Sponsored How In Vitro and In Vivo Studies Help You Understand Your Drugs Clearance

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.

Extended Clearance Classification System (ECCS)

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.

Plasma Protein Binding (PPB)

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).

Drug Transporter Studies

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.




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