lec 24 - precision med (guo)

what is precision med?

• ‘personalized' medicine’ = older term with a meaning similar to ‘precision medicine’

• precision med = focus is on identifying which approaches will be effective for which patients based on genetic, environmental and lifestyle factors

many drugs can be ineffective in…

• drug → non-response rate

• hypertension drugs → 10-30%

• heart failure drugs → 15-25%

• anti depressants → 20-50%

• cholesterol drugs → 30-70%

• asthma drugs → 40-70%

some experience adverse effects

• just in hospitals → 6.7% of patients experience serious adverse drug reactions

• serious adverse drug reactions in even smaller percentages of treated populations have led to withdrawal of several drugs from the market

  • baycol

  • fen-phen

  • lotronex

  • propulside

  • tysabri

  • vioxx

  • are good drugs going to wrong people?

qualitative understanding of variability

• assumption that all people are alike in PK should be challenged

• differences among people do exist including their responsiveness to drugs (PD)

• frequency need to tailor dosing regimen to individual patient

• a failure to do so can lead to ineffective therapy, toxiciy or both

• magnitude and relative contribution of PK/PD to variability in response to a given dosage within a pt population vary with the drug and to some extent, the condition being treated

quantitative understanding of variability

• to minimize the confounding (inability to tell whats truly causing variability) from various doses and time in explaining variability, let’s express variability in terms of parameter values defining PK and PD

  • PK

    • bioavailibility

    • absorption rate constant

    • CL

    • V

    • t_1/2

  • PD

    • maximal response (Emax)

    • concentration to achieve 50% of max response (EC50)

    • factor defining the steepness of the concentration-response relationship for PD (n: Hill coeff)

    • equation in photo = hill equation

      • E = effect

variables (‘covariates’) affecting PD/PD variability

• age

• size (WT, BSA)
  gender

• race

• genotype/phenotype

• food effect

• renal function status

• hepatic function status

• concomitant medications

  • enzyme inducers

  • enzyme inhibitors

  • compete renal CL

  • displace plasma protein binding

  • impair GI absorption

• route of admin

• enantiomeric drugs

• disease states

age: remifentanil

• bolus doses should be reduced by 50% in the elderly

• V1 decreases with age → older adults have less volume to distribute the drug

• CL decreases with age

• EC50 decreases with age → older adults require less drug to achieve the same effect → increased sensitivity

body weight: atracurium

• obese subjects have higher exposure but as less sensitive to drug

  • V_ss and CL = decreased but PK t_1/2 is unchanged

  • CL decreased → more drug stays in plasma as time goes on but not as sensitive to drug so need higher concentrations to achieve same effect

• NO difference in the time of recovery of neuromuscular blockade, so dosing based on total body weight (TBW)

race: propranolol

• PK → lower clearance in white

• PD → less sensitive in white → higher doses

• label → 45% higher free fraction (of propranolol due to NO protein binding) in chinese

• to produce the same degree of beta-blockage, plasma propranolol concentrations had to be twice as high in whites v chinese

genetics: apolipoprotein E (APOE) genotype distribution

• one of the variants of the APOE genes, e4, has been found to be associated with increased risk of Alzheimers disease

• impact of NOT having genotype information in this case → may discontinue the development of this drug

impact of food

• chemicals in grapefruit juice inhibits CYP3A4 and increases the plasma concentrations of nitrendipine

• other drugs that interact with grapefruit juice

  • felodipine

  • nifedipine

  • verapamil

  • terfenadine

  • cisapride

  • carbamazepine

  • atoravastatin

  • lovastatin

  • simvastatin

  • buspirone

  • midazolam

  • diazepam

  • cyclosporine

  • tacrolimus

  • saquinavir

inhibition and induction: saquinavir (AIDS)

• ketoconazole → inhibition of saquinavir metabolism

• rifampin → induction of saquinavir metabolism

• CYP3A4 plays major role in elimination of saquinavir

disease states

• hepatic impairment

• renal impairment

• GI diseases

• CV diseases

• respiratory diseases

• endocrine diseases

hepatic impairment

• hepatic diseases can result in decrease in CYP3A4 activity

• grepafloxacin, CYP3A4 substrate, eliminated more slowly in patients with advanced liver disease

  • increased half life

  • decreased CL/F since CL decreases

hepatic impairment cont.

