Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative

Karen Sinclair1, Els Kinable1, Kai Grosch1

  • 1Novartis Pharma AG Basel, Basel, Switzerland.

Related Concept Videos

Pharmacokinetic–Pharmacodynamic Relationship: Problems01:24

Pharmacokinetic–Pharmacodynamic Relationship: Problems

The empirical approach to drug therapy optimization relies on correlating pharmacological response with administered dosage. Such an approach can be costly, time-consuming, and often yields poor correlation due to variables like formulation factors and drug elimination characteristics. A more precise approach correlates response with plasma drug concentration or the amount of drug in the body, rather than dosage. This is achieved through pharmacokinetic-pharmacodynamic (PK/PD) modeling, which...
73
Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions01:15

Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions

PK–PD modeling has significantly influenced FDA regulatory decisions, particularly drug approval, dosage optimization, and labeling. These models integrate pharmacokinetics (PK) and pharmacodynamics (PD) to predict drug behavior and effects, aiding in optimizing dosing regimens and enhancing the probability of clinical trial success.One notable example is Nesiritide (Natrecor®), a recombinant human brain natriuretic peptide for treating acute decompensated congestive heart failure...
63
Pharmacokinetic–Pharmacodynamic Relationship: Model Components01:14

Pharmacokinetic–Pharmacodynamic Relationship: Model Components

Pharmacokinetic-pharmacodynamic (PK–PD) modeling is essential in drug development and clinical pharmacology. It provides a quantitative framework to predict drug behavior and response over time. This approach integrates pharmacokinetics (PK), which describes the drug's absorption, distribution, metabolism, and excretion, with pharmacodynamics (PD), which characterizes the drug’s biological effects and mechanisms of action.The disposition kinetics of a drug determine its plasma...
109
Pharmacokinetic–Pharmacodynamic Relationship: Exposure, Response and Effect01:26

Pharmacokinetic–Pharmacodynamic Relationship: Exposure, Response and Effect

The pharmacokinetic-pharmacodynamic (PK-PD) relationship describes the intricate link between drug exposure, efficacy, and toxicity, forming the foundation for optimal dosing regimens. This relationship uses mathematical modeling to characterize drug concentration-effect dynamics, ensuring precise therapeutic outcomes.Exposure represents the pharmacokinetic aspect of the PK-PD relationship, denoting the drug amount that elicits a biological response. It is typically quantified by administered...
180
Pharmacodynamic Models: Linear Concentration–Effect Model01:15

Pharmacodynamic Models: Linear Concentration–Effect Model

The linear concentration–effect model, underpinned by the principle that pharmacological effect (E) is directly proportional to plasma drug concentration (C), emerges as a pivotal simplification of the Emax model for conditions where C is significantly less than EC50. This model portrays a linear trajectory of the concentration–effect relationship when drug levels are markedly below the EC50 threshold.Despite its inherent assumption of continuous effect augmentation with increasing...
56
Pharmacokinetic–Pharmacodynamic Relationship: Duration of Dose-Effect Relationship01:14

Pharmacokinetic–Pharmacodynamic Relationship: Duration of Dose-Effect Relationship

For drugs producing a quantal response, onset occurs when plasma concentration reaches a minimum effective level (Cmin). The drug's action duration depends on how long the plasma concentration remains above Cmin.Two primary factors influence this duration: dose size and the rate of drug removal from the action site. Both depend on the drug's redistribution to poorly perfused tissues and elimination processes. A larger dose promotes rapid onset and prolongs the effect's duration.Consider a...
84