Science of Medicines Week 25 Flashcards
define extravascular administration
administration by any route other than the intravenous route (not into the vascular system)
What are examples of extravascular administration methods?
oral, subcutaneous, intramuscular, inhalation
define oral dosage form
drug that are taken orally for a systemic effect in the body after absorption
What is a benefit about oral dosage forms?
there is potential to make different mechanisms for drug release like delayed, immediate, extended and controlled drug delivery
Why is oral the preferred route?
- GI tract is good for absorption
- no infection risks due to needles
What does a plasma concentration graph look like for extravascular administration?
- begin at zero concentration at time zero
- concentration of drug increases to a maximum
- exponential decline from peak
How are ADME processes different in extravascular administration compared to IV bolus and infusion?
there is ABSORPTION as well as distribution, metabolism, excretion
define absorption
the passage of the drug from the absorption site to the systemic site of measurement (blood)
By which 2 processes does absorption occur?
passive diffusion and active transport
Which law applies to the passive diffusion for absorption of drugs?
Fick’s 1st law - the rate of absorption is proportional to the concentration of the drug at the absorption site
Which type of kinetics does active absorption use?
Michaelis-Menten kinetics - the rate of absorption is proportional to the amount of drug at the absorption site as long as the transporters are not saturated
What type of process is absorption usually modelled as?
first order process
What is ka?
the rate constant for absorption
What is the equation for the rate of absorption?
dX/dt = ka x X
X = the amount of drug at the absorption site
What is the equation used to work out the amount of drug remaining at the absorption site?
lnX = lnX0 - ka x t
When is the rate of absorption highest for an extravascular administration?
just after administration assuming all the drug is dissolved at time 0
What type of process is elimination?
a first-order process
What is the equation for the variation of A (amount of drug) in the body with time?
dA/dt = (ka x X) - (k x A)
absorption rate - elimination rate
What is the equation for the concentration of drug in plasma at time ‘t’ for extravascular administration?
C = (B x e^-kt) - (B x e^-kat)
What is the equation for B (given in the exam)?
B = (ka x F x D) / V x (ka - k)
What happens to the rate of absorption and elimination at time 0?
all the drug is at the absorption site and none is in the body, so
rate of elimination = 0
the rate of absorption is maximum = X0 = dose
What is happening in the absorption phase?
- the elimination rate will be increasing, but the absorption rate is always more than the elimination rate - so we gain drug in the body
- the drug concentration increases in the plasma until a maximum concentration is reached at time tmax
- as more drug is absorbed, the rate of absorption decreases, and rate of elimination increases
What is the equation to describe what occurs at the peak (Cmax)?
ka x X = k x A
absorption rate = elimination rate
define Cmax
the maximum concentration of drug in plasma after extravascular dosing
define Tmax
the time at which Cmax is achieved
What must we know in order to work out Tmax?
k and ka
What is the equation for T max (given in exam)?
t max = ln (ka/k) / ka - k
What does the value of T max depend on?
ONLY ka and k - the elimination and absorption rate constants
Does T max depend on dose administered?
NO - T max is dose independent
How does ka influence T max?
the larger the ka, the faster the absorption rate, so the lower Tmax
How can we predict Cmax if we know Tmax?
just use the general equation for Cmax but substitute in Tmax for time:
Cmax = (B x e^-ktmax) - (B x e^-katmax)
What does Cmax depend on?
since B is used to work out Cmax, Cmax depends on:
- ka
- k
- dose
- bioavailability or fraction absorbed (F)
- volume of distribution (V)
What is happening in the terminal phase?
after Tmax:
- the amount of drug in the body and its elimination rate has increased
- all the drug has been absorbed
- the elimination rate is greater than the absorption
How do we estimate k from the terminal phase?
- absorption stops some time after Tmax, so therefore the equation simplifies to:
Cterminal = B x e^-kt - represent concentration against time data as lnC - the points should fall in a straight line
- from the slope of the terminal phase, work out k using two points on the line - essentially the same as IV bolus and post-infusion phase
- use lnC = lnB - kt
How do you work out B from the terminal phase?
- the equation used to get k is lnC = lnB - kt
- if you extrapolate to t=0, the y-intercept gives you lnB
- antilog to find B
How do you work out clearance (Cl) from extravascular data?
- use the equation:
AUC = (D x F) / Cl - if you know AUC, D and F, you can work out Cl
- use the trapezium rule (like in IV bolus)
What do you have to be cautious with when working out clearance from AUC?
- F may be unknown, and we can only get the combined value of Cl/F
- this is sometimes described as ‘oral clearance’
- oral clearance gives little information as F ranges from 0-1 - therefore, is potentially misleading if it is confused with Cl - pay attention to values!
How do we work out volume of distribution (V) from extravascular data?
- cannot get it directly from oral data using extrapolation like for IV bolus
- we need to know Cl and k as Cl = k x V
- or use the equation for B if you know ka, k, D and F
When comparing different drug formulations, what is important to look at?