• phenytoin is highly protein bound

• therapeutic effect and the degree of toxicity are dependent on free phenytoin concentration which is turn depend on the albumin binding

  • less albumin → greater drug displacement → more adverse rxns

renal impairment

• levofloxacin excretes primarily as unchanged drug into the urine

  • drug CL is dependent on the renal function status of the patients

  • CL of levofloxacin is substantially reduced in patients with impaired renal function → requires dosage adjustment to avoid accumulation

CYP450s involved in phase I drug metabolism

• predominant phase I metabolizing enzymes

• high inter-individual variation in expression

polymorphism in phase I metabolism

• individuals are classified as poor (PM) or extensive (EM) metabolizers

  • mutation on the gene coding for a metabolizing enzyme = major cause of variation in drug metabolism → results in allelic variants producing enzymes with altered metabolizing activity

  • affect the efficacy and adverse effects of drugs

• incidence of poor metabolizers

  • CYP2D6 (marker: dextromethorphan)

    • 5-10% caucasians

    • 3.8% blacks

    • 0.9% asians

    • 1% arabs

  • 2C9 and 2C19 also have polymorphism

  • half life of dextromethorphan was significantly increased in PM compared with EM

    • dextrophan = active metabolite with anticonvulsant, sedative and antitussive properties → contributes to dextromethorphan abuse liability → PMs less likely to abuse dextromethorphan

phase II metabolism

• drugs that are subject to this metabolism pathway have high water solubility and their metabolisms become usually biologically inactive

• in most phase II reacitons

  • conjugation groups are activated by coenzyme

  • many endogenous processes utilize the same coenzymes

• acetylation, methylation, sulfation, glucuronidation

polymorphism in phase II metabolism

• acetylation activity is bimodally distributed in human populations

  • classified as either slow or rapid acetylators

  • marker = isoniazid (primarily metabolized by acetylation)

• most asians are rapid acetylators

• a little more of caucasians are slow but pretty even

• more middle easterns are slow acetylators

drug-drug interactions

• enzyme induction

  • nicotine induces CYP1A2

  • rifampin and st johns wort induce CYP3A4

• enzyme inhibition

  • grapefruit juice and ritonavir inhibit CYP3A4

transporter drug-drug interaction

• P-glycoprotein 1 (Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243)

• cell membrane protein that pumps many foreign substances out of cells; more formally = ATP-dependent efflux pump with broad substrate specificity

• extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics (such as toxins or drugs) back into the intestinal lumen in liver cells where it pumps them into bile ducts in the cells of the proximal tubule of the kidney where it pumps them into urine-conducting ducts and in the capillary endothelial cells composing the BBB and blood-testis barrier where it pumps them back into the capillaries

• some cancer cells express large amounts of PGP which ernders these cancers multi-drug resistant

drug development and drug interactions: table of substrates, inhibitors and inducers

physiology: a source of variability

• age

• children cannot be viewed simply as little adults

• PK differences

• altered PD responses

• process of growth (body proportion) and development (organ functionality)

age classification

• pre-term newborn infants

• term new born infants → 0-27 days

• infants and toddlers → 28 days - 23 months

• children → 2-11 years

• adolescents → 12 to 18-18-21 years (dependent on country)

• elderly → >65 years

PK of levaquine is age-dependent

• even after dose was based on weight, age influences PK

• healthy adult = 500 mg

• peds = 7 mg/kg

developmental changes in physiology

• integumentary system = organ system that protects the body from various kinds of damage such as loss of water or abrasion from outside

