Blood CsA Concentrations Research Articles

Pharmacodynamic monitoring of cyclosporine A by NFAT‐regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients

Pharmacokinetic monitoring of CsA is unsatisfactory, because at comparable CsA blood concentrations, the frequency and severity of adverse effects vary considerably among patients. We have therefore recently developed a precise, reliable, and robust whole-blood pharmacodynamic assay that measures the suppression of CsA-target genes in T lymphocytes. Because of the different characteristics of CsA pharmacokinetics in children and the higher propensity for infectious complications, this assay requires validation in the pediatric patient population. We therefore quantified in a prospective study of 45 pediatric renal transplant recipients the residual expression of NFAT-regulated genes in lymphocytes by RT-PCR and correlated these findings with the frequency of recurrent infections in the maintenance period post-transplant. Patients with recurrent infections showed a significantly stronger inhibition of NFAT-regulated gene expression (18.2%) than patients without recurrent infections (31.7%; p = 0.012). This difference was specific, because various PK parameters of CsA and the concomitant immunosuppressive therapy were comparable between patients. Multivariate regression analysis showed that patient age and residual NFAT-regulated gene expression were the only independent determinants of recurrent infections. By ROC curve analysis, a cutoff value of 23% residual NFAT-regulated gene expression had the highest sensitivity (71.1%) and specificity (65.4%) for the discrimination of patients with and without recurrent infections. Pharmacodynamic monitoring of CsA by measurement of residual NFAT-regulated gene expression in T lymphocytes has the potential to identify over-immunosuppressed pediatric renal transplant recipients and is therefore a useful tool for the optimization of CsA therapy.

Low-Dose Cyclosporine Treatment in Chinese Nephrotic Patients With Idiopathic Membranous Nephropathy: An Uncontrolled Study With Prospective Follow-up

IntroductionThe optimal dose of cyclosporine A (CsA) in treatment of nephrotic proteinuria in idiopathic membranous nephropathy (IMN) remains inconclusive. We evaluated the efficacy and safety of low-dose CsA combined with low-dose prednisone as induction therapy for Chinese nephrotic patients with IMN. MethodsWe conducted a prospective observational cohort study in 18 patients with IMN and nephrotic proteinuria. Twelve patients were refractory to other immunosuppressive therapies. The initial dose of CsA was 1 to 1.5mg/kg/d combined with 0.15 to 0.50mg/kg/d prednisone. The dose of CsA was adjusted monthly by 20% to 30% according to efficacy and the 12-hour trough blood concentration (C0) of CsA around 100 ng/mL for 6months; when proteinuria was <1 g/d, CsA was tapered gradually to a dose of 0.6 to 1mg/kg/d. ResultsTwo patients discontinued CsA because of refractory hypertension. The remaining 16 patients had been followed up for 44 ± 15 weeks. Remission was observed in 11 patients (68.8%: complete remission, 6 and partial remission, 5). The effective dose of CsA for remission was 2.1 ± 0.4 (1.5–2.5) mg/kg/d, and the mean C0 of CsA was 92.5 ± 23.5 (58–124) ng/mL. All the 16 patients experienced well-controlled adverse effects, including hypertension (n=12), hyperuricemia (n=12), increase of serum creatinine (n=2), etc. ConclusionsLow-dose CsA combined with low-dose prednisone was effective and safe as induction therapy in majority of Chinese nephrotic patients with IMN, including those refractory to other immunosuppressive regimens.

