Describe the concept of steady state and how it relates to continuous dosing.
Determine optimum dosing for an infused drug by calculating pharmacokinetic parameters from clinical data.
Calculate loading doses to be used with an intravenous infusion.
Describe the purpose of a loading dose.
Compare the pharmacokinetic outcomes and clinical implications for a drug that follows a one-compartment model to a drug that follows a two-compartment model with or without a loading dose.
Drugs may be administered to patients by oral, topical, parenteral, or other various routes of administration. Examples of parenteral routes of administration include intravenous, subcutaneous, intramuscular, and other routes that require the drug to be given by sterile injection. Intravenous (IV) drug solutions may be either injected as a bolus dose (all at once) or infused slowly through a vein into the plasma at a constant rate (zero-order). The main advantage of giving a drug by IV infusion is that it allows precise control of plasma drug concentrations to fit the individual needs of the patient. For drugs with a narrow therapeutic window (eg, heparin), IV infusion maintains an effective constant plasma drug concentration by eliminating wide fluctuations between the peak (maximum) and trough (minimum) plasma drug concentration. Moreover, the IV infusion of drugs, such as antibiotics, may be given with IV fluids that include electrolytes and nutrients. Furthermore, the duration of drug therapy may be maintained or terminated as needed using IV infusion.
The plasma drug concentration−time curve of a drug given by constant IV infusion is shown in Fig. 14-1. Because no drug was present in the body at time zero, drug level rises from zero drug concentration and gradually becomes constant when a plateau or steady-state drug concentration is reached. At steady state, the rate of drug leaving the body (elimination rate) is equal to the rate of drug entering the body (infusion rate). Therefore, at steady state, the rate of change in the plasma drug concentration dCp/dt = 0, and
Plasma level–time curve for constant IV infusion.
Based on this simple mass balance relationship, the following pharmacokinetic equation for infusion may be derived:
where R is the infusion rate and CL is the drug clearance. This equation is accurate and always valid regardless of the number of compartments characterizing the pharmacokinetic profile of the drug.
Should we want to define this equation using rate constants and volumes, its exact expression will then depend on the number of compartments that characterize the PK behavior of the drug under study. We will present examples for a drug whether it follows a one- or a two-compartment model.
ONE-COMPARTMENT MODEL DRUGS