  • comprises the skin and its appendages (including hair, scales, feathers, hooves, and nails)

• aminohippuric acid or para-aminohippuric acid (PAH), a derivative of hippuric acid = diagnostic agent useful in medical tests involving the kidney used in the measurement of renal plasma flow

• changes in metabolic capacity

  • CYP enzymes activity gradually increase with age

• distribution changes

  • total body water is very high at birth and decreases with age

  • body fat increases later in infancy

• changes in GI function

  • neonates have low hydrochloric acid, immature bile acid secretion, incomplete enzyme activity

• renal function

  • GFR and tubular secretion = immature at birth and increase as you get older

• integumentary development

  • preterm infants = thin, highly permeable skin and a high surface area-to-weight ratio

absorption factors

factors influencing GI absorption

• gastric acidity

  • high pH in neonates, infants and young children

• GI motility

  • low in neonates and young infants

  • high in older infants and children

• enzymatic activity

  • low beta-glucuronidase and UDP-glucuronyl transferase in neonates

• bile acids

  • low in neonates

• mucosal membrane permeability

• bacterial flora

• dietary components

• diarrheal episodes

distribution factors

• body water composition

  • total body water

    • ~75% of body weight in neonates and infants vs 55% in adults

      • high Vd

    • extracellular water (high in neonates, infants and children)

      • high Vd

    • intracellular water (similar % to adult)

• albumin concentration & plasma protein binding

  • low in neonates and infants

• body fat content

distribution factors: developmental changes in total, intra- & extracellular water & body fat

• total body water

  • starts high in neonates and gradually decreases

  • higher total water = more distribution space for hydrophilic drugs → higher Vd

• extracellular water

  • very high in neonates and drops with age

  • hydrophilic drugs tend to distribute in extracellular fluid → higher Vd in neonates

• intracellular water

  • fairly stable across age groups

  • slightly lower in neonates, increases then plateaus

• body fat

  • low in neonates

  • increases during infancy and childhood

  • lipophilic drugs will have lower Vd in neonates due to less fat to accumulate in

metabolism factors

• drug metabolism occurs in

  • liver (majority)

  • GI tract

  • kidney

  • lung

  • skin

• 4 principal metabolism pathways

  • oxidation → phase I, mainly via CYP450

  • reduction → phase I

  • hydrolysis → phase I

  • conjugation → phase II

development of CYP: abundance

• some enzymes negligible at birth but some are NOT

• CYP2A6/CYP2D6 → faster postnatal maturation → most dominant enzymes

• CYP1A2 → slow onset, does NOT reach adult levels until around 10 yrs

• CYP2C9 → rapid onset, reaches near adult levels within months

metabolism factors

conjugation

• glucuronide conjugation

  • UDP-glucuronyl transferase activity depressed at birth → reaches adult levels by 3 yo

  • chloramphenicol (antibacterial) accumulation → grey baby syndrome

    • glucuronidation = only pathway for detoxification

• sulfate conjugation

  • phenosulfotransferase activity higher in neonates than adults

  • acteaminophen glucuronide conjugates lower but sulfate conjugates higher in neonates

    • compensatory mechanism

excretion factors

• drug & metabolite excretion routes

  • renally into urine (majority)

  • biliary into gut

  • pulmonary thru lung

  • transfermal thru skin

• renal excretion is controlled by:

  • renal blood flow

  • GFR

  • tubular secretion

  • tubular reabsorption

excretion factors: kidney function

• developmental changes in kidney function

• kidney function increasing till you reach adult levels around like 9??? and then elderly decreases

excretion factors: kidney cont

• dosage adjustment based on maturation of kidney function

  • digoxin CL → lower in neonates

    • decreased GFR and tubular function

  • aminoglycoside → correlate with creatinine CL

    • controlled by GFR

excretion factors: renal function estimation (schwartz equation)

just look at photo bruh

• basically a greater factor you multiple length by for children 1-12 years

renal function estimation for adults

• cockcroft and gault equation

• serum creatinine should represent a steady state of renal function

closing remarks for everything before this

• understanding the various factors that can alter the PK of a drug in targeted patient population = crucial proper for proper dosage regimen recommendation