Paricalcitol attenuates cyclosporine-induced kidney injury in rats

Despite its benefits, the clinical use of cyclosporine A (CsA) is limited by its nephrotoxic properties. Because paricalcitol (19-nor-1,25-hydroxyvitamin D(2)) has renoprotective effects, we tested whether it can blunt renal dysfunction and fibrosis in a rat model of CsA-induced nephropathy. Treatment with CsA decreased creatinine clearance, increased monocyte/macrophage infiltration, and increased the expression of inflammatory cytokines within the kidney. Paricalcitol reduced the decline in kidney function and pro-fibrotic changes and also blunted the increased transforming growth factor (TGF)-beta1 expression and Smad signaling. Using an in vitro model, we treated HK-2 cells with CsA and found that paricalcitol attenuated the CsA-induced increases in phosphorylated extracellular signal-regulated and c-Jun N-terminal kinases, and also prevented the activation of nuclear factor-kappaB. Paricalcitol effectively prevented TGF-beta1-induced epithelial-to-mesenchymal transitions and extracellular matrix accumulation as evidenced by attenuated collagen deposition and fibrosis in CsA-treated rats. In addition, paricalcitol decreased the number of TUNEL-positive nuclei and reduced the expression of pro-apoptotic markers in CsA-treated HK-2 cells. Thus, paricalcitol appears to attenuate CsA-induced nephropathy by suppression of inflammatory, pro-fibrotic, and apoptotic factors through inhibition of the nuclear factor-kappaB, Smad, and mitogen-activated protein kinase signaling pathways.

Long-term follow-up of co-administration of diltiazem and cyclosporine in Chinese kidney transplant recipients

Background: Co-administration of diltiazem and cyclosporine A (CsA) in kidney transplant recipients shows improvement of renal transplantation outcomes. Methods: We respectively analyzed 1531 kidney transplant recipients treated by different immunosuppressive therapy schemes from 1986 to 2003. They were divided into three groups depending on their immunosuppressive therapy schemes: control group with a standard triple therapy without use of diltiazem; study group I with the combination of diltiazem and the standard triple therapy but slightly low CsA; study group II with combination of diltiazem and a modified standard triple therapy but lower CsA. The CsA blood concentrations, posttransplant complications, and long-term survival in the three groups were compared. Results: The results showed that the patient and allograft survival in the study group II was 69.9 and 65.1%, respectively, significantly higher than that in the control group (50.7 and 47.6%). Occurrence of hepatotoxicity and nephrotoxicity episodes was higher in the control group than those in the study group I and the study group II. The incidence of acute rejection in the control group was 30.3% (23/76), similar to 28.0% (184/657) in study group I, but statistically significantly higher than 7.6% (61/798) in the study group II. Conclusion: Combination of diltiazem and CsA in the kidney allograft recipients tends to reduce the CsA oral dosage, improve patient survival, and decrease the occurrence of hepatotoxicity and nephrotoxicity.

Computer-Assisted Cyclosporine Dosing Performs Better Than Traditional Dosing in Renal Transplant Recipients: Results of a Pilot Study

Cyclosporine A (CsA) is widely used after organ transplantation. Its narrow therapeutic window and large pharmacokinetic variability makes therapeutic drug monitoring (TDM) demanding and frequent dose adjustments are needed, especially early after transplantation. The aim of the present pilot study was to compare accuracy of CsA TDM by experienced clinicians against a computer-assisted dosing model. Renal transplant recipients on CsA, prednisolone, and mycophenolate were included 2 weeks after transplantation, randomized (1:1) to either computer dosing (MAP-BE) or control (CONTR) and followed for at least 8 weeks. A maximum a posteriori probability Bayesian estimation method, applying a population pharmacokinetic model and the POSTHOC option in nonlinear mixed effects modeling, was used to individualize CsA doses in the MAP-BE group. Forty patients (31 men, 27.5% living donor) between 28 and 80 years were included. A total of 798 CsA concentration measurements and adherent dosing evaluations/adjustments were performed. During the entire study, blood concentrations were on average 10% +/- 5% from the predefined therapeutic target range in the MAP-BE group, as compared with 13% +/- 8% in the CONTR group (P = 0.042). However, there was no significant difference between groups regarding the percentage of CsA concentrations truly within the therapeutic windows [MAP-BE: 37% +/- 17%, CONTR: 33% +/- 15% (P = 0.57)] or in CsA dose [MAP-BE: 3.55 +/- 0.8, CONTR: 3.90 +/- 0.9 mg/kg/d (P = 0.26)]. Acute rejections were present in 4 and 3 patients, respectively (P = 1.00). The computer-assisted TDM-targeted CsA blood concentrations significantly better than experienced transplant physicians. A possible favorable effect on short- and long-term outcome needs to be verified in further, properly powered, clinical trials.

