Abstract
4 min readSirolimus (SRL) is an immunosuppressive drug extensively metabolized by the cytochrome P450 (CYP3A4) system. Therefore, its pharmacokinetics is influenced by drugs that interfere with CYP3A4 activity, such as cyclosporine A (1). Patients on SRL therapy frequently require omega-3 polyunsaturated fatty acids (PUFA) to control hypertriglyceridemia, a common side effect of chronic treatment with mammalian target of rapamycin inhibitors. Although experimental studies (2, 3) have shown that omega-3 PUFA inhibit the activity of CYP3A4, the impact of these lipid-lowering agents on daily SRL exposure in transplant recipients has not been investigated so far. To address this issue, we performed a retrospective analysis of a SRL pharmacokinetic data set of two groups of patients: one with and one without omega-3 PUFA treatment. To exclude the potential confounding factor related to concomitant cyclosporine A administration, only patients given SRL on a calcineurin inhibitor-free immunosuppressive regimen were considered in this study. Four hundred forty-five SRL trough levels and 55 SRL daily pharmacokinetic profiles were collected from 22 kidney transplant recipients given low-dose SRL and low-dose mycophenolate mofetil as maintenance immunosuppressive regimen during a 36-month follow-up. Detailed information on study population and pharmacokinetic measures were reported elsewhere (4). Demographic and hematochemical data measured periodically posttransplantation were comparable between patients given or not omega-3 PUFA, except differences on serum lipid profile. Indeed, 9 of 22 patients started omega-3 PUFA administration at different time-points posttransplantation to reduce triglyceride concentrations (Fig. 1). From month 4 posttransplantation mean dose-normalized SRL trough concentrations were higher in patients given omega-3 PUFA in comparison with those not receiving these lipid-lowering agents. The difference became statistically significant from month 7 after surgery, and it remained significant throughout the follow-up (Fig. 1). Moreover, when we compared mean dose-adjusted SRL trough levels in the same patients before and after starting omega-3 PUFA, we found that the treatment resulted in a significant increase of dose-adjusted SRL trough concentrations (2.5±1.1 ng/mL/mg before vs. 3.8±2.5 ng/mL/mg after omega-3 PUFA; P<0.001). Intrapatient and interpatient variability of SRL trough levels was not affected by omega-3 PUFA administration (data not shown). Pharmacokinetic studies—performed every 6 months after surgery—demonstrated that the concomitant administration of omega-3 PUFA also increased dose-adjusted SRL area under curve (AUC0–24) values compared with untreated patients (98±38 vs. 79±23 ng×hr/mL/mg; P=0.007). Interestingly, the major differences in the pharmacokinetic profiles between patients given or not omega-3 PUFA were found from 240 to 480 min after SRL administration, namely during the phase of drug metabolism. Nearly 25% reduction in the SRL dose was required to reach SRL trough concentrations and AUC0–24 values comparable with those found in patients not given these agents (3.2±1.3 vs. 4.2±1.5 mg SRL, P<0.001). To assess whether higher lipid concentrations observed in patients given omega-3 PUFA could have biased the results, dose- adjusted SRL AUC0–24 values were stratified according to total cholesterol and triglyceride concentrations. No significant differences were observed on dose-normalized AUC0–24, when dividing data according to total cholesterol less than or equal to or more than 200 mg/dL (87±31 vs. 86±32 ng×hr/mL/mg; P=NS) or to triglyceride levels less than or equal to or more than 170 mg/dL (87±32 vs. 88±37 ng×hr/mL/mg; P= NS). Similarly, no impact of statin treatment on SRL pharmacokinetics was observed (data not shown). To further confirm the predictive role of omega-3 PUFA administration on SRL exposure, a multivariate regression analysis was performed considering dose-adjusted SRL AUC0–24 as the dependent variable and the patient demographic and biometric characteristics as the independent covariates. According to the multivariate regression analysis, the use of omega-3 PUFA and red blood cell count (RBC) were the only independent factors significantly associated to SRL exposure.FIGURE 1.: Distribution of dose-adjusted sirolimus (SRL) trough levels in kidney transplant recipients on calcineurin inhibitor-free regimen reported as mean (±SD) of the measurements performed during each of the indicated time intervals. Black circles represent patients treated concomitantly with omega-3 polyunsaturated fatty acids (PUFA), whereas those not given these agents were drawn as white circles. (#P<0.05 vs. patients not given omega-3 PUFA).Altogether, these clinical data suggest that daily SRL exposure was significantly increased by the concomitant administration of omega-3 PUFA and extend previous in vitro and in vivo experimental observations showing the inhibitory activity of omega-3 PUFA on CYP3A4, the main enzyme involved in SRL metabolism (2, 3). Multivariate analysis showed that in addition to omega-3 PUFA, SRL exposure was also independently associated to RBC. In particular, low RBC was related to lower SRL AUC0–24 values. This finding could be explained considering that in the blood, SRL is mainly partitioned in erythrocytes (5); thus, as RBC decrease, there will be an increase in the drug-free concentration, namely the fraction available for metabolism by the cytochromial system. In conclusion, we have provided evidence that concomitant administration of omega-3 PUFA significantly increases SRL exposure in kidney transplant recipients on calcineurin inhibitor-free immunosuppression, ultimately requiring a 25% reduction of SRL dose to keep patients in the expected SRL trough concentration-based window. These findings may help transplant physicians to better individualize SRL therapy in kidney allograft recipients. Monica Cortinovis Eliana Gotti Giuseppe Remuzzi Norberto Perico Department of Medicine and Transplantation Ospedali Riuniti di Bergamo Mario Negri Institute for Pharmacological Research Bergamo, Italy Center for Research on Organ Transplantation Chiara Cucchi De Alessandri & Gilberto Crespi Bergamo, Italy Dario Cattaneo Sara Baldelli Unit of Clinical Pharmacology Luigi Sacco University Hospital Milan, Italy
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