Precision Medicine Notes

Precision Medicine

Precision Medicine Initiative

• President Obama's Precision Medicine Initiative was launched with a $215$ million investment in the President's 2016 Budget.

• It aims to revolutionize how we improve health and treat disease through patient-powered research.

• The initiative promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select treatments that will work best for individual patients.

• Traditional medical treatments are designed for the "average patient," leading to varying success rates.

• Precision medicine considers individual differences in genes, environments, and lifestyles for disease prevention and treatment.

• Precision medicine gives clinicians tools to better understand the complex mechanisms underlying a patient's health and disease to predict treatment effectiveness.

What is Precision Medicine?

• "Personalized medicine" is an older term with a similar meaning.

• Precision medicine focuses on identifying effective approaches for patients based on genetic, environmental, and lifestyle factors.

• Precision medicine is more of a grouping concept than personalized medicine.

Drug Ineffectiveness

• Many drugs can be ineffective in a percentage of patients:

  • Hypertension Drugs (ACE Inhibitors): $10-30$%

  • Heart Failure Drugs (Beta Blockers): $15-25$%

  • Anti-Depressants: $20-50$%

  • Cholesterol Drugs (Statins): $30-70$%

  • Asthma Drugs (Beta-2-agonists): $40-70$%

Adverse Drug Reactions

• About $6.7$% of patients in hospitals experience serious adverse drug reactions (2.2 million).

• Serious adverse drug reactions have led to the withdrawal of several drugs from the market (e.g., Baycol, Fen-Phen, Lotronex, Propulsid, Tysabri, Vioxx).

• Question: "Are good drugs going to the wrong people?"

Lecture Outline

• Part One: Overview of variability in drug response

• Part Two: Genomic effect on PK & drug-drug interaction

• Part Three: Age effect on PK

• Part Four: Methodology to explain variability

• Part Five (homework): Application

Part One: Overview of Variability in Drug Response

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

• Differences among people exist, including their responsiveness to drugs (PD).

• There is a frequent need to tailor dosing regimen to individual patients.

• Failure to do so can lead to ineffective therapy, toxicity, or both.

• The magnitude and relative contribution of pharmacokinetics and pharmacodynamics to variability in response to a given dosage within a patient population vary with the drug and, to some extent, the condition being treated.

Quantitative Understanding of Variability

• To minimize confounding from various doses and time, variability is expressed in terms of the parameter values defining pharmacokinetics (PK) and pharmacodynamics (PD):

  • PK: Bioavailability, absorption rate constant, CL, V, and $t_{1/2}$

  • PD: Maximal response ($E<em>{max}$), concentration to achieve 50% of the maximum response ($EC</em>{50}$), and factor defining the steepness of the concentration-response relationship for pharmacodynamics (n: Hill coefficient)

Variables Affecting PK/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 clearance

  • Displace plasma protein binding

  • Impair GI absorption

• Route of administration

• Enantiomeric drugs

• Disease states

Age: Remifentanil

• Minto et al. Anesthesiology: Bolus doses should be reduced by $50$% in the elderly general anesthesia

• $EC_{50}$: the lower value, the higher potency

• LBM: Lean Body Mass

Body Weight: Atracurium

• Skeletal muscle relaxant: polar drug

• Obese subjects have higher exposure but are less sensitive to this drug

• Vss & CL , but PK $t_{1/2}$  (Varin et al. CPT, 1990)

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

• $C<em>0 = {Dose}/V</em>c$

• $HL = 0.693 {x} V / CL$

Race: Propranolol

• Treatment of hypertension

• PK - lower clearance in White

• PD - less sensitive in White

• Label: $45$% higher free fraction (of propranolol due to no protein binding) in Chinese

• To produce the same degree of beta-blockade, plasma propranolol concentrations had to be twice as high in the white as in the Chinese subjects.

Genetics: Apolipoprotein E (APOE)

• One of the variants of the apolipoprotein E (APOE) genes, e4, has been found to be associated with an increased risk of Alzheimer's disease (AD).

