5. Pharmacokinetics Flashcards by Theo Tait

What are the four aspects of pharmacokinetics?

-Absorption
-Distribution
-Metabolism
-Excretion

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What may influence a prescribed dosing regiments?

-Compliance
-Dosing and medication errors
-Absorption
-TIssue and body fluid mass, and volume
-Drug interactions
-Elimination
-Drug metabolism

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What may influence a drug’s effects at the body?

-Drug receptor status
-Genetic factors
-Drug interactions
-Tolerance

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What may be used to quantify drug concentrations in patient samples?

-LC-MS/MS (Liquid Chromatography-Mass Spectrometry) – Gold standard for PK studies.
-HPLC (High-Performance Liquid Chromatography) – Alternative for routine analysis.
-ELISA (Enzyme-Linked Immunosorbent Assay) – Used for biologics and large molecules
-Atomic absorption spectrometry

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Give the equation for the semi logarithmic graph of drug elimination in first-order processes

lnC = -kt +lnCo

C=drug concentration at time T
Co=Initial drug concentration
k=Elimination rate constant (h^-1)
t=time

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Give the equation for the semi logarithmic graph of drug elimination in zero-order processes

C = -kt + Co

C=drug concentration at time T
Co=Initial drug concentration
k=Elimination rate constant (h^-1)
t=time

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How do you calculate elimination rate constant (k)

k = (lnC1 - lnC2) / (t2 - t1)

C=Drug concentration at t
t=time

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How do you calculate drug half life (t1/2)

t1/2 = 0.693/k

t1/2 = half life
k= elimination rate constant

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Give some parameters of absorption and exposure

-Cmax: Maximum Concentration
-Tmax: Time at which Cmax is reached
-AUC: Measures total drug exposure
-Bioavailability: Extent of absorption after extravascular administration
-Absorption rate constant: How quickly a drug enters the bloodstream

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Give some parameters of distribution

-Volume of distribution (volume into which a drug distributes within the body)
-Calculated as total amount of drug in body/plasma concentration

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Give some parameters of elimination

-Clearance: Volume of plasma cleared of drug per unit time
-Elimination rate constant: Fraction of drug eliminated per unit time
-Half life: Time required for plasma drug concentration to reduce by 5-%

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How do you calculate clearance following IV dosing?

Cl = IVdose / IVauc

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How do you calculate clearance following oral dosing?

Cl = Oral dose x F / OralAUC

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Describe the relationship between clearance, volume of distribution and elimination rate constant

Cl / Vd = K

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What does the one compartment model of pharmacokinetics assume?

-Assumes the body is a single, uniform compartment where the drug distributes instantly after administration.
-Drug elimination occurs directly from this compartment

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What does the two compartment model of pharmacokinetics assume?

-Divides the body into:
1. Central Compartment (blood & well-perfused organs like liver & kidney).
2. Peripheral Compartment (poorly perfused tissues like fat & muscle).
-Drug distributes first to the central compartment before reaching the peripheral compartment.

What do generic multi compartment models of pharmacokinetics assume?

-Extends the two-compartment model to three or more compartments (e.g., blood, liver, muscle, fat).
-Used for drugs with complex distribution and metabolism patterns.

Describe physiologically based pharmacokinetic models (PBPK)

-Most detailed PK model, using actual physiological compartments (heart, liver, kidneys, fat, etc.).
-Based on real anatomical and physiological data rather than empirical parameters.
-Uses differential equations to model drug movement based on blood flow, tissue composition, enzyme activity, transporter proteins, etc.

What can physiologically based pharmacokinetic models (PBPK) be used for?

-Simulation of clinical trials without the need for clinical data
-Estimation of tissue specific drug concentration
-Assessment of potential for drug-drug interactions

What is allometric scaling?

Allometric scaling is a mathematical approach used to predict pharmacokinetic (PK) parameters across different species based on body size and metabolic rate.

