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For drugs that follow the first‐order kinetics, the pharmacokinetic parameters such as the plasma concentration at the steady state (C_ss) and the area under the curve (AUC) of a plasma concentration–time profile is linearly related to the administered dose. An increase in the dose, therefore, can result in a linear increase in the C_ss or the AUC (Figure 2.14). This linear relationship helps in simple dosage adjustment to achieve desired blood concentrations in the body.

Often for some drugs, one of the pharmacokinetic processes, i.e., t_½, k, V, Cl_, is not governed by the simple first‐order kinetics, instead it follows non‐linear pharmacokinetics. This is when one of the absorption, distribution, metabolism or excretion processes in the body are saturable on increasing the dose. Most drugs still follow first‐order pharmacokinetics in practice as the saturation in ADME processes is attained beyond clinical dose ranges. However, this can be a problem for some drugs where saturation is observed at a clinically relevant dose, for instance, phenytoin (Figure 2.15). This non‐linear behaviour in phenytoin pharmacokinetics is explained by the saturable hepatic metabolism of the drug. The pharmacokinetics of such drugs can be explained by the Michaelis–Menten model which can be used to calculate dosages required to achieve a desired steady state for a patient.

The saturable processes in drug distribution, for instance, plasma protein binding, can also lead to non‐linear pharmacokinetics for certain drugs. For instance, the volume of distribution of disopyramide increases with the dose due to increased free fraction of the drug once plasma protein binding sites are saturated at higher dosages. For drugs that are actively secreted into the renal tubule by active transport, for instance, dicloxacillin, the renal clearance decreases when transport proteins at the renal tubules are saturated on increasing the dose. The decreased clearance leads to disproportional increase in circulatory concentration of the drug when the dose is increased.

Figure 2.14 The linear relationship of the administered dose with the area‐under‐the‐curve (AUC) and plasma concentration of a drug. Increase in the dose proportionally increases the steady‐state concentration and the AUC.

Figure 2.15 Illustration showing non‐linear increase in steady state concentration of phenytoin on increasing the dose.

Dose‐dependent saturation in drug absorption can also be responsible for the non‐linear pharmacokinetics for some drugs. For example, amoxicillin relies on transporters in the gut for its absorption (influx or active transport) that can be saturated on increasing the dose. Therefore, drug absorption does not increase proportionally on increasing the dose from a point when absorption transporters are saturated. The drugs exhibiting saturable pharmacokinetics are often prone to more drug–drug or drug–food interactions when co‐administered drug or food competes for the similar molecular pathway involved in its absorption, distribution, metabolism or elimination. Some excipients and formulation strategies can manipulate this interaction and can affect drug’s binding to the transport proteins or enzymes at the gut, liver or kidney and therefore can manipulate drug’s pharmacokinetics. The underpinning biopharmaceutical principles are therefore key considerations in the dosage form design.