• MMSE: mini mental state examination

• Impact of not having genotype information in this case → May discontinue the development of this drug!

Impact of Food

• Nitrendipine + grapefruit juice

• 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

  • atorvastatin

  • lovastatin

  • simvastatin

  • buspirone

  • midazolam

  • diazepam

  • cyclosporine

  • tacrolimus

  • saquinavir

• Cefaclor: antibiotics

Inhibition & Induction: Saquinavir (AIDS)

• Ketoconazole: inhibition of Saquinavir metabolism

• Rifampin: induction of Saquinavir metabolism

• CYP3A4 plays major role in the elimination of saquinavir

• Ketoconazole inhibits CYP3A4

• Rifampin induces CYP3A4

• Careful comedication advice – your job!

Disease States

• Hepatic impairment

• Renal impairment

• Gastrointestinal diseases

• Cardiovascular diseases

• Respiratory diseases

• Endocrine diseases

Hepatic Impairment

• Hepatic disease can result in a decrease in CYP3A4 activity.

• Grepafloxacin, a CYP3A4 substrate, is eliminated more slowly in patients with advanced liver disease

• $ {t}_{1/2}$ , CL/F 

Adverse Reactions to Phenytoin as a Function of Serum Albumin Concentration

• Phenytoin is highly protein-bound

• The therapeutic effect and the degree of toxicity are dependent on free phenytoin concentrations, which in turn depend on the albumin binding

Renal Impairment

• Levofloxacin excretes primarily as unchanged drug into the urine.

• Drug clearance is dependent on the renal function status of the patients

• Clearance of levofloxacin is substantially reduced in patients with impaired renal function, requiring dosage adjustment in such patients to avoid accumulation

Part Two: Closer Look on Genomic Effect on PK

• Drug-Drug Interaction

CYP450s Involved in Phase I Drug Metabolism

• Predominant Phase I metabolizing enzymes

• High inter-individual variation in expression

• Phase I metabolism by oxidation, reduction, and hydrolysis

• The oxidative reaction typically involves a CYP450 monooxygenase, NADPH, and oxygen

Polymorphism in Phase I Metabolism

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

• Mutation on the gene coding for a metabolizing enzyme is a major cause of variation in drug metabolism, resulting in allelic variants producing enzymes with altered metabolizing activity.

• Affect the efficacy and adverse effects of drugs

• Incidence of poor metabolizers:

  • CYP2D6 (marker: dextromethorphan) – $5$ to $10$% Caucasians, $3.8$% Blacks, $0.9$% Asian, $1$% Arabs

• 2C9 and 2C19 also have polymorphism

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

• Dextrorphan is an active metabolite with anticonvulsant, sedative, and antitussive properties, contributes to dextromethorphan abuse liability. PMs may be less likely to abuse dextromethorphan

Phase II Metabolism

• Drugs that are subject to this metabolism pathway have high water solubility, and their metabolites become usually biologically inactive

• In most Phase II reactions:

  • Conjugation groups are activated by a coenzyme

  • Many endogenous processes utilize the same coenzymes

• Acetylation, methylation, sulfation, glucuronidation

Polymorphism in Phase II Metabolism

• Acetylation activity is bimodally distributed in the human population

• Individuals are classified as slow or rapid acetylators

• Marker: isoniazid (primarily metabolized by acetylation)

Drug-Drug Interactions

Enzyme Induction

• Examples:

  • Cigarette smoking (nicotine) induces CYP1A2

  • Rifampin and St. John’s wort induce CYP3A4

Enzyme Inhibition

• Examples:

  • Grapefruit juice and Ritonavir inhibit CYP3A4

Transporter Drug-Drug Interaction

• P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or 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.

• 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 blood-brain barrier and blood-testis barrier, where it pumps them back into the capillaries. Some cancer cells also express large amounts of P-gp, which renders these cancers multi-drug resistant.

