Blood Concentrations Of Calcineurin Inhibitors Research Articles

Clinical impact of variability in blood concentrations of calcineurin inhibitors in heart transplant: a double-edged sword

Clinical impact of variability in blood concentrations of calcineurin inhibitors in heart transplant: a double-edged sword

Correlation between gene polymorphism and blood concentration of calcineurin inhibitors in renal transplant recipients: An overview of systematic reviews.

Background:To provide an overview of systematic reviews and meta-analyses (SRs/MAs) of the correlation between genetic polymorphisms and blood concentrations of calcineurin inhibitors (CNIs) in recipients of renal transplant.Methods:Databases including Medline, EMBase, The Cochrane Library (Issue 7, 2016), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, the China Science and Technology Journal Database, and the Wan Fang Database were searched for SRs/MAs of the correlation between genetic polymorphisms and blood concentrations of CNIs in renal transplant recipients from inception to July 2016. Two reviewers independently screened the literatures and extracted data, then the AMSTAR measurement tool was used to assess the methodological quality of SRs/Mas included in the overview.Results:Fourteen SRs/MAs met the inclusion criteria. The most commonly reported genotype was CYP3A5∗3/∗3, which was strongly associated with cyclosporine A (CsA) and tacrolimus (FK506). MDR1 C3435T CC was also associated with CNI use, especially with CsA therapy. Other less commonly reported genotypes such as CYP3A4∗1B, MDR1 C1236T CC, and MDR1 G2677T/A GG also affected the blood concentrations of CNIs.Conclusions:Our overview showed that polymorphisms influence the blood concentrations of CNIs, which suggests the necessity to monitor these concentrations in patients with genotypes that affect dose-adjusted trough concentrations (C0/D) or dose-adjusted peak concentrations (C2/D) to regulate the dosage for individual administration. Because of the limited number of included studies, these findings should be verified in more high-quality studies.

Genetic association of interleukin-2, interleukin-4, interleukin-6, transforming growth factor-β, tumour necrosis factor-α and blood concentrations of calcineurin inhibitors in Turkish renal transplant patients.

Cytokines are essential for the control of the immune response as most of the immunosuppressive drugs target cytokine production or their action. The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are immunosuppressive drugs widely used after renal transplantation to prevent allograft rejection. They are characterized by large interindividual variability in their pharmacokinetics; therefore, monitoring their blood concentrations is important to predict their optimal dosage following transplantation. Calcineurin inhibitors inhibit the phosphatase activity of calcineurin, thereby suppressing the production of other cytokines such as transforming growth factor (TGF-β), tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-2, and IL-4. The aim of this study was to investigate the relationship between polymorphisms of cytokines and blood concentrations of CNIs in renal transplant patients. The study included 53 CsA-treated renal transplant patients and 37 tacrolimus-treated renal transplant patients. Cytokine polymorphisms were analysed using polymerase chain reaction (PCR) sequence-specific primers with the cytokine CTS-PCR-sequence-specific primers Tray Kit; University of Heidelberg. Blood concentrations of CNIs were determined with Cloned Enzyme Donor Immunoassay (CEDIA) method. Patients with TC genotype of TGF-β at codon 10 had lower CsA blood concentrations than the TT and CC genotypes (P = 0.005) at 1 month in CsA treatment group. The ratio of blood concentration/dose of CsA for patients with TGF-β1-codon 10 TC genotype was lower than for patients with TT, CC genotypes, and the dose given to these patients was higher in the first month (P = 0.046). The ratio of blood concentration/dose of CsA for patients with IL-2-330 GG genotype was higher than for patients with GT, TT genotypes, and the dose given to these patients was lower at first month and sixth months (P = 0.043, P = 0.035 respectively). The tacrolimus blood concentrations were significantly higher in patients with the genotype GG of IL-2-330 (P = 0.012) at the third month. Patients who had the TC genotype TGF-β codon 10 had lower CsA blood concentrations and this group had higher acute rejection (P = 0.033). These results suggest that the genotyping for TGF-β-codon 10, IL-2-330 and IL-6-174 polymorphisms may help individualized immunosuppressive dosage regiments.

The Proton Pump Inhibitor Lansoprazole, but not Rabeprazole, the Increased Blood Concentrations of Calcineurin Inhibitors in Japanese Patients with Connective Tissue Diseases

Proton pump inhibitors (PPIs) are frequently coadministered with calcineurin inhibitors (CNIs) such as tacrolimus (TAC) and cyclosporin A (CSA), to treat or prevent upper gastrointestinal complications in Japanese patients with connective tissue diseases (CTDs). The coadministration of PPIs increases the blood concentration of TAC due to drug interaction. We retrospectively investigated the influence of the coadministration of PPIs and CNIs, as well as the influence of the cytochrome P450 (CYP) 2C19 gene polymorphism status, on the blood concentrations of TAC and CSA in patients with CTDs. Patients treated with TAC (n=35) or CSA (n=30) were enrolled and divided into three groups according to the PPI they received: lansoprazole (LPZ)-combined, rabeprazole (RPZ)-combined, and non-PPI-combined groups. We compared the blood concentrations of TAC or CSA and the incidences of adverse events among the three groups. CYP2C19 gene polymorphisms were also assessed to investigate its influence on the blood concentration of TAC or CSA. LPZ significantly increased the blood concentration of TAC 12 hours after TAC administration (p=0.030 and p=0.003, respectively) and CSA (p=0.047 and p=0.014, respectively) in comparison with RPZ and non-PPI-combined treatment. There were no significant differences in the mean CSA blood concentration two hours after administration in patients with or without PPI treatment, in the incidence of adverse events, or in the CYP2C19 gene polymorphism status among the three groups. Combining agents that are mainly metabolized by CYP3A4 such as LPZ elevates the blood concentrations of TAC and CSA, which could leading to adverse events.

