Multicompartment Models (Delayed Distribution Models)
Why Do We Need Multicompartment Models?
The one-compartment model assumes that the drug distributes instantly and uniformly in the
body. However, in reality, this is not true for most drugs.
Many drugs show delayed distribution because the body has different tissues with varying
blood flow and drug affinity.
So, instead of a single compartment, we divide the body into multiple compartments for better
accuracy.
Basic Assumptions of Multicompartment Models:
1. What is the Central Compartment?
It includes blood/plasma and well-perfused (high blood flow) organs like brain, heart,
lungs, liver, and kidneys.
When a drug is injected intravenously (IV), it first enters this compartment.
2. What is the Peripheral Compartment?
This includes other tissues that receive drug slowly due to lower blood flow.
Instead of considering each tissue separately, they are pooled together as a single
peripheral compartment.
3. How Does the Drug Move Between Compartments?
When given IV, the drug first enters the central compartment.
It then distributes reversibly to the peripheral compartment before being eliminated.
4. How is the Drug Eliminated?
Drug elimination (by metabolism in the liver or excretion by kidneys) occurs only from the
central compartment.
The peripheral compartment does not eliminate the drug.
5. How Fast Does the Drug Move?
The movement of the drug between compartments and its elimination follows first-order
kinetics (i.e., the rate depends on the concentration of the drug).
The plasma concentration graph is described by multiple exponential terms, not just one.
Kinetics of Multiple Dosing
Multiple-Dosage Regimens
A regimen refers to a planned schedule or system for taking medication. In includes
The dose of the drug (how much to take).
The dosing interval (how often to take it).
The duration of treatment (how long to take it).
When a drug is given repeatedly at fixed time intervals, it is called a Multiple-Dosage
Regimen. The goal is to maintain a steady and effective drug concentration in the body
without causing toxicity or loss of effect.
For example: "Take 500 mg of Paracetamol every 8 hours for 5 days."
Need Multiple-Dosage Regimens
i. If the single-dose administration is not enough – The drug is eliminated from the
body over time.
ii. To maintain therapeutic effect – Regular dosing helps keep drug levels in the desired
range.
iii. To avoid toxic effects – Proper interval dosing prevents drug accumulation to harmful
levels.
Key Terms to Understand
1. Peak Plasma Concentration (Cmax): The highest concentration of the drug in the blood
after each dose.
2. Trough Plasma Concentration (C min): The lowest concentration of the drug just
before the next dose.
3. Steady-State Concentration (Css):
After multiple doses, the drug concentration fluctuates within a stable range.
Achieved when drug input = drug output (elimination).
Typically reached after 4-5 half-lives of the drug.
4. Dosing Interval (τ, Tau): The time gap between two successive doses.
5. Accumulation: With repeated doses, the drug does not fully eliminate before the next
dose, leading to buildup. It continues until a steady state is reached.
6. Fluctuation: Drug levels rise after a dose and fall before the next dose. It can be
controlled by choosing the right dosing frequency.
Factors Affecting Multiple-Dosage Regimens
1. Dosing Interval (τ):
Shorter intervals → Higher accumulation and lower fluctuation.
Longer intervals → More fluctuation but less accumulation.
2. Elimination Half-Life (t½):
Affects how quickly the drug is removed.
A longer half-life leads to slower elimination and higher accumulation.
3. Volume of Distribution (Vd):
Affects drug concentration in plasma.
Higher 𝑉𝑑 means more distribution into tissues.
This graph shows how the dose size affects drug concentration in the blood when taken at fixed
time intervals (τ).
Three Dose Profiles
1. Larger Dose Profile (Top Curve)
Drug concentration rises high and drops significantly before the next dose.
Fluctuations are large, leading to both therapeutic and toxic effects.
2. Optimum Dose Profile (Middle Curve)
Drug remains between MSC (Maximum Safe Concentration) and MEC (Minimum Effective
Concentration).
This ensures effectiveness without toxicity.
This is the ideal dosing regimen.
3. Smaller Dose Profile (Bottom Curve)
Drug concentration remains too low to have a therapeutic effect.
It does not reach MEC (Minimum Effective Concentration).
The drug is ineffective.
Conclusion:
Too high a dose → Toxicity risk
Too low a dose → No effect
Optimum dose → Safe and effective treatment
This graph shows how changing the dosing frequency (τ) affects drug concentration in
the blood over time.
Three Dosing Frequency Cases
1. High Dosing Frequency (τ < t₁/₂) – Top Curve
Drug is given very frequently.
Small fluctuations, but drug may accumulate → risk of toxicity.
Crosses MSC, causing both therapeutic and toxic effects.