Part Three: Age Effect on PK

• Pediatrics

• Children cannot be viewed…simply as little adults

  • pharmacokinetic differences

  • altered pharmacodynamic responses

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

Age Classification

• Preterm newborn infants

• Term newborn infants (0 to 27 days)

• Infants and toddlers (28 days to 23 months)

• Children (2 to 11 years)

• Adolescents [12 to 16-18-21 years (dependent on country)]

• Elderly (>65 years)

Pharmacokinetics of Levaquine is Age-Dependent

• Even after the dose was based on weight, age influences PK

Developmental Changes in Physiology

• The integumentary system is the organ system that protects the body from various kinds of damage, such as loss of water or abrasion from outside. The system 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, is a diagnostic agent useful in medical tests involving the kidney used in the measurement of renal plasma flow.

• UGT: UDP glucuronyl transferase

Absorption Factors

• Factors Influencing GI Absorption

  • Gastric acidity (high pH in neonates, infants & young children)

  • GI motility (low in neonates & young infants, high in older infants & children)

  • Enzymatic activity (low -glucuronidase & 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 & infants vs. $55$% in adults)

  • high volume of distribution

  • Extracellular water (high in neonates, infants & children)

  • high volume of distribution

  • Intracellular water (similar % to adult)

• Albumin concentration & plasma protein binding (low in neonates & infants)

• Body fat content

Developmental Changes in Total, Intra - & Extracellular Water & Body Fat

• Changes in body composition with age impact drug distribution

Metabolism Factors

• Drug Metabolism Occurs in

  • Liver (majority)

  • GI tract

  • Kidney

  • Lung

  • Skin

• Four Principal Metabolism Pathways

  • Oxidation (Phase I, mainly via Cytochrome P450)

  • Reduction (Phase I)

  • Hydrolysis (Phase I)

  • Conjugation (Phase II)

Development of CYP: Abundance

• Some enzymes negligible at birth, but some are not

Metabolism Factors

• Conjugation

  • Glucuronide conjugation

    • UDP-glucuronyl transferase activity depressed at birth, reaches adult levels by 3 years of age

    • Chloramphenicol (antibacterial) accumulation → “gray baby syndrome”

  • Sulfate conjugation

    • phenosulfotransferase activity higher in neonates than adults

    • Acetaminophen glucuronide conjugates  but sulfate conjugates  in neonates

Excretion Factors

• Drug & Metabolite Excretion Routes

  • Renally into the urine (majority)

  • Biliary into the gut

  • Pulmonary through the lung

  • Transdermal through the skin

• Renal Excretion Is Controlled By:

  • Renal blood flow

  • Glomerular filtration

  • Tubular secretion

  • Tubular reabsorption

Developmental Changes in Kidney Function

Excretion Factors

• Dosage adjustment based on maturation of kidney function

  • Digoxin clearance → lower in neonates

  • Aminoglycoside → correlate with creatinine clearance

Renal Function Estimation (Schwartz’ Equation)

• Infants less than one year: CLcr (mL/min/1.73 m2) = $\frac{0.45 \times length (cm)}{serum creatinine (mg/dL)}$

• Children 1-12 years: CLcr (mL/min/1.73 m2) = $\frac{0.55 \times length (cm)}{serum creatinine (mg/dL)}$

Renal Function Estimation for Adults

• Cockcroft and Gault equation:

• Men: Creatinine Clearance (mL/min) = $\frac{Weight (kg) \times (140 - age)}{72 \times serum creatinine (mg/dL)}$

• Women: $0.85 \times$ the value calculated for men.

