PKPD Exam 4

Pristiq (desvenlafaxine)

• 80% Bioavailability

• 30% Plasma Binding

• Primarily metabolised by conjugation (UGT), secondly by CYP3A4

• Not affected by CYP2D6, unlike Venlafaxine

• No Apparent food effect

Box & Whisker Plot

• Outliers

• Upper & Lower Range

• 75% and 25% quartiles

• Median

How can Bioavailability effect variatiability?

• Greater variability in a group of subject when F is lower

Spaghetti Plot

• Shows the pharmacokinetics of every subject in a study

Racial Differences in Propranolol in Chinese vs American men

• Chinese men had higher clearance and therefore lower AUC of Propranolol

  • However, Chinese men had a lower IC20, meaning they were more sensitive to propranolol and needed less to reduce heart rate

CYP2D6

• Shows great genetic variability

• Can cause an increase in exposure of drug, or decreased exposure of pro drug metabolite

Coefficient of Variation

• CV = Standard Deviation / Mean

Physiological Function Trend with Increase in Age?

• Decreasing about 1% per year

• GFR, Renal flow, drug metabolism, etc..

Renal Clearance with Age

• Peaks around 2 years of age

V, Cl, EC50 Trend with Age

• V tends to increase (more fat for lipophilic drugs)

• Cl tends to decrease (and renal excretion)

• Therefore, T1/2 tends to increase with age

• EC50 can be higher or lower in the elderly, with no clear patterns

  • Lower EC50 seen in anesthetic and sedating drugs

Renal Blood Flow in Infants

• Renal blood flow and clearance increases rapidly within first year of birth

• However, infants still show lower clearance and greater sensitivity to other age groups

Allometric Scaling

• Relates V and Cl to body weight

• Cl = a * BW^(0.75)

  • a changes between drugs

  • 0.75 ideal for drugs in human for Cl

  • a value of 1.0 is used for finding V

Enzymes that show higher activity in Females

• CYP3A4 → ex. lovastatin, methylprednisolone (also had higher sensitivity)

Enzymes that show higher activity in Males

• CYP2D6 → Metoprolol (almost 2x clearance)

• CYP1A2 → Theophylline

Ketoconazole and Terfenadine

• One of the strongest inhibitors of CYP3A4

• Females had almost 2.5x more deaths from terfenadine compared to males

  • QTc prolongation, torsades des pointes

• FDA requires all new drugs to undergo QT assessment with ECG’s

  • if QT change more than 10 = not passed

Caffeine during Pregnancy

• CYP1A2 inhibited → higher AUC of caffeine in pregnant women

• recommended not to drink caffeinated beverages

Effect of Pregnancy on PK

• Somewhat unpredictable

Effect of Oral Contraceptives on PK

• Can sometimes cause faster or slower metabolism of drugs

• Ex. slower CYP1A2 metabolism of Tizanidine in women taking OC

• Can increase metabolism of drugs that are metabolized by conjugation

Complexities in Obesity

• higher BW = bigger liver = more clearance

• higher BW = bigger Vd = high logP drugs can absorb into fat prolonging T1/2

• Absolute clearance almost double but when normalized very similar to normal BW clearance

Levonorgestrel (Plan B) in Obese Women

• Less effective in obese women → more rapid metabolism

Theophylline & Smoking

• Smoking can increase clearance of theophylline through CYP1A2

• Passive smoking also resulted in an increase in clearance

Thiocyanate & Smoking

• Thiocyanate is a component metabolite of smoking

• Smokers all had high levels of SCN-

• Ex-smokers had major reduction in levels of SCN-

• Non smokers had very low levels or none

Cotinine & Smoking

• Primary metabolite of Nicotine

• Smokers all had high levels of cotinine

• Non smokers had very low levels of cotinine

Tizanidine & Smoking

• Tizanidine is a CYP1A2 substrate

• Smokers had a lower AUC of Tizanidine due to a higher clearance from CYP1A2 induction from smoking

Smoking and Drug Clearance correlation

• Selective and unpredictable

Why does smoking cause enzyme induction?

• Polycyclic Aromatic Hydrocarbons are most likely the cause

  • Carcinogenic

• Nicotine is not the reason for induction

Nicotine Metabolite Ratio for CYP2A6 Activity

• Nicotine is metabolized by CYP2A6 into Cotinine

• Can use nicotine metabolize to determine patients CYP2A6 clearance activity

• Those with low Cotinine plasma levels are usually slow metabolizers, and have higher quitting rates

Smoking & Oral Contraceptives

• Smokers over 35+ are at a dramatically increased risk of CV diseases when using an OC

Congestive Heart Failure (CHF) and Renal Impairment

• Clearance is reduced due too lower blood flow to liver

• Vancomycin clearance is lower in both CHF and renal impairment due to being excreted mainly in the urine

Inflammation and Metabolism

• TNF-a & IL-6 are both pro inflammatory cytokines

• Increase in IL-6 (inflammation) results in decreased metabolism

  • Obese patients have higher than normal serum IL-6

• Inflammation increases and falls during surgery

Thyroid Diseases on Metabolism

• Hyperthyroidism

  • Increase in everything (clearance)

• Hypothyroidism

  • Decrease in everything (clearance)

• V not affected

Cystic Fibrosis

• Increases Renal Clearance

  • Kidney size increases 1.5x normal

• Increase in Hepatic Clearance

Erythromycin Breath Test

• Erythromycin metabolism by CYP3A4 releases labeled CO2

• CYP3A4 clearance can be determined from this

• Women naturally have higher CYP3A4 clearance

• During peal IL-6 (inflammation), erythromycin breath test shows decreased metabolism