Outcomes of kidney transplantation in HIV-positive patients: the UK experience

BackgroundHIV infection is an independent risk factor for end-stage kidney disease in HIV-positive patients of black ethnicity. Highly effective antiretroviral therapy has allowed these patients to be considered for kidney transplantation (KT). We report the outcomes of KT in a national observational cohort study. MethodsWe retrospectively identified HIV-positive patients who had undergone KT up to December, 2010, through all 25 UK KT centres and major HIV clinics, and included follow-up until December, 2011. Patient characteristics, treatments, and complications were described. Patient and graft survival rates and cumulative incidence of acute rejection were estimated with Kaplan-Meier and Nelson-Aalen analyses. Findings35 HIV-positive KT recipients (median age 40 years, 66% male, 74% black ethnicity) were identified. At the time of KT, all patients were stable on antiretroviral therapy with undetectable HIV RNA and median CD4 cell count of 366 cells per mL. Patient survival at both 1 and 3 years was 91·3%, and graft survival was 91·3% and 84·7%, respectively. In the first year after KT, blood concentrations of calcineurin inhibitors (CNI) were frequently outside the therapeutic reference range. At 1 year after KT, the cumulative incidence of acute allograft rejection was 48%, and the median estimated glomerular filtration rate 61 mL/min/1·73 m2 (IQR 46–78). Although HIV viraemia and HIV disease progression were uncommon, renal complications were relatively frequent. InterpretationOur study corroborates the feasibility of KT in HIV-positive patients. Co-administration of antiretroviral therapy and CNI is challenging, and sub-therapeutic CNI concentrations may contribute to the high rate of acute allograft rejection. The optimum immune suppression strategy in this population remains to be refined. FundingKing's College London.

Effects of the Intensity of Immunosuppressive Therapy on Outcome of Treatment for CMV Disease in Organ Transplant Recipients

An effective host immune response, critical for successful control of Cytomegalovirus (CMV) disease in solid organ transplant recipients, is affected by intensity and type of immunosuppressive therapy. We used information prospectively captured in the VICTOR-trial to investigate the impact of immunosuppressive therapy on short- and long-term outcomes of CMV treatment in organ transplant recipients. Dual, as compared to triple, immunosuppressive therapy ([odds ratios] OR of 2.55; 95% CI: 1.51-4.60; p = 0.002), lower blood concentrations of calcineurin inhibitors (OR of 5.53; CI: 1.04-29.35; p = 0.045), and longer time since transplantation (OR of 1.70; CI: 1.01-2.87; p = 0.047) all showed better early (Day 21) CMV DNAemia eradication. We observed no effect of the intensity of the immunosuppressive therapy on overall rates of viral eradication or recurrence. The type of calcineurin inhibitor (tacrolimus/cyclosporine) or use of mycophenolate did not affect treatment efficacy, although both tacrolimus and mycophenolate treated patients showed a lower rate of virological recurrence OR 0.51 (95% CI: 0.26-0.98; p = 0.044) and OR 0.45 (95% CI: 0.22-0.93; p = 0.031), respectively. Lower total intensity of immunosuppressive therapy was associated with more effective early, but not overall, CMV DNAemia eradication by valganciclovir/ganciclovir therapy. Both mycophenolate and tacrolimus (rather than cyclosporine) therapy seem to be associated with reduced risk of recurrence.

造血幹細胞移植患者におけるカルシニューリン阻害剤とアゾール系抗真菌剤の薬物動態学的相互作用の評価

Calcineurin inhibitors are used as immunosuppressive agents for graft-versus-host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation.Since azole antifungals are frequently used for prophylaxis and treatment of infection under immunosuppressive therapy,it is highly possible that azole antifungals will affect blood concentrations of calcineurin inhibitors by inhibiting the drug metabolizing enzyme cytochrome P450 (CYP) 3A4.However,dosage adjustment with individual azole antifungals when administered by different routes has yet to be fully examined.In this study,we examined the effect of azole antifungals on blood concentrations of tacrolimus administered by intravenous constant infusion and cyclosporine administered orally in hematopoietic stem cell transplant patients.Oral voriconazole increased the blood concentration/dose (C/D) ratio of tacrolimus 2.7-fold,a significant increase.Oral itraconazole and intravenous voriconazole increased the C/D ratio 2.4-fold and 2-fold,respectively,but these changes were not statistically significant.The effects of oral and intravenous fluconazole were less potent than those of voriconazole and itraconazole,and tended to increase the C/D ratio of tacrolimus by 1.5-fold.The potencies of interactions between these azole anitifungals and oral cyclosporine blood concentrations were similar to those for intravenous tacrolimus.In consideration of these results,the dosages of calcineurin inhibitors should be reduced by 50-65% when concomitantly administered with voriconazole or itraconazole,and by around 35% in the case of fluconazole.However,dosage adjustment for these drugs should also be based on therapeutic drug monitoring because of the large inter-individual variability of pharmacokinetic interactions.

Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: Involvement of the suppression of intestinal cytochrome P450 3A and P‐glycoprotein

We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.