What is PK (Pharmacokinetics) when dosing?

What is PK (Pharmacokinetics) When Dosing?

PK (pharmacokinetics) is the study of what the body does to a drug over time—specifically how the drug is absorbed, distributed, metabolized, and excreted (ADME)—and understanding these processes is essential for determining the right dose to achieve therapeutic drug concentrations at the target site while avoiding toxicity. 1

Core PK Principles for Dosing Decisions

Pharmacokinetics describes the time course and relationship between the administered dose and resulting drug concentrations in plasma and tissues. 1, 2 This relationship is critical because:

• Free (unbound) drug concentration at the site of action drives pharmacological effects, making PK assessment fundamental to predicting therapeutic response 3, 4
• PK parameters directly determine dosing regimens including dose amount, frequency, and route of administration 1, 5
• Pathophysiological changes alter PK, necessitating dose adjustments in specific patient populations 2

Key PK Parameters That Guide Dosing

Clearance

• Clearance determines the maintenance dose needed to achieve steady-state concentrations 1
• Systemic clearance includes hepatic, renal, and biliary elimination pathways that must be characterized for each drug 1
• For small molecules, clearance predictions evolved from allometric scaling to in vitro extrapolation methods for improved accuracy 3

Volume of Distribution

• Volume of distribution determines the loading dose required to rapidly achieve therapeutic concentrations 1
• Modern predictions use the Oie-Tozer method based on tissue composition and plasma protein binding 3

Half-Life and Steady-State Metrics

• For drugs with short half-life, the choice between Cmax, Cmin, or Cav as the PK metric for efficacy significantly impacts dose predictions 3
• As half-life increases, differences between Cmax and Cmin diminish, making the choice of PK metric less critical 3
• Drug type (agonist vs antagonist), target turnover, and reversibility of binding influence which PK metric drives efficacy 3

Integration of PK with Pharmacodynamics (PD)

PK must be integrated with PD (what the drug does to the body) through PK/PD modeling to predict biologically effective doses in humans. 3

• PK/PD models establish dose-exposure-response relationships by linking drug concentrations to biomarker modulation and efficacy 3
• Translational PK/PD requires validated disease models, appropriate biomarkers, and understanding of target modulation needed for efficacy 3
• Success in predicting active human doses is highest (83%) when both appropriate exposure-response relationships in animal models AND translatable biomarkers are available 3

Population Variability and Individualization

Population PK (POPPK) modeling accounts for between-subject variability and identifies patient covariates that affect drug exposure. 2

• POPPK can use sparse sampling data to provide accurate estimates of variability and support individualized dosing 2
• Genetic variations in CYP2C9 and VKORC1 enzymes significantly affect PK, requiring lower initial doses for certain patients 6
• Age, renal function, hepatic function, and disease state alter PK parameters and must be considered in dose selection 6, 2

Drugs with Narrow Therapeutic Index

For narrow therapeutic index (NTI) drugs, precise PK-guided dosing is critical because small changes in exposure can result in toxicity or loss of efficacy. 7

• NTI drugs require therapeutic drug monitoring (TDM) when they exhibit significant inter-individual PK variability, well-defined exposure-response relationships, and are used long-term 7
• Model-informed precision dosing (MIPD) combines patient characteristics with population PK models to maximize achievement of PK and PD targets 7
• Target concentration intervention (TCI) provides more accurate dose predictions than traditional therapeutic windows by accounting for between-subject variability 7

Practical Application: Warfarin Example

Warfarin dosing exemplifies PK-guided therapy for an NTI drug, requiring:

• Initial doses of 2-5 mg daily with adjustments based on PT/INR monitoring (the PD endpoint) 6
• Lower doses for elderly patients, those with genetic variations, and patients with hepatic dysfunction due to altered PK 6
• Daily PT/INR determination until stable, then intervals of 1-4 weeks to maintain therapeutic range 6
• Recognition that Asian patients may require lower doses (mean 3.3 mg daily) due to PK differences 6

Common Pitfalls in PK-Guided Dosing

• PK models are rarely externally validated, and studies performing validation frequently report clinically significant biases 3
• Measurement discrepancies between assay methods (e.g., one-stage vs chromogenic) can affect PK assessments 3
• Ignoring below-limit-of-quantification (BLQ) data may bias individual PK estimates and should be reported rather than discarded 3, 4
• Drug-drug interactions, botanical medicines, and dietary factors alter PK and require more frequent monitoring when initiated or discontinued 6