In a PK model, hepatic impairment is commonly reflected by adjusting which parameters?

• A. Increase intrinsic clearance and Qh.
• B. Decrease intrinsic clearance and possibly alter protein binding (fu).
• C. Eliminate intrinsic clearance and set fu to zero.
• D. Only adjust hepatic blood flow while keeping CLint and fu constant.

Answer: (B)

Hepatic impairment mainly reduces the liver’s metabolic capacity, which shows up as a lower intrinsic clearance (CLint). CLint reflects how quickly the liver can metabolize unbound drug per unit time, independent of blood flow. When the liver is diseased, enzyme activity and hepatocyte function decline, so CLint tends to decrease. At the same time, disease can change plasma protein levels (like albumin), altering the fraction unbound (fu). If fu increases because binding sites are reduced, more drug is available for metabolism, which can shift the overall hepatic clearance in combination with the lower CLint. The hepatic clearance in the well-stirred model is governed by CLh = Qh × fu × CLint / (Qh + fu × CLint); thus, decreasing CLint is a primary way hepatic impairment shows up, with fu changes as a secondary, potentially important factor. That’s why adjusting intrinsic clearance downward, and possibly altering fu, best reflects hepatic impairment.