2. Optimum Dosing Frequency (τ = t₁/₂) – Middle Curve
Drug is given at half-life intervals.
Maintains concentration between MSC and MEC.
Therapeutically effective and safe.
3. Low Dosing Frequency (τ > t₁/₂) – Bottom Curve
Drug is given after long gaps.
Large fluctuations, dropping below MEC → ineffective treatment.
Conclusion:
Too frequent dosing → Risk of toxicity.
Too infrequent dosing → Ineffective treatment.
Ideal dosing interval = Drug half-life (t₁/₂) for best therapeutic effect.
This graph illustrates how a drug accumulates in the body when given at regular dosing
intervals (τ = t₁/₂, i.e., equal to the drug's half-life). X₀: The initial dose of the drug.
Understanding the Curve
1. First Dose (At 0τ):
The drug is administered, and its amount starts decreasing due to elimination.
By the next dosing interval (1τ), half of the drug is eliminated.
2. Second Dose (At 1τ):
A new dose (X₀) is added while half of the previous dose remains.
Total drug in the body = X₀ + (1/2) X₀ = (1 + 1/2)X₀.
3. Third Dose (At 2τ):
Another dose is added, and elimination continues.
Total drug in the body = (1 + 1/2 + 1/4) X₀.
4. Fourth & Fifth Dose (At 3τ, 4τ, etc.):
Drug keeps accumulating but at a slower rate.
The formula follows a geometric series: Total drug=X0(1+1/2+1/4+1/8+1/16+...)
Eventually, the drug reaches steady-state, where the amount of drug entering equals
the amount eliminated per dosing interval.
Calculation of Loading & Maintenance Dose and their Significance in Clinical Settings
Loading Dose
A loading dose is a higher first dose of a drug given to quickly reach the desired drug level
in the blood (steady-state), especially if the drug takes a long time to reach steady-state on
its own.
This is helpful when waiting for 5 half-lives (which is the usual time to reach steady-state)
is too slow.
Loading Dose Formula
𝑪𝒔𝒔,𝒂𝒗 ⋅ 𝑽𝒅
𝑿𝟎,𝑳 =
𝑭
Where:
𝑋0,𝐿 = loading dose
𝐶𝑠𝑠,𝑎𝑣 = average steady-state concentration
𝑉𝑑 = volume of distribution
𝐹 = bioavailability (fraction of drug absorbed)
Another formula is used when the volume of distribution 𝑉𝑑 is not known:
𝑿𝟎,𝑳 𝟏
= −𝑲 𝝉
𝑿𝟎 (𝟏 − 𝒆 𝒂 )(𝟏 − 𝒆−𝑲𝑬 𝝉 )
Here:
𝑋0 = maintenance dose (regular dose)
𝐾𝑎 = absorption rate constant
𝐾𝐸 = elimination rate constant
𝜏 = dosing interval
This formula works when the drug is absorbed much faster than it is eliminated, i.e., 𝐾𝑎 >>
𝐾𝐸 .
Accumulation Index (For IV or Fast Absorption)
If the drug is given through IV or has very fast absorption, the absorption phase is ignored
and the formula is reduced to:
𝑿𝟎,𝑳 𝟏
= = 𝑹𝒂𝒄
𝑿𝟎 𝟏 − 𝒆−𝑲𝑬𝝉
This shows how much the drug accumulates in the body over repeated doses.
𝑋0,𝐿
Dose Ratio and Its Effects: The ratio is called the dose ratio.
𝑋0
If 𝜏 = 𝑡1/2 → dose ratio = 2
If 𝜏 > 𝑡1/2 → dose ratio < 2
If 𝜏 < 𝑡1/2 → dose ratio > 2
This figure shows what happens when the loading dose is:
Too high (Dose ratio > 2): Drug levels shoot up and can cross the maximum safe
concentration (MSC).
Just right (Dose ratio = 2): Drug levels are steady and within the safe therapeutic
range.
Too low (Dose ratio < 2): It takes a long time to reach therapeutic level; not effective
in emergencies.
Loading Dose – Clinical Significance
1. Helps to quickly reach the required drug level in the blood.
2. Useful in emergency situations where immediate action is needed.
3. Ensures fast therapeutic effect, especially for drugs with long half-lives.
4. Prevents delay in treatment by avoiding waiting time for steady-state.
5. Must be used carefully to avoid toxicity.
Maintenance Dose – Clinical Significance
1. Maintains the drug level in the body within the therapeutic range.
2. Ensures continuous effect of the drug during long-term treatment.
3. Helps in chronic diseases like diabetes, epilepsy, hypertension, etc.
4. Dosing can be adjusted based on patient's condition (e.g., kidney/liver issues).
5. Prevents drug accumulation and side effects.