Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based...

Area of Science:

• Pharmacology
• Drug Metabolism
• Computational Toxicology

Background:

• Opioid analgesics (fentanyl, sufentanil, alfentanil, hydrocodone) are primarily metabolized by CYP3A4.
• Ritonavir is a potent CYP3A4 inhibitor, known to cause significant drug interactions.

Purpose of the Study:

• To investigate the impact of various ritonavir dosing regimens on the pharmacokinetics of commonly used opioid analgesics.
• To predict drug-drug interaction effects using physiologically based pharmacokinetic (PBPK) modeling.

Main Methods:

• Physiologically based pharmacokinetic (PBPK) modeling and simulation were employed.
• The study simulated the co-administration of ritonavir with fentanyl, sufentanil, alfentanil, and hydrocodone.

Main Results:

• Co-administration with ritonavir led to over a 10-fold increase in alfentanil and sufentanil exposure.
• Ritonavir had a modest effect on fentanyl exposure due to alternative metabolic pathways.
• Steady-state exposure of hydrocodone and hydromorphone increased by up to 87% and 95%, respectively, with ritonavir, especially affecting extended-release formulations.

Conclusions:

• PBPK modeling accurately predicts significant increases in opioid exposure when co-administered with ritonavir.
• Findings provide crucial guidance for optimizing opioid dosage regimens to mitigate toxicity risks in patients receiving ritonavir.