Pharmacokinetics of immunosuppressive agents during hemoperfusion in a sheep model

Abstract

IntroductionHemoadsorption shows promising signals in organ preservation and post lung transplantation. However, its potential impact on the pharmacokinetics of immunosuppressant drugs (ID) is still unknown.MethodsIn this interventional study, CytoSorb® hemoperfusion was tested in healthy sheep (n = 5) against a sham extracorporeal circuit (n = 3). Seven different ID (tacrolimus (TAC), cyclosporin A (CYA), mycophenolate mofetil (MMF), everolimus (EVER), basiliximab (BAS), methylprednisolone (MP) and prednisolone (PRED)) were administered in clinically relevant doses and combinations. Their levels were measured repeatedly in blood samples from the extracorporeal circulation over 6 h following administration. Population pharmacokinetic modeling analysis (NONMEM® 7.5) was performed.ResultsNegligible clearance was observed for PRED and BAS. For all other substances, a saturable adsorption sub-model with linear decrease of the adsorption effect over the adsorbed amount best described the measured concentrations. The maximum absolute adsorbed amounts (95% CI) for TAC, CYA, MMF, EVER, and MP were 0.040 (0.028–0.053), 1.15 (0.39–1.91), 4.17 (2.00–6.35), 0.0163 (0.007–0.026), and 53.4 mg (20.9–85.9), respectively, indicating an adsorption of less than 5% of the daily administered dosages for all investigated substances.DiscussionIn this large animal model, CytoSorb® hemoperfusion appears to have a limited effect on the clearance of tested ID.

Use of intraoperative haemoadsorption in patients undergoing heart transplantation: a proof‐of‐concept randomized trial

“… 35 Also, a very recently published large animal study reported on an adsorption rate of less than 5% for immunosuppressive agents such as tacrolimus, cyclosporin A, mycophenolate mofetil, everolimus, and methylprednisolone during 6 h of in vivo extracorporeal haemoadsorption treatment. 36 Data presented in our RCT strongly substantiate these previous investigations. Similar MPA concentrations were measured pre‐CPB and at 2 h of CPB run in the study groups ( Figure 4 ), and there were no differences in the frequencies of cardiac allograft rejection over the 1‐month follow‐up period between the groups ( Table 3 ).…”

“…Interestingly, Lindstedt et al did not find histopathological signs of acute rejection at 1‐ and 3‐month post‐transplant in patients who received cytokine adsorption during lung transplantation, compared to patients managed without the adsorber 35 . Also, a very recently published large animal study reported on an adsorption rate of less than 5% for immunosuppressive agents such as tacrolimus, cyclosporin A, mycophenolate mofetil, everolimus, and methylprednisolone during 6 h of in vivo extracorporeal haemoadsorption treatment 36 . Data presented in our RCT strongly substantiate these previous investigations.…”

The role of hemoadsorption in cardiac surgery – a systematic review

“…These bene ts translate to lower 30-day mortality in intraoperative hemoadsorption patients treated signi cantly. Notably, no device-related adverse events were reported (Evidence table, Additional le 2), suggesting that there was also no clinically relevant inadvertent immunosuppressant removal, consistent with the recently published animal study showing minimal removal of these agents by CytoSorb [27].…”

The role of hemoadsorption in cardiac surgery – a systematic review

“…The use of hemoadsorption in organ transplants has been controversial due to the already discussed potential for unwanted drug removal, specifically immunosuppressants. However, a detailed investigation in a large animal model reassuringly reported a minimal level of removal with frequently used immunosuppressant regimens [ 63 ]. A very recent RCT [ 64 ] confirmed CytoSorb ® did not affect levels of mycophenolic acid, used to prevent organ transplant rejection, and found that concentrations were comparable to the control group at all pre-defined time points.…”