Closing Remarks for Part 1-3

• Understanding the various factors that can alter the pharmacokinetics of a drug in targeted patient population is crucial for proper dosage regimen recommendation

• Integration of ADME principles, population pharmacokinetic analysis approach, and simulation technique maximizes the quality/utility of the information generated

Part Four: Data Analysis Methodology to Explain Variability

• Descriptive: Population Modeling Analysis

• Predictive: Clinical Trial Simulation

Population PK/PD Modeling Advantage

• Study broader spectrum of patients

• Can analyze data pooled from multiple studies

• Screen for drug-drug interactions (comedication)

• Identify important covariates

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

• Limited experts available (who know physiology, pharmacology, pharmaceutics, and statistics) → team work

Population PK/PD Modeling: Fixed and Random Effects

• Estimate the population mean PK and PD parameters and their relationships with patient-specific covariate (age, weight, disease state…) in order to explain the observed inter-individual variability in response (fixed effect)

• Estimate the probability distribution of inter-individual random effect that is not explicable by patient-specific covariate (random effect – true biological variability)

• Estimate the residual variability due to measurement error and intra-individual variability (random effect – background noise)

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: Trial execution characteristics (compliance, missing records, demography distribution)

  • Disease: Disease progress models

  • Drug: Drug action models (PK, PD, placebo)

Clinical Trial Simulation Monte Carlo Simulation: Inclusion of Variability

Designing an Optimal Trial

• Recommend optimal trial designs to achieve reasonable statistical criteria and assess precision/accuracy of model parameters

Part Five: Homework

• Understanding PK/PD variability to recommend dosage for each patient

A Case for Dosage Recommendation

• Consider the following scenarios: Dr. Y wants to prescribe an antibiotic X of 500 mg q.d. p.o. for 7 days to a white female elderly patient (80 y.o., 45 kg in weight) hospitalized for acute bacterial exacerbation of chronic bronchitis.

• Concerns:

  • Can X be taken with food or milk?

  • The patient is on warfarin (anticoagulant), does it matter?

  • The patient has hepatic disease (moderate according to the Child-Pugh classification), any need to adjust the dose?

  • Her serum creatinine level was 0.5 mg/dL (normal range is 0.7 to 1.4 mg/dL for female), any need to adjust the dose?

From Package Insert of X

• Drug X is a fluoroquinolone antibiotic, has the potential to form stable conjugation compounds with many metal ions

• Absorption: rapid (Tmax ~1 to 2 hours), essentially complete orally (F ~99%). Food intake delays Tmax about one hour but have no influence on the extent of absorption (F)

• Distribution: large volume of distribution (~100 L), slightly bound to serum albumin (< 20%)

• Metabolism: less than 5% metabolized

• Excretion: plasma half-life ~7 hours, total body clearance ~160 mL/min, renal clearance ~140 mL/min

Dosage Adjustment Information from Package Insert of X

Q&A 1 Can X be taken with food or milk?

• Yes, she can take X with food. X has large volume of distribution (100 L) indicating the majority of X is not in the plasma compartment (or systemic circulation). Under such circumstances, 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.

• However, X should not be given with milk to avoid chelation with the metal ions in milk.

Q&A 2 The patient is on warfarin (anticoagulant), does it matter?

• It shouldn’t matter as X is slightly bound to serum albumin only. Therefore, it is unlikely for X to displace warfarin from the binding site. X is hardly metabolized and so will not influence the metabolism of warfarin.

• However, warfarin has a very narrow therapeutic window, therefore need to monitor closely.

Q&A 3 The patient has hepatic disease (moderate according to the Child-Pugh classification), any need to adjust the dose?

• No, as X is minimally metabolized and slightly bound to plasma albumin. See the wordings from FDA draft labeling guidance in patients with impaired hepatic function: “The influence of hepatic impairment on the pharmacokinetics of 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 _elimination.”

Q&A 4 Her serum creatinine level was 0.5 mg/dL (normal range is 0.7 to 1.4 mg/dL for female), any need to adjust the dose?

• No. As calculated from the creatinine clearance equation, renal function of the patient is only moderately impaired, and no dosage adjustment is recommended under such circumstance according to the Package Insert

• $CLcr = 0.85 \times \frac{45 \times (140 - 80)}{72 \times 0.5} = 64 mL / min$