Patients with Chronic Inflammatory Diseases Can Experience Higher Exposure of Small Molecule Drugs than Healthy Volunteers: An Analysis of Recently Approved Drugs

Chronic inflammation has long been known to downregulate the activity of certain cytochrome P450 (CYP) enzymes-the main enzymes responsible for the phase I metabolism of many small molecule drugs-potentially leading to higher exposures in patients with chronic inflammatory diseases compared to healthy volunteers. Neglecting this potential difference in the pharmacokinetics can have several implications for dose translation from healthy volunteers to proof of concept studies in patients: sub-optimal design of dose-ranging studies and increased risk of adverse events due to overprediction of safety margins. Yet this disease-drug interaction has rarely been prospectively considered in drug development in the past. This review aims to quantify the extent of decreased (apparent) clearance in patients compared to healthy volunteers of small molecule drugs that were approved by the FDA in the past 15 years for important chronic inflammatory indications. Based on reported population pharmacokinetic analyses, 25% (5 of 20) of small molecule drugs approved for the selected indications showed a meaningfully higher area under the curve (AUC) by more than 25% in patients compared to healthy volunteers. As a common feature, all five drugs are primarily metabolized by CYP3A4 or CYP2C19 and for four of the five drugs, the contribution of metabolism to their elimination is more than 50%. These findings highlight the need to assess a drug's susceptibility to changes in the metabolic activity under chronic inflammation when translating dose predictions from healthy volunteers to patients.