Cyclosporine A exposure during pregnancy in mice: effects on reproductive performance in mothers and offspring

Pregnancies after organ transplantation and under immunosuppressive treatment are associated with slightly elevated risks for obstetric and post-natal complications but can usually be managed well. However, little is known about the effects of intrauterine exposure (IUE) to immunosuppressants in the growing and adult offspring. One major issue is the potentially negative effects of immunosuppressive medication on reproduction. This study investigates the effect of exposure during pregnancy to the most commonly used immunosuppressant in organ transplantation, cyclosporine A (CsA), on the reproductive outcome in mothers and offspring. Female C57CBA-F1 mice received 0, 10, 20 or 30 mg/kg bodyweight of CsA daily by subcutaneous mini-osmotic pumps during mating and pregnancy. Blood concentrations of CsA, implantation rates, resorption rates and fetal weights were analysed. In addition, female and male mice exposed to CsA in utero were mated to unexposed partners and pregnancy outcomes were analysed. Direct maternal exposure to CsA at high doses reduced implantation rates and fetal survival. IUE to CsA reduced adolescent growth but did not affect fertility, although a reduction in birthweight was seen in offspring of females exposed to CsA in utero. CsA exposure during pregnancy correlates with impaired reproductive outcome, but offspring fertility is not affected. The cause of reduction in adolescent weight gain and low birthweight in offspring of females exposed to CsA in utero need further investigation.

Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate.

Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina. Mid-gestational (day 75 +/- 13, n= 7) and late-gestational (day 150 +/- 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, (11)C-verapamil (13.7-75.4 MBq.kg(-1)), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg.kg(-1).h(-1)). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0-9 min) under the (11)C-radioactivity concentration-time curve in the tissue (AUC(tissue)) to that in the maternal plasma (AUC(plasma)). The CsA-induced change in AUC(fetal liver)/AUC(maternal)(plasma) of (11)C-radioactivity significantly increased from mid- (35 +/- 25%) to late gestation (125 +/- 66%). Likewise, the CsA-induced change in AUC(maternal brain)/AUC(plasma) increased from mid- (172 +/- 80%) to late gestation (337 +/- 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating (11)C-verapamil metabolites were significantly affected by gestational age. P-gp activity at the blood-brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy.

Life-Threatening Complications Suspected Due to Clinical Pharmacokinetic Interaction Between Cyclosporine A and Triazole Antifungal Agents in Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Recipients.

Abstract 4319 BackgroundIt is well documented that the co-medication with the triazole antifungal agents is associated with a flattening of the CSA blood concentration profile via the cytochrome P450 3A4 dependent metabolic pathway in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Then it raises the question if the therapeutic monitoring of CsA trough levels is sufficient enough to reflect the drug exposure and to assess the transplant-related complications such as transplant rejection and drug toxicity. ObjectivesTo evaluate the tolerability, toxicity and clinical outcome of the co-administration of CSA and triazole antifungal agents in allo-HSCT recipients. Patients and methodsA retrospective review of the medical records of 104 consecutive patients undergoing allo-HSCT for hematologic malignancies at our transplant center over past 5 years was conducted. The causality of administration of CSA in combination with triazole in 12 cases with life-threatening complications experiencing supratherapeutic trough levels of CSA were identified and analyzed. ResultsIn all these 12 patients, the CSA trough levels remained highly than therapeutic range even after gradual tapering of CSA dosage. Shortly after the engraftment, 6 patients (50 %) developed acute graft-versus-host disease (aGVHD) and non-infectious pulmonary complication, and 2 patient (16.66 %) acute graft rejection. Which indicates the trough plasma concentration might be inadequately reflect CSA absorption profile. Whereas, 4 (33.33 %) patients were evaluated with neurological complications, 1 (8.33%) patient cardiovascular complication accompanied by acute renal failure and liver dysfunction, that might be ascribed to CSA-related adverse effects. 10 (83.33 %) out of the 12 patients eventually died, 2 (16.66 %) patient are still alive after graft rejecting. The major causes of death were GVHD related pulmonary injury with fungi infection ConclusionAlthough preemptive CSA dosage reduction and the close monitoring of its whole blood trough levels may minimize the drug-toxicity when co-administration with triazole antifungal agents, the different clinical spectrum and different disease evolution post transplant in this group warn that in the set of hematopoietic cell transplantation with CSA as immunosuppression agent the individual variables influence the drug-exposure and drug-toxicity. Thereof, as clinicians we should not be mislead by trough plasma concentrations as a routine therapeutic drug monitoring in terms of CSA exposure related efficacy or toxicity, especially when CSA in combination with triazole. Disclosures:No relevant conflicts of interest to declare.

