CsA Blood Levels Research Articles

Effects of Triazole Antifungal Agents on the Plasma Concentration and Dosage of Cyclosporin in Patients with Aplastic Anaemia

Objectives. This study aimed to investigate the effects of different triazole antifungal agents on the blood concentration and dosage of cyclosporine (CsA) in patients with aplastic anaemia (AA). Methods. This retrospective study enrolled AA patients who received CsA and triazole antifungal agents simultaneously between January 2018 and December 2022. The ratio of CsA blood concentration (ng/mL) to dosage (mg/day) (C/D) co-administration with and without azoles was compared. The effects of different triazole antifungal agents on blood concentrations and dosages of CsA were analysed. Results. The mean C/D ratio of CsA increased 1.97 times when co-administered with posaconazole (POS), while the mean C/D ratio of CsA increased 1.76 times when co-administered with fluconazole (FCZ). Compared with CsA monotherapy, there was a significant difference in CsA concentrations among patients with azoles (P<0.05). The mean dose of CsA decreased was 0.26 (−0.25—1.05) mg/kg/day and 0.18 (−0.50—0.69) mg/kg/day when co-administered with POS and FCZ, respectively. There is a wide interindividual variability in the magnitude of drug interaction between azoles and CsA. Conclusions. Although azoles increased CsA concentration, a wide individual variability was found in the patients with CsA C/D ratio. Therefore, the CsA dose should be adjusted by closely monitoring the blood levels of CsA co-administered with triazole antifungal agents. In addition, we observed that POS had a greater effect on the blood concentration of CsA than FCZ. When adjusting the dose of CsA in clinical practice, the blood concentration of CsA and the type of co-administered triazole antifungal agents should be considered.

Could salivary cyclosporine dosage replace the whole blood cyclosporine measurements in renal transplant patients?

Background:Cyclosporin (CsA) has been extensively used as the immunosuppressant of choice in renal transplantation. Currently available approaches to assess CsA levels, both in serum and blood, fail to accurately reflect the concentration of the pharmacologically active drug fraction. Free CsA levels in biological fluids (blood or saliva) have been advocated to play an important role. Traditional salivary CsA monitoring tests are based on available archaic salivary techniques that are nonspecific and require large amounts of saliva. The aim of this study was to assess salivary CsA correlation using a novel and more accurate technique and to correlate with CsA levels in blood.Material and Methods: Patients provided blood samples of 2 ml and 2 ml of unstimulated saliva on the same day 2 h after the morning CsA dose (C2). Whole blood levels of CsA were determined using the monoclonal fluorescent polarization immunoassay (FPIA) kit. The FPIA kit was adapted to salivary testing by using a novel extraction method developed and patented under the name of Middle East Research Institute (MERI). Wilcoxon signed rank test compared the differences in blood and salivary CsA. Pearson's correlation coefficient assessed the linear association between blood and salivary CsA concentrations. All analyses were performed using IBM-SPSS version 23 (IBM Corp, Armonk, NY, USA).Results: No significant correlation was observed between blood and salivary CsA levels.Conclusion: Salivary CsA concentrations at C2 cannot adequately replace C2 blood levels as an indicator of CsA bioavailability despite improved performance of monoclonal FPIA and application of the MERI technique. More studies may be warranted to design more reliable and less invasive procedures for therapeutic drug monitoring.

Cyclosporine A lipid nanoparticles for oral administration: Pharmacodynamics and safety evaluation

The pharmacodynamic effect and the safety of cyclosporine A lipid nanoparticles (CsA LN) for oral administration were investigated using Sandimmune Neoral® as reference. First, the biocompatibility of the unloaded LN on Caco-2 cells was demonstrated. The pharmacodynamic response and blood levels of CsA were studied in Balb/c mice after 5 and 10days of daily oral administration equivalent to 5 and 15mg/kg of CsA in different formulations. The in vivo nephrotoxicity after 15days of treatment at the high dose was also evaluated. The results showed a significant decrease in lymphocyte count (indicator of immunosuppression) for the CsA LN groups which was not observed with Sandimmune Neoral®. CsA blood levels remained constant over the time after treatment with LN, whereas a proportional increase in drug blood concentration was observed with Sandimmune Neoral®. Therefore, CsA LN exhibited a better pharmacological response along with more predictable pharmacokinetic information, diminishing the risk of toxicity. Moreover, a nephroprotective effect against CsA related toxicity was observed in the histopathological evaluation when LN containing Tween® 80 were administered. Therefore, our preliminary findings suggest LN formulations would be a good alternative for CsA oral delivery, enhancing efficacy and reducing the risk of nephrotoxicity.

Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients.

Advances in immunosuppressive therapy allowed renal transplantation to become the treatment of choice for suitable candidates with (end stage renal disease) ESRD. The post-transplant therapeutic strategy is difficult due to narrow therapeutic indices for the currently used immunosuppressive drugs. Inter-individual differences in drug bioavailability are related to genetic and non genetic factors. The idea of targeted and personalized therapy is to achieve therapeutic success. The empirical dose has lost its value in the post-transplant therapy and an individualized dosage regimen must be established. Interindividual heterogeneity in expression of ABCB1 and CYP3A4 has been suspected to be one of the factors resulting in cyclosporine (CsA) pharmacokinetic variation. This study aimed to investigate the impact of inter-individual CYP3A4 rs4646437C>T and MDR1 G2677T/A polymorphisms on cyclosporine dose requirements among a sample of renal transplant Egyptian recipients. Fifty adult Egyptian patients on CsA were genotyped for CYP3A4 rs4646437C>T and MDR1 G2677T/A and correlated with CsA dose requirement and dose-adjusted CsA (C0) blood levels at 3, 6, and 9months post transplantation. CYP3A4 rs4646437C>T influenced significantly cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. Daily dose requirements were also significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9months post transplantation. Genotyping of both CYP3A4 and MDR1 SNPs may be helpful in providing pre-transplant pharmacogenetic information to individualize CsA dosing. Heterozygous CT genotype is the most frequent CYP3A4 rs4646437C>T genotype in the studied group of Egyptian population (48%) followed by CC genotype and TT genotype. Daily dose requirements were significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9months post transplantation.

Cyclosporine vs. Tacrolimus: Which Is a Better Match With Everolimus?

Background: In heart transplant (HTx) patients (pts), everolimus (EVR) may limit cardiac allograft vasculopathy, cytomegalovirus infection, and malignancy. However, there is increased nephrotoxicity when a calcineurin inhibitor (CNI) is combined with EVR. This has been well established in clinical trials using EVR in combination with cyclosporine (CSA). To compare the effect of EVR in combination with CSA vs tacrolimus (TAC), we reviewed the experience at our center. Methods: We assessed 38 HTx pts who were started on EVR in combination with either TAC or CSA between 2000 and 2012. Serum creatinine (SCr) and CNI trough levels were measured at EVR initiation and 1, 3, 6, and 12 months later. Endpoints were assessed: subsequent 1-year survival, 1-year freedom from dialysis, 1-year freedom from rejection. Results: Both TAC and CSA blood levels were maintained in the usual therapeutic range (5-10ng/ml and 100-200 ng/ml respectively) before and after EVR initiation, but pts on EVR /CSA had significantly higher SCr at follow-up (table). There was no significant difference in subsequent 1-year survival, freedom from dialysis, treated cellular rejection, or treated antibody mediated rejection.Table: No Caption available.Conclusion: When used in combination with EVR, TAC is associated with less nephrotoxicity than CSA with no increase in adverse events. Further study in a large patient sample is needed to confirm these findings. DISCLOSURES:Patel, J.: Grant/Research Support, Alexion Pharmaceuticals. Moriguchi, J.: Grant/Research Support, Grant from Thoratec and Syncardia Inc. Chang, D.: Stockholder, Abbot Pharma. Kobashigawa, J.: Grant/Research Support, Xdx Inc., Novartis Phamaceuticals, Transmedics Inc.

Conversion to Generic Cyclosporine to Formulation in Kidney Transplantation: Experience of a Center in Argentina.

