29 January 2021
Systemic clearance, denoting how much drug is cleared from blood over time, is of critical importance to a drug candidate’s pharmacokinetic (PK) profile. Tools such as the Extended Clearance Classification System (ECCS) and in vitro-in vivo extrapolation (IVIVE) can help predict the rate at which a compound is eliminated and support a risk-based approach to PK evaluation, dosing considerations and clinical study design.
There can be a lot of complexity involved in your drug’s mechanisms and rate of clearance, including turnover by drug-metabolizing enzymes, transport to and from tissues, biliary excretion and more. Fortunately, many of these factors can be estimated using in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) early in development pipeline.
The Extended Clearance Classification System (ECCS) has been proposed as a tool to predict the rate-limiting step in a drug’s clearance using physicochemical properties. Depending on molecular weight, permeability, and ionization, drugs can be categorized into one of four classes which predict whether drug transport, renal elimination, or hepatic metabolism is most likely to critically impact clearance. Equipped with a sound prioritization strategy, drug developers can make informed decisions regarding timing of preclinical investigations into their drug compound’s interaction with drug-metabolizing enzymes and transporters.
Only free (unbound) drug is available for therapeutic action and clearance from the body, so experiments to determine your drug’s affinity to plasma proteins, e.g. albumin, provide insight to clearance rate as well as exposure. Plasma Protein Binding (PPB) studies use techniques like equilibrium dialysis, ultrafiltration, and ultracentrifugation to calculate fraction unbound (fu).
Transporters represent a critical component of a drug’s ADCE—No, that isn’t a typo for ADME. ADCE stands for absorption, distribution, clearance, and elimination. While a drug’s metabolism is important in understanding the fundamental pharmacokinetic principle of how a drug is changed, it’s equally important to take into account how it navigates the body by considering drug transport.
Transporter proteins can affect the elimination of a drug compound just as much as drug-metabolizing enzymes. Even if a drug is rapidly metabolized by a high-turnover enzyme, its clearance may be slowed by slow transport to the site of metabolism. For example, MAO-A is an enzyme that can metabolize drugs very quickly, but some drugs (e.g., sumatriptan) only get to MAO-A through the transporter OCT1. In people with low OCT1 activity, OCT1 is expressed very differently between individuals. Metabolism is slowed and clearance is reduced, so exposure (concentration of drug compound in plasma) is increased, which could lead to negative effects, such as toxicity.
Print14 March 2024
26 February 2024
NovaMedica team wishes you a Merry Christmas and a Happy New Year!
26 December 2023
Russian drug for the treatment of viral hepatitis will be exempt from duty in Mongolia
24 April 2024
PM Mishustin: “We need to increase the production of vital and essential drugs in Russia”
24 April 2024
The Future of Pharmacy: How Advancements in Technology Are Transforming the Field
23 April 2024
Analysis Forecasts Up to 16.5% of Population Will Have Chronic Kidney Disease by 2032
23 April 2024