Pharmacokinetics ▶️ Flashcards
Define absorption
Movement of unchanged drug from the site of administration into the bloodstream or lymph,, usually across a membrane. Passage into the site of measurement.
Loss of drug in process decreases systemic availability.
Describe the absorption of oral drug administration (extravascular)
•Disintegration of dosage form e.g. tablet
• Dissolution - drug in solution
• Permeability - movement across the wall
of GIT
• Gastric and intestinal transit (movement eg gastric emptying)
•First-pass metabolism - gut and liver
Each one of these can cause a delay or loss or drug
What is F?
Fraction of administered dose that reaches systemic circulation
Absolute availability- uses IV for reference when doing extravascular calc.
Frel : relative bioavailability as IV reference not used ( another extravascular route)
What is Ka?
Rate of drug transfer from absorption site to system circulation (plasma)
Describe the plasma concentration- time profile following extravascular dose: oral where it is elimination limited.
It is elimination limited (where elimination is the decline) because absorption is faster and absorption is shown first on the profile
(If elimination is quicker and absorption is much slower, the initial path would be elimination instead and switched to absorption declining after the peak)
Plasma concentration-time profile starts from 0. (drug has to move from absorption site into systemic circulation unlike IV bolus), increases until it reaches a peak and begins to decline.
During the initial phase where drug conc is increasing, rate of absorption is greater than rate of elimination (both are still happening).
When it reaches the peak, a balance occurs . Rate of absorption and elimination are equal.
Beyond this point, plasma conc starts decreasing as rate of elimination is greater than the rate of absorption as absorption eventually completes.
Sometimes delay in drug appearance in plasma - lag time (tlag)
(drug has to disintegrate to release drug before it appears in systemic circulation)
What is k?
Elimination rate constant
Slope of the elimination phase
Rate that it is eliminated from plasma conc
Assuming first order, what is the question for rate of absorption?
Ka x Aa (amount of drug in absorption site)
For the absorption compartment, this equation would give the rate of drug loss
For the central compartment (where the drug is moving into), this would give the rate of drug gain
Drug Aa >>>>>>>>>>>> Cp (plasma compartment) >>>>>>
Ka K
Assuming first order, what is the rate of elimination?
K x Ab (which = Cl x C)
Ab (amount of drug in the compartment after the central compartment, as it goes into elimination)
Ab = Cp x V
V = volume of distribution
Cp = plasma concentration
Balance of two processes following oral plasma concentration profile (extravasular)
Rate of change of drug in body = dA/dt
= Rate of absorption -rate of elimination
What does the absorption phase on a plasma concentration profile for an extravascular dose represent?
First phase (usually) before it reaches peak
Represents the absorption, distribution and elimination of the drug (absorption is dominating)
Once absorption is complete, oral and IV profiles are parallel (elimination phase)
Describe 2 ways to obtain plasma data & PK parameters from an oral dose
1) Non-compartmental analysis (NCA)
Obtaining the AUC, Cmax (max conc,peak) , Tmax (time taken to reach Cmax), K, Ka, Cl, V
2) Compartmental analysis (model-based approach)
Important equations for NCA for oral dose
(t1/2= ln (2) / K)
To find AUC, integration of the exponential curve (profile) > use trapezoidal rule to approximate and extrapolate end of graph
Amount eliminated = Cl x AUC
Amount absorbed = amount eliminated
F x D = Cl x AUC
Cl = F x D / (AUC) (for IV f =1)
V = Cl / K
NCA method
During the absorption phase, as elimination is also occurring it’s hard to get data on just Ka as K is occurring. How can we get this?
