Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole – A probe drug of CYP2C19 metabolism

Abstract

Objective: Targeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest. Methods: This prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling. Results: 16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8–4.8 h) in P1, 2.8 h (2.1–6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 – 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3. Conclusion: CYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.

Keywords

• Targeted temperature management
• Cardiac arrest
• CYP-metabolism
• Pharmacokinetics
• Intensive care