Pharmacokinetics of CsA during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation

We investigated the serial changes in the blood CsA concentration during the switch from continuous intravenous infusion to twice-daily oral administration in allogeneic hematopoietic stem cell transplant recipients (n=12). The microemulsion form of CsA, Neoral, was started at twice the last dose in intravenous infusion in two equally divided doses. The area under the concentration-time curve during oral administration (AUC(PO)) was significantly higher than the AUC during intravenous infusion (AUC(IV)) (median 7508 vs 6705 ng/ml x h, P=0.050). The median bioavailability of Neoral, defined as (AUC(PO)/DOSE(PO)) divided by (AUC(IV)/DOSE(IV)), was 0.685 (range, 0.45-1.04). Concomitant administration of oral voriconazole (n=4) significantly increased the bioavailability of Neoral (median 0.87 vs 0.54, P=0.017), probably due to the inhibition of gut CYP3A4 by voriconazole. Although the conversion from intravenous to oral administration of CsA at a ratio of 1:2 seemed to be appropriate in most patients, a lower conversion ratio may be better in patients taking oral voriconazole. To obtain a similar AUC, the target trough concentrations during twice-daily oral administration should be halved compared with the target concentration during continuous infusion.

Cyclosporine and sirolimus pharmacokinetics and drug‐to‐drug interactions in kidney transplant recipients

This study was conducted to evaluate the pharmacokinetics (pk) and drug interactions between cyclosporine (CsA) and sirolimus (SRL) in kidney transplant recipients. The morning (a.m.) and evening (p.m.) pk of CsA (4-5 mg/kg/dose) and SRL (2 mg, n = 20; 5 mg, n = 33) were evaluated on day 7 (n = 53). CsA showed circadian variation when comparing a.m. and p.m. administration [AUC: 8066 vs. 6699, P < 0.001 (CI 970.9; 1763.6); C0: 272 vs. 245, P = 0.007 (CI 7.5; 46.1)]. SRL showed dose-proportional pk. Significant and drug-to-drug concentration-dependent pk interactions were observed within a narrow concentration range for both drugs. A fivefold increase in SRL AUC (from a mean of 130 to 538 ng h/mL) was associated with a 25% increase in mean a.m. CsA AUC [7021 to 8811 ng h/mL, P = 0.037, CI (-3461.2; -118.9)] and with a 42% increase in mean p.m. CsA AUC [5386-7639, P = 0.024, CI (-4164.4; -340.7)]. A twofold increase in a.m. CsA AUC (from 5860 to 10 974 ng h/mL) was associated with a 70% increase in mean SRL AUC [223 to 380 ng h/mL, P = 0.0026, CI (-291.7; -22.8)]. A twofold increase in p.m. CsA AUC (from 4573 to 9692 ng h/mL) was associated with a 63% increase in mean SRL AUC [246 to 400 ng h/mL, P = 0.032, CI (-290.7; -16.6)]. CSA shows circadian pk regardless of sirolimus dose or blood concentration. Significant drug-to-drug interactions occur within narrow blood drug concentrations. The magnitude of the effect of CsA on SRL blood concentration is higher than that of SRL on CsA blood concentrations. These findings emphasize the need for therapeutic drug monitoring using this drug combination.