Aim: Evaluate the safety and effectiveness of Generic Cyclosporine A in a selected patient population. Methods. We evaluated patients who metthe following criteria: Adults, have obtained a renal transplant at least 6 months prior to the switch to the original formulation, maintain stable cyclosporine dose for at least one month before the change, maintain stable levels of cyclosporine for at least one month before the change, and being clinically stable prior to switch. Generic Cyclosporine was provided by the Heath Ministry of Argentina since 2010. The study was descriptive, retrospective and no randomized. Design Study: Comparison problem related samples. Results. 34 patients were included. All patients received care on an outpatient. The change was 1:1. The average age was 46 years (27/72).21 male and 13 female and graft of 108 months (61.2/175.2). The mean time before replacement was 45 days (SD 36.6) and 63 days post substitution (SD 46.4). Mean levels of creatinine before and after the substitution showed no statistical significant differences (1.53 mg/dl vs 1.46 mg/dl). No differences were found in the levels of the C2 dosages of cyclosporine (516 ng/ml (SD 149) and 502 ng/ml (SD 175).Although blood levels of CSA remained above the target, in 13 patients blood levels were higher ( 20% ) and 21 patients were lower(by 21 %). When blood levels is related to the dose of cyclosporine used (CSA (ng/ml) /(dose mg/kg /day) statistically significant differences were observed (268.7/255.7). Rejection or deaths were no evidenced. Conclusion. Switch to Generic Cyclosporine in stable patients appears to be safe and effective when accompanied by monitoring therapeutic drug.

Renal Sodium Transporters Are Increased in Urinary Exosomes of Cyclosporine-Treated Kidney Transplant Patients

Background/Aims: Cyclosporine (CsA) is a calcineurin inhibitor widely used as an immunosuppressant in organ transplantation. Previous studies demonstrated the relationship between CsA and renal sodium transporters such as the Na-K-2Cl cotransporter in the loop of Henle (NKCC2). Experimental models of CsA-induced hypertension have shown an increase in renal NKCC2. Methods: Using immunoblotting of urinary exosomes, we investigated in CsA-treated kidney transplant patients (n = 39) the excretion of NKCC2 and Na-Cl cotransporter (NCC) and its association with blood pressure (BP) level. We included 8 non-CsA-treated kidney transplant patients as a control group. Clinical data, immunosuppression and hypertension treatments, blood and 24-hour urine tests, and 24-hour ambulatory BP monitoring were recorded. Results: CsA-treated patients tended to excrete a higher amount of NKCC2 than non-CsA-treated patients (mean ± SD, 175 ± 98 DU and 90 ± 70.3 DU, respectively; p = 0.05) and showed higher BP values (24-hour systolic BP 138 ± 17 mm Hg and 112 ± 12 mm Hg, p = 0.003; 24-hour diastolic BP, 83.8 ± 9.8 mm Hg and 72.4 ± 5.2 mm Hg, p = 0.015, respectively). Within the CsA-treated group, there was no correlation between either NKCC2 or NCC excretion and BP levels. This was confirmed by a further analysis including potential confounding factors. On the other hand, a significant positive correlation was observed between CsA blood levels and the excretion of NKCC2 and NCC. Conclusion: Overall, these results support the hypothesis that CsA induces an increase in NKCC2 and NCC in urinary exosomes of renal transplant patients. The fact that the increase in sodium transporters in urine did not correlate with the BP level suggests that in kidney transplant patients, other mechanisms could be implicated in CsA-induced hypertension.

Impact of Cyclosporine Levels on the Development of Acute Graft versus Host Disease after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

We analyze the impact of cyclosporine (CsA) levels in the development of acute graft-versus-host disease (aGVHD) after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC). We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10–444), 219 (54–656), 253 (53–910) and 224 (30–699) ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2–4 aGVHD for a cumulative incidence of 45% (95% CI 34–50%) at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P = 0.02) and development of grade 2–4 aGVHD (HR: 2.5, P < 0.01), while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P = 0.06). These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

Dyslipidemia After Kidney Transplantation and Correlation With Cyclosporine Level

