Pharmacokinetics (PK)

1. What is PK?

Pharmacokinetics (PK) investigates how drugs interact with the human body throughout their exposure period following administration. The main goal involves mapping out how a drug travels through the body and the mechanisms for its removal. This process mainly involves four steps: In pharmacokinetics four key phases work together which include absorption, distribution, metabolism, and excretion and professionals use the acronym ADME to describe them.

• Absorption refers to the process where a drug transitions from its application point directly into the bloodstream. The assessment of bioavailability determines the extent of a drug's presence in the bloodstream and its target site which depends on the selected administration route. Routes include oral, intravenous, intramuscular, inhalation, etc. Intravenous delivery ensures complete bioavailability by introducing drugs straight into the bloodstream but oral administration shows diminished bioavailability because of gut metabolism and first-pass effects.
• The distribution phase begins once the drug enters the bloodstream and circulates to various body parts. Drug distribution relies on several determinants which include blood flow rates along with lipophilicity characteristics and molecular dimensions together with plasma protein binding plus physiological barriers like the blood-brain barrier. Small molecules that are lipophilic cross the blood-brain barrier easily while drugs that bind strongly to plasma proteins like warfarin maintain lower free drug levels which alters their therapeutic action. The necessity of PK testing becomes evident when studying large molecules.
• The liver functions as the primary organ where drugs are metabolized by the cytochrome P450 (CYP450) enzyme system. During metabolism drugs are transformed into inactive metabolites but prodrugs like codeine become active compounds which helps their excretion.

Multiple factors influence drug metabolism including age where seniors have a slower processing rate increasing toxicity risk and infants need dose adjustments due to immature liver functionality together with drug interactions that modify enzyme activity and genetic variations like CYP2D6 gene variants that impact drug effectiveness and safety.

• Excretion describes the elimination of drugs and their metabolites from the body through renal pathways (urine), hepatic pathways (bile), and alternative systems such as pulmonary exhalation, skin secretions, or milk production. Altered kidney performance such as renal insufficiency impacts drug clearance which necessitates dosage modifications. When drug excretion becomes impaired it causes drug buildup that may result in toxic effects.

Figure 1. Multiple Clearance Pathways Affecting the Pharmacokinetics of a mAb (Source: Ryman JT, Meibohm B. et al. 2017)

Apart from the ADME definition, several key parameters in PK research should be understood:

Cmax (maximum plasma concentration): The highest concentration of the drug in the blood.

Tmax (time to peak concentration): The time it takes to reach the maximum plasma concentration.

AUC (area under the curve): The total exposure to the drug in the body.

t½ (half-life): The time required for the drug concentration to decrease by half.

CL (clearance): The body's ability to eliminate the drug.

Vd (volume of distribution): A measure of how the drug is distributed in the body's tissues.

Figure 2. Relationship Between Charge/pI and Half-life and Clearance in PK of mAbs (Source: Igawa T, et al. 2018)