for water soluble drugsWater soluble drug - conc. Ex. ethanolFat soluble drugs conc.Increased fat serves as a repository for fat soluble drugsEx. Amiodarone, desipramine, diazepam, haloperidol, digitoxinImpact on drug therapy in general is not great. Protein binding to albumin and -1 acid glycoprotein is more affected by disease than age. Decreased albumin can result in increased free fraction of drugs.Increased delivery to receptorIncreased drug interactions

Volume of Distribution by Age

Geriatric Pharmacokinetics - MetabolismPhase II reactions are better preserved than Phase I. 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 - EliminationRenal Elimination Cl and t1/2 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 FunctionCockcroft Gault estimationAssumes steady state production of creatinine.Very limited utility in critically ill, clinically unstable, malnourished or wasted patients.Measure creatinine clearance or use extrinsic marker if critically important.Other formulas may be more accurate in special populations.

(multiply by 0.85 for women)

CLCr (ml/min) = (140 age) (lean weight in kg)72 (serum creatinine in mg/dL)

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

Geriatric Pharmacokinetics Drug EliminationDrug dosing requires adjustment for changed pharmacokinetic parameters. Vd is smaller for water soluble drugsClearance is usually diminished with age

t 1/2 =0.693 X VdClearance

Geriatric PharmacodynamicsReceptor alteration with age best documented for adrenergic receptors and autonomic nervous system.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 PatientsObtain a complete drug historyAvoid prescribing before a diagnosis is madeReview medications regularly and before prescribing a new medicationKnow the actions, adverse effects, and toxicity profiles of he medications you prescribeStart low dose and titrate dose based on tolerability and responseGeriatric dictum:Start low and go slow

Appropriate Prescribing for Geriatric PatientsEducate patient and/or caregiver about each medicationAvoid using one drug to treat the side effects of anotherAttempt to use one drug to treat two or more conditionsUse combination products cautiouslyCommunicate with other prescribersAvoid using drugs from the same class or with similar actions

How do you adjust drug therapy for special populations?

Drug InformationOn-line decision supportInstitutional: CPOE (Computerized Physician Order Entry)Guidelines, rules, protocolsText-based (online and print)Secialized informationJohns Hopkins: The Harriet Lane Handbook: A Manual for Pediatric House Officers, 16th ed 2002 Mosby, Inc.Geriatrics At Your Fingertips, 2005 by D Reuben, and Others. The American Geriatrics Society (AGS)Literature (Medline, full-text, etc)ExceptionsInvestigational drugsNME (New Molecular Entity)Indication not labeledLiterature, FDA, SponsorsUnusual patients (age, disease, indications)International patients (online resources, Pharmaceutical regulatory agencies)

Drug Information Age-specificFDA, Government and professional organizations web sitesMedical departments of Pharmaceutical ManufacturersMost have available physicians who have specialized knowledge of productsDifferent constraints on information sharing when physician-to-physician

Case Study - 1NICU, 32 week infant; 1 wk p delivery, wt 1800 gmApparent pneumonia, worried about sepsis; blood culture growing MRSA; intermediate vancomycin sensitivitiesIs Linezolid a therapeutic alternative in this patient?

What information do you need to gather?

Case 1Has there been documented efficacy for the medication for the disorder in newborn or older infants/children?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 InformationOn-line sources: Manufacturer, FDAOther compendia: MicroMedex, Epocrates Note: The FDA may be revising OPI format.See FDA announcement:

OPI

Official Product Insert (Approved labeling)DescriptionClinical PharmacologyPharmacokineticsAbsorption, Distribution, Metabolism, ExcretionSpecial populations: Geriatric, pediatric, gender, renal insufficiency, hepatic insufficiencyDrug-drug interactionsSpecial: Antibiotics|MicrobiologyIndications and UsageContraindications (do not use)Warnings (use with caution)Precautions (during therapy)Information for patients

Labeling, contd.InteractionsDrug-drugDrug-laboratoryUse in special populations or extraordinary considerationsPediatric, geriatricCarcinogenesis, mutagenesis, impairment of fertilityPregnancy; teratogenesis, lactationOther pharmacologyAnimal studies

Labeling, contd.Adverse ReactionsSigns, symptoms, laboratory changes, etcPost-marketing experienceToxicity and OverdoseAbuse and dependenceDosage and AdministrationHow suppliedClinical StudiesReferences

Case 1. Contd.Recognized text books either hard print or online sourcesEx. Johns Hopkins: The Harriet Lane Handbook, The Sanford guide to antimicrobial therapyOfficial guidelinesIs the data from adequate clinical trials (randomized, controlled, size, power, similar age/maturity)?Approved labeling Official guidelines (www.guidelines.gov)Some compendia will list sourcesMedline or other primary literature resources

Case 1, contdHave 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)?Official compendiaSecondary sourcesPrimary literature (animal studies are not reliable for most metabolic data)

Metabolism

Metabolism

Pediatric kinetics

Elderly NO

Case 1, contdIs 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 labelingOfficial 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.Manufacturers Medical DepartmentInvestigatorsInternational sources

Summary: Pediatric pharmacologyChildren and infants, especially neonates, have different pharmacokinetic parameters than adultsAppropriate 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 Normal homeostatic mechanisms are blunted and sometimes produce inappropriate responses. Metabolism and renal elimination are most often impactedPhase 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 contd 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?Blair Holbein, Ph.D.Presbyterian Hospital of DallasEmail: bholbein@hcin.netWebsite: http://phdres.caregate.netAnnotated bibliographySlidesApril 29 : Age and Pharmacokinetics: Pediatric and Geriatric Considerations May 2: Drug Interactions

Figure 1. Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents.

Physiologic changes in multiple organs and organ systems during development are responsible for age-related differences in drug disposition. As reflected by Panel A, the activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the first two months of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific. Panel B shows age-dependent changes in body composition, which influence the apparent volume of distribution for drugs. Infants in the first six months of life have markedly expanded total-body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults. Panel C shows the age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (Panel A), the activity of cytochrome P-450 1A1 (CYP1A1) in the intestine is low during early life. Panel D summarizes the effect of postnatal development on the processes of active tubular secretion -- represented by the clearance of para-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 months of age. Panel E shows age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin-surface area (reflected by the ratio of body-surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood. Data were adapted from Agunod et al.,4 Rodbro et al.,5 Poley et al.,9 Gibbs et al.,21 Okah et al.,24 West et al.,27 Friis-Hansen,38 Young and Lietman,39 Hines and McCarver,40 Treluyer et al.,41 Kinirons et al.,42 Pynnonen et al.,43 Aranda et al.,44 Miller et al.,45 Barrett et al.,46 Murry et al.,47 and Robillard et al.48