BackgroundDyslipidemia after kidney transplantation is a frequent finding and is multifactorial. Immunosuppressive agents such as cyclosporine (CsA) can cause hypercholesterolemia.ObjectivesAs there were few reports with conflicting evidence on whether CsA related dyslipidemia is dose related and that CsA monitoring assays (trough level, C0, or two hour post dose level, C2) is a better predictor for dyslipidemia development; hence, the current study, in a large sample size, was designed to answer these questions.3. Patients and MethodsIn the current retrospective cross sectional study, 1391 kidney transplant recipients were enrolled. All patients received CsA plus mycophenolatemofetile or azathioprine and prednisolone. Serum creatinine, CsA blood levels and lipid profile were measured after 12-14 h fasting. Mann-Whitney and Kruskal-Wallis, Pearson`s test and logistic regression were used for data analyses.ResultsMean age of 1391studied population was 38.7 ± 15 years old. Hypercholesterolemia and hypertriglyceridemia were observed in 58.9% and 86.6%, respectively and they were more significantly detected in cadaveric kidney transplantation. Dyslipidemia had weak correlation with age of recipient, serum creatinine, C0 and C2 levels of CsA. At logistic regression, serum creatinine was the only risk factor for hypercholesterolemia development after kidney transplantation (OR = 1.6, CI 95%: 1.4 -1.8).ConclusionsDyslipidemia is a common finding after kidney transplantation and has no correlation with CsA level. According to conflicting data on the precise effect of different factors in inducing dyslipidemia, prospective large sample size studies should consider better control of dyslipidemia.

Comparison of Antibody-Conjugated Magnetic Immunoassay and Liquid Chromatography-Tandem Mass Spectrometry for the Measurement of Cyclosporine and Tacrolimus in Whole Blood

The aim of this work is to compare the results of a commercially available liquid chromatography tandem mass spectrometry (LC-MS/MS) method in a clinical pathology laboratory for routine Therapeutic Drug Monitoring (TDM) of cyclosporine (CsA) and tacrolimus (Tacr) in pediatric patients with those obtained with the current antibody-conjugated magnetic immunoassay (ACMIA). Whole blood levels of CsA (n= 135) and Tacr (n=100) were sequentially analyzed by using ACMIA and LC-MS/MS on pediatric transplanted patients. The differences were analyzed by using the Passing Bablok regression analysis and the Bland and Altman test. The LC-MS/MS method showed excellent reproducibility and lower limits of quantification compared to the ACMIA. A linear relationship between ACMIA and LC-MS/MS was obtained for both CsA Tacr. No significant inter-method biases were observed. The analytical performances of the LC-MS/MS method make it suitable for the accurate measurement of CsA and Tacr in pediatric transplanted patients. However ACMIA results are also accurate and reliable. For this reason the choice of the method to be used in a routine clinical pathology laboratory can be made on the bases of non-analytical considerations such as costs, organization, availability of skilled personnel.

Influence of Serum Uric Acid Levels in Response to the Conversion From Mycophenolate Mofetil to Mizoribine in Kidney Transplant Recipients

BackgroundCurrently, hyperuricemia is reported to be one of the most common side effects of mizoribine (MZR). However, previous clinical trials have not specially focused on MZR-related hyperuricemia. MethodsThirty-nine kidney recipients underwent a switch from mycophenolate mofetil (MMF) to MZR due to adverse clinical events. The control group included 39 kidney recipients continuing MMF without obvious adverse clinical events. They all received cyclosporine (CsA), prednisone, and MMF before enrollment. Every control was matched with a study group patient based on each pair undergoing kidney transplantations during the same week. Over the 24-month follow-up, every recipient underwent a physical examination including blood pressure, and laboratory screening of serum uric acid (sUA), creatinine, albumin, and CsA trough concentrations. We also calculated the estimated glomerular filtration rate (eGFR). ResultsThe sUA level of the study group significantly and consistently increased during the first 5 months, and then decreased. By 18 months, sUA concentrations were not significantly different between the 2 groups (P = .068). There were more new hyperuricemic cases in the study group at 24 months. There were no significant differences in blood pressure, eGFR, and CsA levels between the 2 groups. ConclusionAdministration of MZR was associated with a significant, transient increase in sUA. The increased uric acid suggested that MZR interferes with purine metabolism. The decrease should be associated with hypoxanthine-guanine phosphoribosyl transferase (HGPRT) enzyme activity, which improved under long-term MZR treatment. Therefore, recipients who receive MZR should be monitored more frequently for sUA during the first 5 months, followed by standard monitoring after 18 months.

