Related Experiment Video
Updated: Feb 5, 2026
08:59
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
8.7K
Predicting the Onset of Nonlinear Pharmacokinetics
Andrew M Stein1, Lambertus A Peletier2
1Novartis Institute for BioMedical Research, Cambridge, MA, USA.
CPT: Pharmacometrics & Systems Pharmacology
|September 10, 2018
Summary
This study derives a simple formula for critical concentration (Ccrit) in pharmacokinetics. This helps determine drug doses for linear clearance, ensuring consistent therapeutic effects.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Quantitative Pharmacology
- Biopharmaceutics
Background:
- Drug concentration-time curves often exhibit a critical concentration (Ccrit) where clearance transitions from linear to nonlinear.
- Maintaining linear pharmacokinetics (PK) is crucial for achieving consistent drug exposure and target engagement during therapy.
Purpose of the Study:
- To derive a straightforward mathematical expression for Ccrit.
- To provide a tool for selecting appropriate drug doses to ensure linear PK behavior.
Main Methods:
- Mathematical derivation of Ccrit for PK models.
- Analysis of models with linear and nonlinear (saturable) clearance, including Michaelis-Menten and target-mediated drug disposition (TMDD).
Main Results:
- A simple expression for Ccrit was successfully derived.
- The derived expression is applicable to various PK models with saturable clearance mechanisms.
Conclusions:
- The derived Ccrit expression facilitates dose selection for maintaining linear PK.
- This aids in achieving predictable drug exposure and ensuring therapeutic efficacy throughout treatment.
Related Concept Videos
01:22Nonlinear Pharmacokinetics: Causes of Nonlinearity
737
Nonlinearity in drug pharmacokinetics is caused by various factors influencing how a drug is absorbed, distributed, metabolized, and excreted. Understanding these nonlinear processes is crucial for predicting drug behavior in the body and optimizing drug dosing regimens.
Nonlinear drug absorption can occur when the process is rate-limited by solubility, carrier-mediated transport systems, or saturation of the presystemic gut wall or hepatic metabolism. For instance, high doses of riboflavin...
Nonlinear drug absorption can occur when the process is rate-limited by solubility, carrier-mediated transport systems, or saturation of the presystemic gut wall or hepatic metabolism. For instance, high doses of riboflavin...
737
01:19Nonlinear Pharmacokinetics: Overview
1.1K
Nonlinear or dose-dependent pharmacokinetics is a phenomenon that occurs when the pharmacokinetic parameters of certain drugs deviate from linear pharmacokinetics at higher doses. These drugs do not follow the expected first-order kinetics, where the rate of drug elimination is directly proportional to the drug concentration. Instead, they exhibit a nonlinear relationship, which can be attributed to several factors.
Nonlinearity can arise due to the saturation of plasma protein-binding or...
Nonlinearity can arise due to the saturation of plasma protein-binding or...
1.1K
01:27Nonlinear Pharmacokinetics: Role of Transporters
295
A drug's nonlinear kinetics can be influenced by a diverse range of transporter proteins that serve as crucial players in drug distribution. These transporters, found within cells, can enhance or reduce local drug concentrations by facilitating the influx or efflux of drugs. For instance, the expression of xenobiotic transporters can be influenced by factors such as age and gender, potentially impacting the linearity of drug response.
Polymorphisms occurring in drug transporters can alter...
Polymorphisms occurring in drug transporters can alter...
295
01:18Nonlinear Pharmacokinetics: Michaelis-Menten Equation
1.1K
The Michaelis–Menten equation is a fundamental model for describing capacity-limited kinetics in drug metabolism. It offers insights into the rate of decline of plasma drug concentration Cp over time, with Vmax and KM as pivotal parameters.
Vmax represents the maximum achievable process rate, while KM, known as the Michaelis constant, signifies the drug concentration at which the process rate reaches half its maximum. This relationship between Vmax, KM, and Cp gives rise to three distinct...
Vmax represents the maximum achievable process rate, while KM, known as the Michaelis constant, signifies the drug concentration at which the process rate reaches half its maximum. This relationship between Vmax, KM, and Cp gives rise to three distinct...
1.1K
01:22Nonlinear Pharmacokinetics: Bioavailability and Protein-Drug Binding
628
When a drug follows nonlinear pharmacokinetics, its bioavailability, the amount of the drug that reaches the systemic circulation, can change with different doses. This is due to the presence of a saturable pathway. The pathway becomes saturated as the drug concentration increases, decreasing the absorption rate. Consequently, the drug's bioavailability may be lower than expected at higher doses.
To quantify the extent of bioavailability, pharmacologists often use a parameter called .
To quantify the extent of bioavailability, pharmacologists often use a parameter called .
628
01:23Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
689
The elimination half-life and drug clearance of drugs following nonlinear kinetics can vary with dosage. The Michaelis-Menten parameters and drug concentration influence these factors. As the dose increases, the elimination half-life tends to lengthen, resulting in a reduction in clearance and a disproportionately larger area under the curve. The total clearance can be derived from the Michaelis-Menten equation for drugs following a one-compartment model.
A study on guinea pigs examined the...
A study on guinea pigs examined the...
689