Wisse van Os (1), J.G. Coen van Hasselt (2), Michael Poppe (3), Christian Clodi (3), Christoph Schriefl (3), Matthias Mueller (3), Raute Sunder-Plaßmann (4), Birgit Reiter (4), Maximilian Rechenmacher (3), Michael Holzer (3), Harald Herkner (3), Michael Schwameis (3), Bernd Jilma (1), Christian Schoergenhofer (1), Christoph Weiser (3)
(1) Department of Clinical Pharmacology, Medical University of Vienna, Austria, (2) Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands, (3) Department of Emergency Medicine, Medical University of Vienna, Austria, (4) Clinical Institute of Laboratory Medicine, Medical University of Vienna, Austria
Introduction: Targeted temperature management (TTM) is part of standard post-resuscitation care. TTM-induced hypothermia and the systemic inflammation that often follows after rewarming may affect the activity of hepatic enzymes like CYP2C19, which is involved in the metabolism of various drugs frequently used in the intensive care unit (ICU). Dosing in TTM is often based on extrapolations from patient populations with different pathophysiological properties, which may be inappropriate. However, to what extent pharmacokinetics (PK) of specific drugs are altered during TTM is not well quantified.
Objective: To evaluate the effect of TTM on the PK of pantoprazole as a probe of CYP2C19-dependent metabolism, using a population PK modelling approach.
Methods: We enrolled 16 patients who underwent successful cardiopulmonary resuscitation and received pantoprazole as part of post-resuscitation care. Patients received a 40 mg intravenous bolus dose of pantoprazole every 24 hours. Pantoprazole PK was evaluated in three study periods: during TTM with a target temperature of 33°C; after controlled rewarming to 36.5°C ± 1°C at the ICU; and during recovery in the normal ward, representing the internal control period. In each study period, 6 post-dose plasma PK samples were drawn over the course of a single dosing interval per patient. PK data was analysed using nonlinear mixed-effects modelling. To quantify the differences in PK between the study periods, we grouped the PK samples in three occasions based on the study period in which they were drawn, and tested the inter-occasion variability (IOV) as an additional level of random effect, besides the inter-individual variability (IIV), on all structural model parameters. Body temperature and C-reactive protein levels, as a marker for inflammation, were tested as covariates. Separately, we tested to what extent the IOV could be explained by estimating a factor by which the typical values of PK parameters increased or decreased in each study period relative to the other study periods. PK parameters were a priori allometrically scaled based on body weight. The M3 method was used to handle data below the quantification limit, amounting to 14% of the post-dose samples.
Results: The PK data was best described by a two-compartment model with IOV on clearance (CL) and the central volume of distribution (Vc), IIV on CL, and a combined error model. The IOV on CL as estimated in the base model could for 21% be explained by estimating factors by which its typical value was altered both during TTM and after rewarming, indicating 40% and 29% lower CL in these study periods, respectively, compared to the internal control period. The data also supported estimating such a factor for Vc in the study period after rewarming, which indicated a 64% increase compared to the other study periods, and explained 15% of the IOV on Vc as estimated in the base model.
Conclusions: TTM at 33°C reduced CYP2C19-mediated pantoprazole metabolism compared to the internal control period, potentially due to the enzymes not functioning at their optimum temperature range. The reduced CL and increased Vc immediately after rewarming are most likely explained by systemic inflammation downregulating enzyme activity and increasing vascular permeability. PK of other drugs with CYP2C19-dependent metabolism that are frequently used in TTM may be subject to similar alterations, potentially resulting in increased toxicity or impaired pro-drug activation.
Reference: PAGE 29 (2021) Abstr 9652 [www.page-meeting.org/?abstract=9652]
Poster: Drug/Disease Modelling - Other Topics