Previous Exposure to Cigarette Smoke Aggravates Experimental Cyclosporine-Induced Nephrotoxicity

Background/Aims: The effects of cigarette smoke (CS) on cyclosporine (CsA)-induced nephrotoxicity are poorly studied. This study aims to assess the effects of previous exposure to CS on CsA nephrotoxicity. Methods: Rats were either exposed to CS or sham (S) procedures for 10 min twice a day for 20 weeks. From the 16th to the 20th week, they received a low-salt diet. Beginning with the 17th week, they were given 2.5 mg/day CsA or vehicle (VH) for 3 weeks. The final groups were VH/CS, CsA/CS, VH/S, and CsA/S. On day 141, glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), tubulointerstitial fibrosis, and CsA blood levels were measured and immunohistochemistry was analyzed for renal α-smooth muscle actin (SMA), nitrotyrosine, and vimentin. Results: CsA decrease in GFR was enhanced by CS exposure. CsA associated with CS induced higher periglomerular α-SMA and renal nitrotyrosine expression. CsA decreased RBF, but increased RVR, tubulointerstitial fibrosis, and α-SMA and renal vimentin expression. These changes and the CsA blood levels were not affected by CS exposure. Conclusion: CS aggravated the CsA-induced impairment of GFR and CS associated with CsA caused the development of periglomerular structural lesions and oxidative stress in a rat model of CsA nephrotoxicity.

Anti‐apoptotic and anti‐oxidant effects of grape seed proanthocyanidin extract in preventing cyclosporine A‐induced nephropathy

Although the pathogenesis of cyclosporine (CsA) nephropathy is not completely understood, it is attributed to oxidative damage and apoptosis. Grape seed proanthocyanidin extract (GSPE) is a molecule with anti-oxidant and anti-apoptotic properties. Our aim was to demonstrate the effects of GSPE in preventing CsA nephropathy. Twenty-four Sprague-Dawley rats were divided into four groups. The control, GSPE, CsA and CsA+GSPE groups were given 1 mL olive oil, 100 mg/kg GSPE, 25 mg/kg CsA and 100 mg/kg GSPE+25 mg/kg CsA, respectively. On day 21, blood samples were taken for blood urea nitrogen (BUN), creatinine and CsA levels, and renal tissue was used for total oxidant system (TOS), total anti-oxidant system (TAS), oxidative stress index (OSI) and malondialdehyde (MDA) measurements. In addition to renal histopathology, apoptosis staining was performed on renal tissue. The BUN, creatinine, TOS, OSI, MDA, histopathological score, and apoptotic index exhibited increases in the CsA group. In the CsA+GSPE group, however, BUN, creatinine, OSI, MDA, renal histopathological score and apoptotic index (AI) decreased and TAS levels increased. In addition, there was no difference between the CsA and CsA+GSPE groups with regard to CsA levels. We demonstrated that GSPE prevents CsA nephropathy and that this effect is achieved by anti-apoptotic and anti-oxidant activity. We also achieved a significant recovery in kidney functions without affecting CsA plasma levels.

Change of Cyclosporine Absorption over the Time After Kidney Transplantation

BackgroundAlthough the immunosuppressant cyclosporine (CsA) is widely used after kidney transplantation over the long term, there is still no firm consensus on the best way to monitor of CsA blood levels.ObjectivesCyclosporine (CsA) assay is critical for the management of renal transplant recipients due to inter– and intra–patient variation in CsA absorption and metabolism. Patients and Methods: In a retrospective cross sectional study, blood levels of CsA (through and 2 hours post dose) measured at least 5 times during 3 years post transplantation, in 7702 kidney transplant recipients from different transplant center of Tehran, IR Iran between 2008 and 2012. Cyclosporine absorption (CA) calculated C2/C0 ratio.ResultsCA had a significant correlation with allograft function (P = 0.000, r =.0.285), this correlation was stronger than its relationship with C0 and C2 blood levels (P = 0.000 and P = 0.000 as well as r = 0.033 and r = 0.090, respectively). In univariate analysis during different times after transplantation, C0 and C2 blood levels significantly decreased over three years follow up (P = 0.000), (P = 0.000); While, CA reversely increases over the time (P = 0.000). In linear regression model overall CA levels had correlation with lower age of recipient (P = 0.02), hypokalemia (P = 0.001), higher level of creatinine (P = 0.02) and triglyceride (P = 0.001).ConclusionsThe present study shows that CsA absorption changes trough the post-transplant time and appears to increases over time in long–term period after kidney transplantation.

