PKPD Exam 3

UBSOPPS

Time for Onset

• IV → fastest

• Inhalation

• Sublingual

• Rectal

• IM & SC

• Oral → one of the slowest

• Transdermal

IV Route

• Pros

  • all dose is delivered directly to blood stream

  • can do bolus or infusion in controlled amounts

• Cons

  • Inconvenient and painful

  • Requires trained personnel

IM Route

• Pros

  • Rapid Onset

  • Depot injections, larger than SC

  • Almost 100% bioavailability

• Cons

  • Not large volumes

  • painful, inconvenient

  • site of injection can influence extent of absorption

SC Route

• Pros

  • Slower constant absorption over longer period of time

  • Almost 100% bioavailability

  • Patient can inject themselves with minimal training.

• Cons

  • Site of injection can influence extent of absorption

  • Can cause tissue damage

  • limited volumes

Intranasal Route

• Pros

  • Ease of Administration

  • Rapid absorption and onset of action

  • Reduction of systemic side effects

• Cons

  • Local irritation

  • lower bioavailability

  • efficiency depends on delivery system

Inhalation Route

• Pros

  • Self administration

  • Large surface area for absorption

  • Reduction of systemic side effects.

• Cons

  • Highly dependent on formulation

  • Highly dependent on delivery system

Sublingual & Buccal Routes

• Pros

  • Avoids first pass metabolism

  • Rapid absorption and onset

• Cons

  • Not suitable for large doses

Transdermal Routes

• Pros

  • Ease of administration

  • Reduction of systemic side effects

  • Controlled prolonged delivery

• Cons

  • Mainly only for local effects

  • Slow absorption

  • Low bioavailability

  • High dependence on drug characteristics such as logP, MW, and delivery system

  • Local irritation

Ocular Route

• Pros

  • high drug concentration in localized area

  • self administration

• Cons

  • limited types of drugs

  • not suitable for irritating drugs

Rectal Route

• Pros

  • avoids first pass metabolism

  • useful for children, elderly, or unconscious patients

  • useful for vomiting or nausea

• Cons

  • Invasive application

  • limited drugs can be administered this way

Oral Route

• Pros

  • Convenient, cheap, painless

  • adjustable doses

  • self administered

• Cons

  • Subject to first pass metabolism

  • Drug taste

  • PKPD of drug

Mechanism of Absorption

• Drugs enter the apical side → Leave out the basolateral side

• Transport

  • Passive Transcellular → high capacity, lipophilic, conc. gradient

  • Active Transcellular → substrate dependent, hydrophilic, active

  • Paracellular → low capacity, hydrophobic, conc. gradient

  • Transcytosis → active, very low capacity, macromolecules

Permeability vs Solubility Limited Absorption

• If dissolution > absorption → most of the drug is dissolved before much is absorbed. Therefore permeability limits absorption

• If absorption > dissolution → absorption cannot go any faster than the rate a drug is dissolved. Therefore absorption is dissolution rate limited

Kinetics of Absorption

• Oral absorption of drugs is often first order kinetics

• Absorption rate constant (ka)

  • corresponding absorption half life = (0.693 / ka)

Bioavailability

• Fraction of dose that is absorbed into systemic circulation

• No method using oral data alone

• Absolute Bioavailability

  • comparing oral AUC data to IV AUC data

• Relative Bioavailability

  • comparing two oral formulations

  • F can be greater than 1

Peak Concentration

• Cmax → peak plasma concentration

  • determined by D, F, Tmax (ka, Cl, V)

  • can calculate Cmax when ka >>> kel

• Tmax → time to peak plasma concentration

Effect of Dose on Graph

• Tmax = ln(ka/kel) / ka - kel, AUC = F x dose / Cl, Cmax = D * F / V

• If you increase dose:

  • Tmax stays the same

  • Cmax increases

  • AUC increases

Effect of F on Graph

• Tmax = ln(ka/kel) / ka - kel, AUC = F x dose / Cl, Cmax = D * F / V

• If you increase F (bioavailability)

  • AUC increases

  • Cmax increases

  • Tmax stays the same

Effect of ka on Graph

• Tmax = ln(ka/kel) / ka - kel, AUC = F x dose / Cl, Cmax = D * F / V

• If ka increases (faster absorption)

  • AUC the same

  • Cmax increases, Tmax decreases

  • ** think more drug absorbed all at once creating a spike on the graph, IV bolus-like **

Effect of Cl on Graph

• Tmax = ln(ka/kel) / ka - kel, AUC = F x dose / Cl, Cmax = D * F / V

• If Cl increases:

  • AUC decreases

  • Cmax decreases

  • Tmax decreases

  • terminal t1/2 decreases

Flip Flop Kinetics

• When ka < kel

• drug absorption controls Cp and not elimination

• sustained release products

  • terminal t1/2 increased

  • one dose has much larger amount of drug for entire day

  • should not be food sensitive

• allows once daily formulations

AUC 0 → infinity = AUC 0 → tau at SS

Time to Reach Steady State

• Only dependent on elimination half life

  • Remember (kel = cl / v )