Give some applications of allometric scaling in drug development

-Predicting Human Clearance from Animal Data
-Determining first-in-human doses (ensuring safety in phase I trials)
-Dose selection for paediatric and geriatric populations

Describe the key features of a phase I trial

-Healthy volunteers (except in oncology, where patients are used)
-Small sample size (20-100 participants)
-Several weeks to months
-Endpoints: Safety, maximum tolerated dose, dose limiting toxicities, pharmacokinetics and pharmcodynamics

Describe the TGN1412 phase I trial

-In a 2006 Phase I trial, six healthy volunteers suffered life-threatening cytokine storms and organ failure after receiving the CD28 superagonist TGN1412, despite prior animal safety testing.
-The disaster exposed flaws in predicting human immune responses and led to stricter first-in-human trial regulations, including staggered dosing.

Describe a Single Ascending Dose (SAD) Phase I trial design

-Participants receive a single dose of the drug
1 - Small group (3-6 participants) gets a low dose.
2 - If tolerated, a new group receives a higher dose.
3 - This continues until side effects become unacceptable (Dose Limiting Toxicity, DLT).

Describe concerns surrounding dosing in very young patients

-Differences in ADME pharmacokinetics in infants -Immature organ function makes neonates more susceptible to drug toxicity, even at therapeutic doses -Elimination organs (kidneys and liver) are still developing -Most drugs require weight or age based dose adjustments

Describe requirements/guidelines for PK studies in neonates

-PK studies in infants require regulatory approval (FDA PSP, EMA PIP, ICH E11). -Ethical considerations (minimal risk, informed consent, blood volume restrictions) are critical. -Population PK & sparse sampling techniques minimize invasiveness. -Dosing must consider organ immaturity, altered drug metabolism, and clearance. -Use of modeling and non-invasive sampling (PBPK, saliva, micro-sampling) is encouraged.

Describe how obesity may affect pharmacokinetics?

-Altered absorption (reduced gastric emptying, reduced gut motility, increased splanchnic blood flow) -Altered distribution (increased fat/Vd, altered protein binding, increased cardiac output) -Altered metabolism (altered enzyme activity, fatty liver disease can impair liver function) -Altered excretion (decreased GFR and kidney function)

How may differences in pharmacokinetics in the obese be addressed?

-Standard dosing based on ideal body weight (IBW) may not be sufficient. Adjusted body weight (ABW) or actual body weight (ABW) may be more appropriate, especially for drugs with high lipophilicity or narrow therapeutic windows -For drugs with a narrow therapeutic index, Therapeutic Drug Monitering can help ensure proper dosing, especially if the drug’s clearance is altered due to obesity.

Describe hepatic function tests for pharmacokinetics

-Used to assess the liver’s ability to metabolize and clear drugs -Tested by measuring levels of liver enzymes (eg alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase) -Tested by measuring levels of bilirubin, with higher levels indicating reduced function

Give differences in levels of compounds that indicate reduced hepatic function

+Liver enzymes (ALT, AST, ALP, GGT) +Bilirubin +Ammonia -Albumin

Which drugs require therapeutic dose monitoring?

-Narrow therapeutic index -High variability in pharmacokinetics -Serious toxicity risks -Long half lives -Ability to correlated measured drug concentration with efficacy/toxicity -Availability of reliably and clinically feasible assays

Give clinical applications of therapeutic dose monitoring

-Cardiovascular disease (antiarrythmics, e.g. digoxin) -HIV/AIDS (protease inhibitors, e.g. nevirapine) -Epilepsy (anticonvulsants, e.g. phenytoin) -Infection / septicemia (aminoglycosides, e.g. gentamicin) -Respiratory disease/asthma (bronchodilators, e.g. theophylline)

Describe how therapeutic dose monitoring is used in carboplatin treatment

-TDM typically aims to maintain a target AUC, which correlates with clinical effectiveness while minimizing toxicity -The typical target AUC for carboplatin varies depending on the type of cancer being treated and individual patient factors. For example, an AUC of 4–7 mg·min/mL is often targeted for ovarian cancer treatment -If carboplatin levels exceed the target AUC range, dose reductions may be necessary to avoid toxicity