Methotrexate dose delivery is more important than ciclosporin level in graft-versus-host disease prophylaxis following T-replete reduced-intensity sibling allogeneic stem cell transplant

We investigated the contributions of methotrexate (MTX) and ciclosporin (CsA) prophylaxis to acute/chronic graft-versus-host disease (a/cGvHD) prevention following reduced-intensity conditioned allogeneic haematopoietic stem cell transplant (HSCT). Ninety-two fludarabine-melphalan sibling allo-SCT received CsA. Nine, 30 and 47 patients received no MTX, 2-3 doses and 4 doses, respectively. Cumulative CsA blood level to day 21 (CsA(21)) was calculated. Grades II-IV aGvHD incidence was 37.2%. In multivariate analysis, MTX omission and increasing donor age significantly associated with aGvHD incidence whilst MTX reduction and CsA(21) did not. Median duration of first immunosuppressive therapy (IST) for aGvHD was 68 days; duration of first IST was significantly longer in older patients but was not associated with MTX or CsA(21). Extensive cGvHD incidence was 60.6% at 1 year. Reduction of MTX to 2-3 doses, but not MTX omission or CsA(21), was associated with greater incidence of cGvHD affecting ≥3 organs. Median IST duration was 22 months; neither MTX nor CsA(21) influenced this. IST duration was significantly greater in patients receiving a CD34 dose below median. Neither MTX nor CsA(21) altered survival or relapse outcomes. MTX influences GvHD following T-replete RIC sibling HSCT.

Sirolimus-based regimen is associated with decreased expression of glomerular vascular endothelial growth factor

Sirolimus (SRL) is a potent immunosuppressant used in organ transplantation. It is known to decrease vascular endothelial growth factor (VEGF) synthesis, making it an interesting treatment option for transplant patients who develop Kaposi sarcoma or other malignant diseases. Because VEGF plays a key role in glomerular function and vascular remodelling, we determined the effect of SRL on renal VEGF expression. Using immunohistochemistry and quantitative image analysis, we examined renal VEGF expression in routine kidney biopsies performed at 1 year post-transplant in the CONCEPT study, a prospective randomized study comparing a cyclosporine (CsA)-based regimen to a SRL-based regimen in association with mycophenolate mofetil (MMF). A total of 74 patients were included in this substudy; 35 were randomized to the CsA group and 39 to the SRL group. Using continuous variables, the mean percentage of glomerular VEGF expression at Week 52 was significantly lower in the SRL group (14.7 ± 13%) compared to CsA group (21.2 ± 14%: P = 0.02). The percentage of glomerular VEGF expression at Week 52 was not influenced by recipient or donor age, gender, renal function, CsA dose, CsA blood level, SRL dose or SRL blood level. It was significantly lower in patients with a proteinuria over versus below 0.5 g/day (11.58 ± 7.9 versus 19.45 ± 15.53; P = 0.036). There is emerging evidence that the VEGF system can play either a beneficial or a detrimental role depending on the specific pathologic situations. Therefore, modulating the renal VEGF axis by using an SRL-based regimen may influence the evolution of kidney injury associated with renal transplantation.

Therapeutic drug monitoring of cyclosporine microemulsion in interstitial pneumonia with dermatomyositis

The prognosis of dermatomyositis (DM)-associated progressive interstitial pneumonia (IP) has recently been improved by steroids/cyclosporine-A (CSA) combination therapy, but treatment outcomes varied. One reason for this variation is thought to be differences in CSA regimen. There is marked interpatient variability in CSA absorption. However, the pharmacokinetics of CSA has rarely been studied. In this study, we calculated the area under the blood concentration–time curve (AUC) of CSA microemulsion in 15 patients with progressive IP complicating DM, and analyzed its correlation with CSA levels at blood sampling time points to investigate the optimum monitoring and dosing regimen. The highest correlation between AUC0–6 and blood level of CSA was observed 2 h (C2) after drug administration (R = 0.910). The trough level (C0) was not correlated with AUC0–6 (R = 0.052). There were no differences in blood levels (AUC0–6, C2, and C6) between postprandial administration in a divided dose (CSA given twice daily) and preprandial administration once daily in a single dose, while C0 was significantly lower (P = 0.020) when the drug was administered once daily before breakfast. These findings suggest that measurement of CSA blood level, especially C2 and C0, is useful to monitor clinical and adverse effects of CSA during combination therapy. It is also suggested that preprandial, once daily administration of CSA is beneficial in DM patients with progressive IP.