Hepatic Disease

• Liver cirrhosis, Liver Cholestasis, Liver Cancer

• reduced blood flow, activity of hepatocytes, production of albumin

• reduced bile flow → reduced clearance of biliary eliminated drugs

Child-Pugh Score

• Class A → 10-15 points

• Class B → 7 to 9 points

• Class C → 5 to 6 points

• Encephalopathy (mental function) → worse at higher points

• Ascites → stomach fluid build up

• Bilirubin → cleared by bile, so builds up in worser liver function

• Albumin → produced by liver, lower levels in worser liver function

• Prothrombin time → coagulation factors produced by liver, longer prothrombin time in worse liver function

Effect on Biliary & Renal Elimination

• Liver disease → reduced formation & secretion of bile → decreased clearance

• Cirrhotics have reduced renal plasma flow & GFR

Hepatic Clearance & Bioavailability

• High ER drugs

  • blood flow (Q) limited

  • Inherently lower F which is sensitive to changes in fu & Clint

• Low ER drugs

  • mainly influenced by changes in Fu & Clint

  • Inherently higher F which is less sensitive to changes in fu & Clint

Liver Cirrhosis effect on Absorption Rate

• Patients are affected by gastritis & upper GI ulcers which can lead to delayed and unpredictable onset of action in cirrhotic patients

• Delayed absorption has been shown for furosemide in cirrhotic patients due to impaired gastrointestinal motility

Liver Cirrhosis Effect on Protein Binding & Vd

• Drugs that are highly bound to albumin or a1-acid glycoprotein have higher fraction unbound in patients with chronic liver disease

  • reduced synthesis of these proteins

• Because of lower plasma binding, the Vd of certain drugs is larger in these patients

• Drugs with high Vd are more sensitive to these changes in fraction unbound (fu)

Steady State Concentrations

• Looking only at steady state concentration is not enough because an increase in fu and be “cancelled out” by a decrease in Clint

• Oral → Cuss = dose / tau * Clint

• IV → Cuss = fu * dose / tau * Q

• REMEMBER THESE EQUATIONS NOT ON SHEET

5 Stages of Chronic Kidney Disease

• Normal 125 mL/min

• Stage 1 → 90 mL

• Stage 2 → 60 - 89 mL

• Stage 3 → 30 - 59 mL

• Stage 4 → 15 - 29 mL

• Stage 5 → 15 mL or less

Assessment of Renal Function

• Renal function is estimated using creatinine clearance

• Creatinine is a by product of muscle metabolism that is primarily eliminated by glomerular filtration

• Women & elderly have lower muscle mass and lower CrCl

Cockcroft - Gault

• Make sure to use right body weight

  • refer to equation sheet

Salazar & Corcoran Equation

• Special Population → obesity

• Use if actual body weight (ABW) is 30% greater than ideal body weight (IBW)

Schwartz Equation

• Special population → children

• Weight independent formula

Renal Impairment Effect on Protein Binding & Vd

• Plasma binding of acidic drugs is decreased in renal dysfunction

• Plasma binding of basic drugs unaffected

  • may be increased for some drugs because a1-acid glycoprotein is elevated in renal disease

• Some drugs Vd may decrease due to fluid over load and an increase in fraction unbound in the tissue (decreased tissue binding)

  • ex. Digoxin → use Jusko equation to estimate

Non-Renal Metabolism Effects

• Uremic toxins that accumulate in chronic renal failure can reduce drug metabolism activity (ex. CYP3A4, 2C9)

• Glucuronide conjugates will accumulate, be hydrolyzed, and not cleared (reduced clearance)

Intact Nephron Hypothesis

• Functions of all segments of a diseased nephron are affected equally

• The loss of function is quantified by GFR

• Renal clearance appears to vary in direct proportion to GFR/CrCl

T1/2 vs. CrCl & GFR Relationship

• Fe = fraction of dose excreted unchanged in the urine

• The higher the Fe, the more pronounced effect that renal failure has on drug PK

Dialysis

• Removes wastes and excess water from blood in people with renal failure

• Supplemental Dose equation

Optimization of Dosing Regimens

• Dettli Rule 1 → elimination rate constant (kel) depends linearly on GFR

  • Drug dose is adjusted to renal function proportionally to Kel, dosing rate stays the same

• Kunin Rule → Give normal first dose, then half dose every half life

• Dettli Rule 2 → Normal dose given at prolonged interval

Drug Interaction Definitions

• Perpetrator → drug, chemical, or food causing the interaction

• Victim → drug affected by interaction

Enzymatic DDI

• Inhibition

  • Decreased metabolism, increased AUC

  • Rapid onset due to direct effect on enzyme, no prior exposure needed

• Induction

  • Increased metabolism, decreased AUC

  • Slow onset due to need of new enzyme synthesis, requires prior exposure

Types of Enzyme Inhibition

• Competitive → reversible

  • graded effect, more perpetrator = more inhibition

• Mechanism based → irreversible

Fm on Graded Effect

• Fm = fraction of drug metabolized by the CYP inhibited

• If Fm is closer to 1, then AUC is sensitive to changes in inhibitor concentration

• If Fm is closer to 0, then AUC is not really effected by changes in inhibitor concentration due to a majority of the drug being metabolized by other pathways

Classifications of Inhibitors

• Weak → 1.25 to 2 fold increase in AUC

• Moderate → 2 to 5 fold increase in AUC

• Strong → >5 fold increase in AUC

Time Course of Inhibition

• Time course of maximum concentration = 5 times T1/2 of inhibitor plus 5 times T1/2 of drug

Effect of Inhibitors on Different Metabolizer Types

• Poor Metabolizers → not sensitives, already at low activity not affected much by changes

• Extensive Metabolizers → sensitive to changes in activity levels