• integration of ADME principles, population PK analysis approach and simulation technique maximizes the quality/utility of the info generated

data analysis methodology to explain variability

• descriptive → population modeling analysis

  • describes observed data by identifying how pt specific factors affect drug exposure and response

• predictive → clinical trial simulation

  • uses the descriptive model to simulate future clinical trials

population PK/PD modeling

• advantage

  • study broader spectrum of patients

  • can analyze data pooled from multiple studies

  • screen for drug-drug interactions (co-medication)

  • identify important co-variates

  • may also provide some understanding of drug exposure-response relationships for efficacy and toxicity

• limited expert available (who know physiology, pharmacology, pharmaceutics and statics) → teamwork

population PK/PD modeling: fixed and random effects

• fixed effect → estimate the population mean PK/PD parameters and their relationship with patient specific co-variate (age, weight…) in order to explain the observed inter-variability in response

• random effect - true biological variability → estimate the probability distribution of inter-individual random effect that is NOT explicable by patient specific covariate

• random effect — background noise → estimate the residual variability due to measurement error and intra-individual variability

what is clinical trial simulation

• generation of virtual patient data by approximating human, disease and drug behaviors with proposed trial designs using mathematical models and numerical methods

• human factors

  • account for variability in:

    • trial execution characteristics (patient compliance, missing records, demography distribution)

• disease model

  • disease progress models

• drug

  • drug action models (PK, PD, placebo)

clinical trial simulation

monte carlo simulation: inclusion of variability

• computational technique that stimulates thousands of ‘virtual’ patients

• randomly samples from distribution of paramters to capture real-world variability

  • PK

  • PD

  • placebo effect

  • compliance & drop outs

  • demographics

  • trial design

designing an optimal trial

• objectives → overall goals of an optimal trial

  • recommend optimal trial designs

    • to achieve reasonable statistical criteria

    • assess precision/accuracy of model parameters

• specific aims → actionable items that guide trial implementation so things you decide for an optimal trial

  • provide

    • dosage regimen

    • # of subjects

    • sampling times

    • patient inclusion/exclusion critera

    • study period

package insert of the drug

dosage adjustment information from package insert of X

case for dosage recommendation

consider the following scenario and questions

1. X can be taken with food as X has Large Vd (100L) which indicates that majority of X is NOT in the plasma compartment (or systemic circulation). under such circumstance a slight decrease in absorption rate but NOT in extent (Tmax shifts one hour) will have minimal effect in altering the plasma concentration-time profile hence the resulting treatment effect

   1. food impacts absorption rate by delaying gastric emptying meaning it takes longer for drug to move from stomach to small intestine where most drug absorption occurs

   2. ok so its saying that b/c of food you’re going to have drug being absorbed at a slightly slower rate but since Vd is high it doesn’t matter b/c most of the drug will still enter the tissue aka the extent will be the same itll just be slower

   3. X should NOT be given with milk to avoid chelation with metal ions in milk

2. X is slightly bound to serum albumin only so it is unlikely for X to displace warfarin from binding site. X is hardly metabolized so it will NOT influence the metabolism of warfarin. however, warfarin has very narrow TI needs to be monitored closely.

3. X is minimally metabolized and slightly bound to plasma albumin so NO (liver does NOT need to metabolize it so don’t matter)

   1. influence of hepatic impairment on PK of X has NOT been evaluated. because greater than 90% of the dose is excreted in the urine as unchanged drug, hepatic impairment would NOT be expected to have a significant effect on X elimination

4. look at image for calculation. NO, as calculated from equation, renal function of the patient is 64 mL/min which is only moderately impaired and NO dosage adjustment is recommended under such circumstance according to package insert