Therapeutic drug monitoring of cyclosporine microemulsion in interstitial pneumonia with dermatomyositis

The prognosis of dermatomyositis (DM)-associated progressive interstitial pneumonia (IP) has recently been improved by steroids/cyclosporine-A (CSA) combination therapy, but treatment outcomes varied. One reason for this variation is thought to be differences in CSA regimen. There is marked interpatient variability in CSA absorption. However, the pharmacokinetics of CSA has rarely been studied. In this study, we calculated the area under the blood concentration-time curve (AUC) of CSA microemulsion in 15 patients with progressive IP complicating DM, and analyzed its correlation with CSA levels at blood sampling time points to investigate the optimum monitoring and dosing regimen. The highest correlation between AUC(0-6) and blood level of CSA was observed 2h (C2) after drug administration (R=0.910). The trough level (C0) was not correlated with AUC(0-6) (R=0.052). There were no differences in blood levels (AUC(0-6), C2, and C6) between postprandial administration in a divided dose (CSA given twice daily) and preprandial administration once daily in a single dose, while C0 was significantly lower (P=0.020) when the drug was administered once daily before breakfast. These findings suggest that measurement of CSA blood level, especially C2 and C0, is useful to monitor clinical and adverse effects of CSA during combination therapy. It is also suggested that preprandial, once daily administration of CSA is beneficial in DM patients with progressive IP.

Can Cyclosporine Blood Level Be Reduced to Half After Heart Transplantation?

BackgroundCyclosporine (CsA) is widely used after heart transplantation. The purpose of this prospective randomized study was to evaluate the safety and efficacy of reduction of CsA blood level to one-half of the traditional blood concentration under a regimen of everolimus (EVL), CsA, and steroid. Materials and MethodsThis prospective, 6 month, randomized, open-label study included adult (aged 18 to 65 years) recipients of a primary heart transplant with serum creatinine ≤2.8 mg/dL. Among 52 patients who underwent heart transplantation from December 2004 to March 2006 we excluded those who were hepatitis B or C carriers, who were recipients of organs from donors >60 years old, had cold ischemia time >6 hours, or had plasma renin activity ≥25%. All patients received CsA (C2 blood level 1000–1400 ng/mL), EVL (C0 target 3–8 ng/mL), and corticosteroids to day 60, before random entry into one of 2 groups: SE (C2 blood level from days 60–149 = 800–1200 ng/mL, and days 150–180 C2 = 600–1000 ng/mL), or RE group with CsA reduced by one-half after 3 months (days 90–149 C2 = 400–600 ng/mL, and from days 150–180 C2 = 300–500 ng/mL). ResultsThe 25 recipients eligible for this study included 13 patients in the SE and 12 in the RE group. There was no operative mortality in either group. No death or graft loss was noted within 6-months in either group. Mean serum creatinine at month 6 tended to be lower in the RE cohort (1.23 ± 0.44 mg/dL versus 1.55 ± 0.85 mg/dL; P = .093). Biopsy-proven acute rejection ≥ grade 3A was observed in only 1 patient (7.7%), who was in the SE group. There were no acute rejection episodes associated with hemodynamic compromise. The incidences of adverse events in each group were similar. ConclusionsConcentration-controlled EVL (C0 target 3–8 ng/mL) in combination with reduced CsA exposure of one-half the usual concentration achieved good efficacy and safety over 6 months. The renal function at 6 months among the RE group showed a trend toward improvement, suggesting a benefit of halving the target CsA blood level after heart transplantation.

The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

Trough- or 2-h post-dose (C2) blood cyclosporine (CsA) concentrations are used for prediction of efficacy and toxicity of CsA in transplant recipients concomitantly treated with antiproliferative agents, but information on utility of blood CsA levels in patients treated with proliferation signal inhibitors (PSIs), such as everolimus, is sparse. Because of the inhibitory effect of PSIs on the P-glycoprotein drug efflux pump present in lymphocytes, we hypothesized that CsA pharmacokinetics in blood and lymphocytes were dissociated in patients concomitantly treated with everolimus. Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). There was a highly significant correlation between blood CsA C2 levels and blood CsA AUC(0-12) in groups of patients treated with MMF or everolimus (R(2) 0.93 and 0.96, respectively; P < 0.001 for both). Whereas blood CsA C2 levels were closely associated with lymphocyte CsA AUC(0-12) in patients treated with MMF (R(2) = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24). Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.