Method of residuals
Separating the elimination phase (only contains K)
Permeability rate limited absorption
Rapid dissolution (not the problem)
Low permeability (problem)
Release/dissolution rate limited absorption
Slow dissolution /disintegration
High permeability
F x dose =
CL x AUC
Changing F causes…(extravascular dose)
AUC and Cmax increase/decrease proportionately
Tmax is unchanged
If F increases then so does AUC and Cmax (graph gets higher)
If Ka decreases (rate of absorption) , and K (rate of elimination) stays the same…(extravascular dose)
Cmax decreases
Tmax increases
AUC stays the same
(Changing K however will also effect Cmax and Tmax)
Compartmental method
Assumes one compartment model for disposition
Doesn’t include absorption compartment
(Rate of change of drug in absorption site)
dAa/dt = -Ka x Aa (loss) becomes
dCp/dt = Ka x Aa (rate of drug gain) / V - K x cp (rate of drug loss from cp)
Differential equation solved for cp (given in exam)
Ka, V, and K can be obtained by regression
Cl and t1/2 can be derived
Following oral administration of 100 mg of one of the drugs that HA is taking resulted in the plasma concentration-time profile as shown below and estimated AUC of 30 mg/L h. Fitting of plasma data resulted in the following parameter estimates:
Estimate Stde
ka (h-1) 1.78 0.41
kel (h-1) 0.17 0.04
tlag (h) 0.39 0.05
where tlag is the time before absorption starts to occur? What is the likely cause of the time lag? What are the absorption and elimination half-lives of this drug?
Absorption half-life calculation
t 1/2, absorption
= ln (2) ÷ ka
= 0.693 ÷ 1.78 hr -1
= 0. 38932584 ≃ 0.39 hr
Elimination half-life calculation
t 1/2, elimination
= ln (2) ÷ kel
= 0.693 ÷ 0.17 hr -1
= 4.076471 ≃ 4.08 hr
Possible reasons for time lag could be:
Patient-related factors, such as fasting or fed state as well as interindividual variations in GI physiology, such as GI disorders, conditions or gastric bypass surgeries which all can potentially impact the lag time
Could be due to slow dissolution or disintegration of the drug
Delayed gastric emptying which leads to a lag time before absorption begins
Individual variability in GI transit times can influence the onset of drug absorption leading to a lag time
Following an intravenous dose of 50 mg of the same drug, the plasma concentration-time profile was characterised, and the AUC of 22.3 mg/L h was calculated.
Using the combined data following oral and intravenous administration calculate:
(i) The oral bioavailability of this drug
(ii) The clearance of the drug
(iii) The volume of distribution of the drug
In photo
1) LG had a baseline pain score 9, measured using the Lickert Pain score. The relationship between pain score and concentration of a drug that she was taking was best described by the following model:
Where E is the measured pain score, E0 is the baseline pain score, C is drug concentration in µg/L, and Emax is the maximum reduction in pain score (from baseline), which was 8. The C50 was 0.1µg/L.
Using the information provided, determine the plasma concentration that would produce a 30% reduction in pain score from baseline for LG.
E = E0 - Emax x C/( C + C50)
0.3 x 9 = 2.7
9 - 2.7 = 6.3 (E)
6.3 = 9 - (8 x C / C + 0.1)
9 - 6.3 =( 8 x C )/ (C + 0.1)
2.7 = 8C /( C + 0.1)
2.7 x (C + 0.1) = 8C
2.7C + 0.27 = 8C
0.27 = 8C - 2.7C
0.27 = 5.3C
C = 0.27 / 5.3
= 0.051mcg/L
(2) In the original study from which the pharmacokinetic and pharmacodynamic parameters were taken, it was noticed that there was a slight time delay between the maximum plasma concentration of the drug and the maximum reduction in pain score. What would explain such a time delay?
Time is required for: the drug to move from the bloodstream to target tissues / conversion into active metabolites / to bind to receptors
The therapeutic effect of a drug may not align with its peak plasma concentration due to factors like receptor interaction and downstream signaling delays.
Drug distribution to target receptors is influenced by tissue perfusion, lipophilicity, and active transport mechanisms, causing a time lag.
Receptor binding and signaling kinetics can delay the onset of the physiological response.
Indirect effects, such as modulation of secondary messengers or neurotransmitters, may introduce additional delays.
Adaptive body responses, including receptor desensitization, feedback mechanisms, and counter-regulatory effects, can affect the timing of drug action.
Individual differences in genetics, metabolism, and health contribute to variability in drug response timing.
Prodrugs require time for metabolic activation, leading to delays between plasma concentration peaks and therapeutic effects.