- Tmax
- Cmax
- AUC
What does Tmax indicate about different formulations?
- Tmax is an indication of the rate if drug absorption from different formulations
- Tmax is shorter for faster absorption rates - so less time is needed to reach Cmax
What does Cmax indicate about different formulations?
- shows the maximum plasma concentration of drug that is reached
- we must use Cmax to consider if it is sufficient for a therapeutic effect or there is too much potential for toxicity
What does AUC indicate about different formulations?
- AUC reflects the total amount of drug reaching systemic circulation - aka the extent of absorption
- AUC may be better to use than Cmax for some drugs - some may just not be absorbed well
What is the effect of dose when comparing profiles?
- Tmax will be the same for all drugs
- however, for example if you administer 250mg and 500mg, at any point one drug will have a plasma concentration 2x the other
- if you increase the dose, you increase the concentration - directly proportional
- given by the equation for B which is put into the general equation
What is the effect of the absorption rate constant ka when comparing profiles?
- if a drug has a higher ka, it is absorbed quicker, so concentration rises quicker
- the Cmax will be higher and Tmax will be lower
If you change a dosage form, what is affected?
ONLY absorption rate
we cannot modify the elimination rate as this is done by the body, but we can modify the absorption rate by changing dosage forms
How does the rate of gastric emptying and enteric formulations affect plasma profiles for extravascular administration?
- if gastric emptying is delayed, the drug will sit in the stomach for longer, but the drug isn’t absorbed here
- the drugs will have the same Cmax, but there will be a lag in Tmax due to delay in entering the GI tract
- gastro-resistant polymers prevent drug release in the stomach, so there is a lag time again
What is the effect of solubility and route of administration on plasma profiles?
- micronised tablets may be used with a larger SA than a normal tablet
- due to Fick’s 1st, absorption is quicker for the micronised tablet
- drugs will have different Cmax as absorption varies
- AUC will be much smaller for the normal tablet as not all of it is dissolved
- hepatic first pass may also cause the fraction absorbed to decrease, for example, in sublingual vs oral administration
define bioavailability
the amount of drug reaching systemic circulation and the rate at which this occurs
define pharmaceutically equivalent
medicinal products that contain the same amount of the same API in the same dosage form and meet the same comparable standards
Does pharmaceutically equivalent mean bioequivalent?
NO as differences in the excipients and/or the manufacturing process can lead to a faster or slower dissolution and/or absorption - so different therapeutic effects
define pharmaceutical alternatives
medicinal products with different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives etc of an API, or which differ in dosage form or strength - NOT pharmaceutically equivalent if different dosage forms
define therapeutically equivalent
medicinal products that can be substituted with full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product - the are PHARMACEUTICAL EQUIVALENTS AND ARE BIOEQUIVALENT
define bioequivalent
two medicinal products containing the same API that are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailability (rate and extent) after administration in the same molar dose lie within acceptable limits
What is the US FDA definition for bioequivalent?
bioequivalence is the absence of a significant difference in the rate and extent to which the API in pharmaceutical equivalents or alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriate study
define generic product
a medicine developed to be the same as a ‘reference medicine’ (RM) already authorised
How are generics similar to RMs?
- same API
- same dose
- treats the same disease(s)
- same dosage form
How may generic differ to the RM?
- name of the medicine
- appearance
- packaging
- excipients
As information on the safety and efficacy of the API is already given from the RM, what do generic developers need to prove?
- information on the quality
- show that the generic medicine produces the same levels of API in the human body as the RM
When can generic drugs be released onto the market?
when the patent on the RM has expired
Which factors are needed for a successful generic drug?
- pharmaceutically equivalent to RM - same API, dose, dosage form, strength, route of admin
- bioequivalent and therapeutically equivalent
How do we establish bioequivalence for 2 drugs?
we need to compare the bioavailability - extent AND rate of absorption
How do we find the extent of absorption?
- through the relative bioavailability - ‘F relative’
- F relative ONLY reflects extent of absorption, NOT rate
What is the equation for F relatve?
Frelative = (AUC test / D test) / (AUC ref / D ref)
How is the RATE of absorption compared in bioequivalence testing?
- usually compared using Cmax and Tmax
- the faster the rate of absorption, the lower the Tmax and higher the Cmax
- if the absorption rate is too slow, the drug concentration may not be enough for a therapeutic effect
What is the criteria for bioequivalent regulatory comparison testing?
the acceptable bioequivalence is when the 90% confidence interval of the ratio of a log-transformed exposure measure (AUC and/or Cmax) falls entirely within the range 80-125%
What does the 80-125% range for a confidence interval correspond to?
a different in clinical exposure by equal to or more than 20%
Why do we need to use confidence intervals?
the bioavailability of a drug will be different among a group of people, so we cannot just compare the mean bioavailability for 2 different groups as there is going to be a large range