Noyes - Whitney Equation

Parameters affecting dissolution

• Diffusion coefficient → molecular size → increased by smaller sizes

• surface area → particle size → increased by smaller particles

• diffusion layer thickness → increased by faster stirring

• Saturated solubility of drug → intrinsic solubility → composition of medium, pH of medium

• Drug concentration → increased by sink conditions

Dissolution Testing Apparatus

• Apparatus 1 → basket

  • tablet in basket that rotates vertically

• Apparatus 2 → paddle

  • paddle rotates in beaker

Lipinski’s Rule of 5’s

Good in vivo oral drug absorption and permeation:

• logP < 5

• H bond donors < 5

• Molecular weight < 500

• H bond acceptors < 10

Why does LogP matter?

Increasing LogP

• increases binding to enzyme & receptor

• increases absorption through membrane

• decreases aqueous solubility

• increases binding to metabolizing enzymes

• increases binding to blood proteins

Biopharmaceutical Classification System

• I → high solubility high permeability

• III → high solubility low permeability

• II → low solubility high permeability

• IV → low solubility low permeability

highly soluble → in 250 mL or 8 oz. of water

Site of Absorption & Permeability

• There can be regional differences in where a drug is absorbed

• drugs with very low permeability are likely to be incompletely intestinally absorbed

  • show low bioavailability because of the limited time in the small intestines where permeability is the highest

Gastric Emptying

• Water leaves stomach fast, than digestible solids, and than large undigestible solids

• Because absorption is greater in small intestines, rate of gastric emptying can be a controlling step in drug absorption

  • gastric retention can be utilized as a mechanism for sustained release oral drug absorption from the small intestines

Absorption Window

• If absorption is mediated only my uptake transporters in a small region, then drug absorption is limited to that window

• drug release must occur before the absorption window

• Big dose of drug is not recommended either because the uptake transporters are often saturable

Lag time

• For some drugs, absorption does not start immediately, due to delay in gastric emptying time or intestinal motility

Site of Injection

• absorption from different areas of the body may differ

• the greater the speed of absorption, the more rapid the exposure, the shorter duration of action

Effect of Food

• Food may effect both rate and extent of absorption

  • positively or negatively

• FDA requires studies on food effects on all new drugs, especially sustained release products

• Large meals can delay gastric transit time

• Some medications (ex. antibiotics) should not be taken with dairy products due to chelation to ions

• Some medications are more soluble in the stomach, so a big meal delaying gastric emptying will allow more drug to dissolve before entering the intestines, increasing bioavailability

  • However this could be negative if a sustained release dose stays in stomach for too long ending in dose dumping

Enterohepatic Circulation & Charcoal

• Drug is reabsorbed back into circulation

• Orally ingested charcoal absorbs drugs in the intestines, preventing their absorption and future enterohepatic circulation

Intrinsic Clearance

• Ability of the organ (liver) to remove drug in the absence of flow limitations and binding to cells or proteins in the blood

High and low ER Drugs (IV)

• High ER (>0.7) → blood flow limited

• Low ER (<3.0) → Fu x Clint limited

Oral Clearance

• Fu x Clint = Cloral

• NOT dependent on blood flow

• High and low ER drugs only influenced by changes in Fu or Clint

Factors Affecting low ER drug PK

• IV

  • Increase Clint → increase in clearance

  • Increase Q → no change

• Oral

  • Increase Clint → increase in clearance

  • Increase Q → no change

Factors Affecting high ER drug PK

• IV

  • Increase Clint → no change

  • Increase Q → increase in clearance

• Oral

  • Increase Clint → increase in clearance

  • Increase Q → higher Cmax and increase in clearance but same AUC

Brand vs Generic

• Same active ingredient

• Same strength and dosage

• Generic is cheaper, almost always covered by insurance

• Inactive ingredients may differ but have to be accepted by FDA

• Appearance and look may differ

• Generics are cheaper in cost

Bioequivalence

• FDA has set standards on rate and extent of absorption by which two products can be considered bioequivalent and therefore able to be substituted for one or another

• Extent → Log AUC

• Rate → Log Cmax

• Adjusted for log transformed data, the range becomes 80% - 125%

  • Thus the two products are bioequivalent if all 4 characteristics are between 0.8 and 1.25

Bioequivalence Testing Preference

1. In vivo measurement of active moiety in biological fluids

2. In vivo PD measurements

3. In vivo clinical comparison

4. In vitro comparison

Bioequivalence Calculation

• Degrees of freedom = subjects (n) - 1

• Confidence = 90% confident → 1-0.9 = 0.1 / 2 = 0.05

• mean difference = e ^ MD

• Cmax = e ^ Cmax

• mean difference and Cmax confidence intervals → use equations. Remember MD is not the same as e^MD value