Introduction and Dose Decisions

Pharmacokinetics describes the movement of a drug into, through, and out of the body — encompassing absorption, bioavailability, distribution, metabolism, and excretion (ADME). Understanding these properties is essential for determining dosage, frequency of dosing, route of administration, and the onset and duration of drug action.

Bioavailability (F) is the fraction of an administered drug dose that reaches the systemic circulation in its active form. For intravenous drugs, F equals 1 (100%). For oral drugs, bioavailability is calculated from the area under the plasma concentration-time curve (AUC), which reflects total drug exposure. AUC depends on the dose administered and the rate of drug elimination.

Physicochemical properties influencing oral bioavailability include molecular weight and size, hydrophilic versus lipophilic character, and ionisation status. A substance becomes more lipid-soluble in a solution with a pH close to its pKa: a weak acid is more lipid-soluble in an acidic environment; a weak base is more lipid-soluble in an alkaline one. Ionised drugs cross membranes poorly and are therefore poorly absorbed.

Volume of distribution (Vd) is a theoretical parameter expressing how widely a drug distributes throughout the body. It is calculated as Vd = Amount of drug administered (Ab) / Plasma concentration at time zero (Cp0). A high Vd indicates extensive tissue distribution; a low Vd means the drug is largely confined to plasma. Lipophilic drugs readily cross membranes, entering more compartments and yielding larger Vd values. A 70 kg adult has approximately 42 litres of total body water (60% of body weight). Factors influencing distribution include membrane permeability, organ perfusion, pH relative to drug pKa, lipid solubility, and plasma protein binding.

Clearance (CL) is the volume of plasma cleared of active drug per unit time. Half-life (t½) is determined by linearising the plasma concentration-time curve; it governs dosing intervals and duration of action. Drug elimination rate after a single dose is primarily determined by plasma drug concentration (Cp): higher Cp drives faster elimination.

Loading doses are used to rapidly achieve therapeutic steady-state concentrations: LD = Vd × target Cp. Repeated intermittent dosing requires balancing plasma levels between the minimum effective concentration and the minimum toxic concentration. Dose or dosing-interval adjustments optimise this balance.