Related Experiment Video
Updated: May 9, 2026
08:59
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Development of a Physiologically-Based Pharmacokinetic Model for Sirolimus: Predicting Bioavailability Based on
1Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
CPT: Pharmacometrics & Systems Pharmacology
|July 26, 2013
Summary
Sirolimus, an mTOR inhibitor, shows variable oral bioavailability due to intestinal CYP3A expression. Physiologically-based pharmacokinetic modeling accurately predicted sirolimus levels, aiding in understanding drug interactions and hepatic impairment.
Area of Science:
- Pharmacology
- Pharmacokinetics
- Systems Pharmacology
Background:
- Sirolimus, an mTOR inhibitor, is vital in transplantation and cancer therapy.
- Sirolimus exhibits low oral bioavailability and significant pharmacokinetic variability.
- Mechanisms underlying sirolimus pharmacokinetic variability remain underexplored.
Purpose of the Study:
- To characterize sirolimus metabolism and estimate in vitro intrinsic clearance.
- To predict sirolimus oral bioavailability using mechanistic models.
- To develop and validate a physiologically-based pharmacokinetic (PBPK) model for sirolimus.
Main Methods:
- In vitro intrinsic clearance estimation and pathway contribution analysis (CYP3A4, CYP3A5, CYP2C8).
- Prediction of sirolimus bioavailability using well-stirred and Qgut models.
- Development of a PBPK model in Simcyp, incorporating adipose tissue distribution and non-CYP elimination pathways.
Main Results:
- CYP3A4 was the primary enzyme in sirolimus metabolism, followed by CYP3A5 and CYP2C8.
- Predicted sirolimus oral bioavailability was 15%, with interindividual variability linked to intestinal CYP3A expression.
- The PBPK model demonstrated acceptable predictive performance for Cmax and AUC, within 20% of observed data.
Conclusions:
- Variable intestinal CYP3A expression contributes to sirolimus pharmacokinetic variability.
- The developed PBPK model accurately predicts sirolimus pharmacokinetics and can assess impacts of hepatic impairment and drug-drug interactions.
Related Concept Videos
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion, mediated...
A recent model describes pravastatin's hepatobiliary excretion, mediated...
01:22Bioavailability Enhancement: Determination and Conceptual Approaches in Overcoming Bioavailability Problems
Bioavailability is a critical pharmacological concept that measures the extent and rate at which an active drug ingredient or therapeutic moiety enters the systemic circulation, remaining unchanged. It's a pivotal factor in determining a drug's efficacy and safety.The Biopharmaceutics Classification System (BCS) plays an essential role in drug development by categorizing drugs into four classes based on their solubility and permeability. This classification aids in understanding drug absorption...
01:15Impact 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 (CHF).
01:27Pharmacodynamic Models: Overview
Pharmacodynamic (PD) responses describe the interaction between a drug and its biological target, culminating in a physiological effect. These responses can be classified into different types: continuous variables, such as blood glucose levels; categorical outcomes, like survival rates; and time-to-event metrics, such as disease progression. Understanding and modeling PD responses are critical for optimizing drug efficacy and safety.PD models describe the relationship between drug concentration...
01:13Physiological Pharmacokinetic Models: Assumption with Protein Binding
Physiological models with protein binding in pharmacokinetics offer a sophisticated approach to understanding drug disposition. These models consider drug-protein interactions, enabling them to effectively predict drug concentrations in different organs and tissues. This precision aids in accurate drug dosing, providing a significant advantage over conventional models. A key process within these models is equilibration, which ensures that drug concentrations achieve a steady state within the...
01:26Pharmacokinetic Models: Comparison and Selection Criterion
Physiological and compartmental models are valuable tools used in studying biological systems. These models rely on differential equations to maintain mass balance within the system, ensuring an accurate representation of the dynamic processes at play.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.