Patients with Chronic Inflammatory Diseases Can Experience Higher Exposure of Small Molecule Drugs than Healthy Volunteers: An Analysis of Recently Approved Drugs.
5 affiliations
- 1PharMetrX Graduate Research Training Program, Berlin/Potsdam, Germany.
- 2Institute of Mathematics, University of Potsdam, Potsdam, Germany.
- 3Merck Healthcare KGaA, Darmstadt, Germany.
- 4EMD Serono Research and Development Institute Inc., an affiliate of Merck KGaA, Billerica, Massachusetts, USA.
- 5Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
Abstract
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.
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BibTeX
@article{tillil2026patients,
title = {{Patients with Chronic Inflammatory Diseases Can Experience Higher Exposure of Small Molecule Drugs than Healthy Volunteers: An Analysis of Recently Approved Drugs.}},
author = {Johannes Tillil and Sathej Gopalakrishnan and Jennifer Dong and Karthik Venkatakrishnan and Charlotte Kloft and Wilhelm Huisinga and Lena Klopp-Schulze},
journal = {Clinical pharmacology and therapeutics},
year = {2026},
month = oct,
doi = {10.1002/cpt.70535},
url = {https://europepmc.org/article/MED/42957589},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Patients with Chronic Inflammatory Diseases Can Experience Higher Exposure of Small Molecule Drugs than Healthy Volunteers: An Analysis of Recently Approved Drugs.
AU - Johannes Tillil
AU - Sathej Gopalakrishnan
AU - Jennifer Dong
AU - Karthik Venkatakrishnan
AU - Charlotte Kloft
AU - Wilhelm Huisinga
AU - Lena Klopp-Schulze
PY - 2026
DA - 2026/10/29
JO - Clinical pharmacology and therapeutics
DO - 10.1002/cpt.70535
UR - https://europepmc.org/article/MED/42957589
AB - 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.
SN - 0009-9236
SN - 1532-6535
ER -