Pharmacokinetics Exam 3

Cartesian Plot of Linear Superimposed Data for a constant multiple IV bolus dose regimen

At each dose there is some drug left from the previous doses and the drug concentration rises until a Css is reached

Equal dose and equal dosing interval Maxima and Minima on accumulation to the Plateau

Once the dose max has been reached, the drug amount will decrease based on an exponential decline, as we have seen for an IV bolus dose or for a post-infusion phase

Accumulation index Rac

Tells you how much drug accumulates relative to the first dose

Multiple dose - change the dose

Rate of administration is constant

The black dose is 2 x the red dose

But the black dose is given in a double interval of time relative to the red doses

• By giving a smaller dose more frequently there is a smaller fluctuation in the drug concentration

• But the downside is patient adherence issues

Multiple Dose: Change the dosing interval

The dose is exactly the same for both cases, but in A the dose has been given twice more often than in B

• If the dose interval is decreased, there will be more drug accumulation and the Css will be larger

Comparison between a constant multiple IV bolus dose and a constant multiple Oral regimen

We assume that F = 1 for the oral dose

The dose and the dosing interval is the same for both IV and Oral regimens

The average values at steady state are exactly the same for the IV and Oral regimens

• However the IV dosing has a much bigger fluctuation than the oral regimen

Turnover rate

If a drug has a slow turnover rate then steady state is not reached until much later.

EX: Cholesterol

• The endogenous pool needs to be reduced which is why it takes so long to get to steady state

Sawchuk-Zaske Method

C_max = C_prev + C_new

Aminoglycosides use

• Bactericidal antibiotics, treat serious gram-negative infections
• Agents: gentamicin, tobramycin, amikacin

• TDM: narrow therapeutic window

• PK characteristics

• Similar kel, CL, and Vd across all agents (gentamicin, tobramycin, amikacin)

• Half-life 2-3 hours

• Vd ~0.25 L/kg • Elimination: 94-98% through renal excretion

Why are aminoglycosides suitable for TDM?

Efficacy: concentration-dependent killing

• Concentration > minimum inhibitory concentration (MIC) needed to kill the bacteria

• Higher concentrations (>>MIC) result in better efficacy

Toxicity: nephrotoxicity, ototoxicity

• Trough >2 mg/L associated with nephrotoxicity

• Trough >4 mg/L for long term (~10 days) associated with ototoxicity

Conventional dosing of aminoglycosides

Usual dose:

• Gentamicin and tobramycin: 1-1.7 mg/kg Q8H infused over 0.5-1 hr

• Amikacin: 5 mg/kg Q8H infused over 0.5-1 hr

• If renal function is reduced, dosing interval Q12 (CrCL 46-60 mL/min) or Q24 (CrCL 20-40 mL/min)

Target concentration:

• Peak: urinary tract infection (4–5 mg/L); sepsis (6–10 mg/L); pneumonia (7–10 mg/L); meningitis (8–10 mg/L)

• Trough: <1 mg/L

When to collect blood sample:

• Steady state peak (0.5 hr after the end of infusion)

• Steady state trough (prior to the next dose, ~0.5 hr)

The Liver

Largest organ in the body

Main function: metabolize, detoxify and inactivate both endogenous substances (e.g. steroids and other hormones) and exogenous substances (e.g. drugs and toxins)

the liver also converts inactive substances to active substances (e.g. inactive prodrug → pharmacologically active species)

Following hepatic biotransformation The Liver:

(i) returns the metabolized substance to the circulation

(ii) excretes the substance into bile

What is the functional unit of the Liver?

Acinus

• Contains Hepatocytes

  • Contains Kupffer cells (separated from the blood by highly fenestrated capillaries)

Kupffer Cells

Macrophages → phagocytose old RBCs

• Some large protein removal

Sinusoidal Capillaries

Very leaky, high permeability vessels with large 100 – 150 nm fenestrations

Hepatocytes

Metabolize hormones, drugs and other chemicals

• Produce and secrete major plasma proteins

• Hepatocytes produce and secrete bile

Blood supply to the liver

dual blood supply to the liver is via the portal vein and the hepatic artery

• blood components are ‘processed’ by hepatocytes and then returned to a single venous drainage system

Acinus

Functional Unit of the liver

Zone 1:

• closest to portal triad

• first to receive drugs / nutrients

Zone 3:

• farthest from portal triad, closest to draining central vein

• highest CYP450 / hydrolytic enzyme content

Drug metabolism and excretion

Class 1 & 2 – mostly metabolized

Class 3 & 4 – mostly excreted

• Most marketed drugs are eliminated primarily by metabolism

• Class 1 & 2 – high permeability (typically relatively lipophilic) drugs predominantly metabolized

Hepatic Clearance is dependent on

1) Hepatocyte activity (intrinsic clearance)

(2) Perfusion

(3) Protein binding (fraction unbound, fu)

*can be better understood by dividing agents into high and low extraction drugs using the concepts of Extraction Ratio (E) and the use of a predictive model

Extraction in the liver

Unlike renal extraction there are many drugs that are highly extracted in the liver

Hepatocyte eliminating activity

Hepatic elimination only occurs because a drug is a substrate for an elimination process within the hepatocyte

• Elimination is therefore dependent on unbound concentration (CuH) within the hepatocyte.

• Rate of Elimination = CL C = CL_int * Cu_H

Intrinsic Clearance

measure of the intrinsic hepatocellular eliminating activity

Most important for Hepatocyte:

1. Induction of a drug metabolizing enzyme (increased expression caused by an inducing substance; typically, takes hours to days) will increase Cl_int

2. Inhibition of a drug metabolizing enzyme (typically faster than induction, min to hrs) will decrease CL_int

Hepatic Extraction Ratio

1. E_H is an indicator of CL_b,h
2. If E_H=1, all drug is removed during a single pass through the liver

3. F_H is the fraction escaping metabolism 4. E_H = 1 – F_H = fraction not escaping hepatic metabolism

Example: a drug with a large first pass effect may have F_H = 0.3 and E_H = 0.7

Extraction ratios for representative drugs

Notice that the rate of of drug elimination in the liver is directly related to the concentration of drug unbound in the incoming delivered plasma

• Thus, Cu can be replaced for Cu_H and one has: Rate of elimination = CL_int Cu (unbound concentration) and

• Hepatic clearance = CL_int * fu (fraction in plasma unbound)

Well Stirred Model of Hepatic Elimination

Key Points:

Model assumes instantaneous and complete mixing occurs within liver

Biliary excretion and enterohepatic cycling

Excretion of substances into the bile allows for the possibility of enterohepatic cycling

• Certain drugs administered

• Generally clearance by biliary excretion is low

When is High Biliary Excretion Possible

High biliary CL – Only really possible for:

• (i) Drugs undergoing significant concentration in bile (achieving very high bile-to-plasma concentration ratios, e.g. 1000:1), requiring active secretion (energy)

AND

• (ii) Drugs that are polar and > 350 Da in size (i.e. not reabsorbed well in GI tract)