Pharmacology: Multiple-Dosage Regimens

Multiple-Dosage Regimens

• Multiple-dosage regimens are used to maintain prolonged therapeutic activity.
• After a single dose, plasma drug levels rise and then fall below the minimum effective concentration (MEC), leading to a reduced therapeutic effect.
• In calculating a multi-dose regimen, the target plasma drug concentration must be correlated with a therapeutic response.
• The regimen must aim to produce plasma concentrations within the therapeutic window, avoiding excessive fluctuations and accumulation outside the window.

Parameters of Multidose Regimen

• The size of the drug dose and the frequency (time interval) of administration can be adjusted.
• The frequency of administration of a drug in a particular dose is called the dosage regimen.
• The plasma levels of drugs given in divided doses must be maintained within the therapeutic window.
• The regimen aims to provide the correct plasma level, without excessive fluctuations, keeping drug accumulation outside the therapeutic window.

Drug Accumulation

• When a drug is administered at regular intervals, the rise and fall of drug concentration in blood depend on the relationship between the elimination half-life and the time interval between doses.
• If the drug amount administered in each dose has been eliminated before the next dose is applied, similar plasma levels will result during repeated intake at constant intervals.
• If intake occurs before the preceding dose has not been eliminated completely, the drug accumulates.
• The shorter the dosing interval relative to the elimination half-life, the more extensive the accumulation in the body.
• At a given dosing frequency, accumulation does not continue infinitely but reaches a steady state (Css) where drug intake and elimination are equal.
• The activity of elimination processes is concentration-dependent, so higher concentrations lead to more rapid elimination.

Time to Reach Steady State

• The time required to reach steady state is dependent on the elimination half-life of the drug and the dosing interval, but independent of the dose size or the number of doses.
• The method for calculating the time to reach a certain percentage of steady-state (for example, 90% or 99%) is described in texts.

Repetitive Intravenous Injections

• The maximum amount of drug in the body following a rapid IV injection is equal to the dose.
• Drug elimination follows first-order kinetics in a one-compartment open model.
• The amount of drug remaining in the body after several hours can be determined with a simple equation relating dosage interval, elimination constant, and initial dose.
• A consistent fraction of the dose remains in the body after the dosage interval, leading to an increasing amount of drug which is not fully cleared until a steady state.
• To reach steady state is depends on the drug's elimination half-life and the dose interval but does not depends on the number of doses.

Multiple Oral Dose Administration

• Calculating plasma concentration after repetitive oral doses is more complex.
• The plasma concentration-time curve after repeated doses has fluctuations. It depends upon the elimination half-life and absorption rate constant and can vary by several factors which are noted.
• The equation for calculating the average plasma concentration at steady state involves the area under the plasma concentration-time curve (AUC) during the dosing interval and the dosing interval length .
• For oral administration, absorption and elimination need to be considered. Steady state (Css) is where elimination rate and intake rate of drug are equal and the maximum total drug amount in body is reached.

Loading and Maintenance Doses

• Loading doses are used to rapidly achieve therapeutically active plasma concentrations.
• Maintenance doses are given to sustain those concentrations.
• Loading doses depend on the volume of distribution and the fraction of the dose absorbed and can differ in one compartment models and multiple compartment models.
• Steady-state concentration will be reached after several loading and maintenance doses.

Distinguishing Between Normal and Flip-Flop Kinetics

• IV bolus data is necessary.
• The slopes of the terminal lines are a key indicator.

Superposition Principle

• It holds when all pharmacokinetic processes are linear or of first order (distribution, metabolism, and excretion).
• It allows calculating concentrations after several doses by summing the concentrations from each dose.
• Simple formulas show that doubling the dose doubles the concentration at each dosage interval.

Non-Uniform Dosing Intervals

• If dosing intervals are not uniform, calculations will differ.
• The model can be adapted to account for irregular dosing practices to establish drug concentrations in the body at different dosing times.

Example and Solutions

• Methods for calculating drug concentrations and accumulation are demonstrated through example problems, such as determining concentration at various dosing times and during steady states.

Homework

• Homework questions related to drug accumulation and relevant pharmacokinetic concepts are listed.

References

• Authors and titles of texts used are cited.