Population Pharmacokinetic Study of Cyclosporine in Patients With Nephrotic Syndrome

Cyclosporine (CsA) is widely used in the treatment of nephrotic syndrome (NS). A population pharmacokinetic (PopPK) model was developed using trough blood CsA concentration data from 106 patients with NS. The pharmacokinetic analysis was performed using NONMEM with 1-compartment linear model and first-order elimination. Proportional and additive error models were used to describe the interindividual and intraindividual variabilities, respectively. Body weight (WT), serum albumin level (ALB), and combination therapy with rifampicin were found to be the most significant covariates explaining the variability of the apparent clearance (CL/F) of CsA among patients. The final model was as follows: TVCL/F=34.1x(WT/67.6)(1.08)x(1+RFAx0.67)x(1-ALBx0.0088); TVV/F=3.5xWT; Ka=1.28 fixed; where RFA=1 with concurrent rifampicin use and 0 otherwise. The interindividual variabilities of CL/F and V/F were 18% and 27%, respectively. The residual error was 0.064 mg/L. The mean+/-SD of CL/F and V/F of the 106 patients were 23.5+/-7.2 L/h and 232.3+/-71.5 L, respectively. The reliability and stability of the PopPK model were confirmed by nonparametric bootstrap procedure.

Improvement of cyclosporine A bioavailability by incorporating ethyl docosahexaenoate in the microemulsion as an oil excipient

The aims of this study were to determine the effect of ethyl docosahexaenoate (DHA-EE) on cyclosporine A (CsA) bioavailability, while also examining the effect of DHA-EE on CsA when DHA-EE was incorporated into a microemulsion formulation as an oil ingredient. The oral co-administration of DHA-EE and CsA increased the blood CsA concentration in a dose-dependent manner, and the AUC and C(max) both increased by about 2-fold with 100mg/kg DHA-EE. The microemulsion formulation of CsA consisted of Tween-20, ethanol, water, and DHA-EE (53.3/6.5/35.9/3.3 w/w%) (namely DHA-ME) was transparent and stable with an average particle size of 50 nm, which was similar to that of the control formulation incorporating vitamin E instead of DHA-EE (namely VE-ME). The permeabilities of CsA from DHA-ME, VE-ME and Neoral formulations across an artificial membrane were not significantly different. The C(max) and AUC(0-infinity) of CsA in rats administered DHA-ME significantly increased by approximately 2-fold in comparison to that of VE-ME. The relative oral bioavailability (F(r)) of DHA-ME in comparison to Neoral was determined to be 114%, while the F(r) of VE-ME was only 60%. It was, therefore, suggested that the use of DHA-EE as an oil excipient may be promising for the development of a microemulsion formulation of CsA with an improved oral bioavailability.

Lung Deposition of a Liposomal Cyclosporine A Inhalation Solution in Patients after Lung Transplantation

Bronchiolitis obliterans is the most important long-term sequelae of lung transplantation limiting survival. Optimized immunosuppression, including inhalation of cyclosporine A (CsA), may be a promising approach to overcome this problem. In this study a liposomal CsA solution was characterized in vitro, doses of 10 and 20 mg were inhaled with the PARI eFlow inhaler by 12 stable lung transplant recipients, and lung deposition was evaluated by gamma scintigraphy. Inhalation of CsA leads to lung deposition of 40 +/- 6% (10 mg) and 33 +/- 7% (20 mg), respectively. This deposition resulted in a peripheral lung dose of 2.0 +/- 0.4 mg (10 mg) and 3.4 +/- 0.8 mg (20 mg), respectively. Extrathoracic deposition was 16 +/- 6% (10 mg) and 14 +/- 4% (20 mg), respectively, and the total deposition was calculated with 56% (10 mg) and 46% (20 mg). Lung deposition and peripheral lung deposition increased significantly with treatment time. The maximum CsA blood concentration and the area under the time course of blood concentration correlated with peripheral lung deposition. There were no statistically significant differences between patients with single- and double-lung transplantation. Inhalation of the study medication was well tolerated, and led to only minor but statistically significant changes in lung function parameters (FEV(1): -0.07 L; FVC: -0.09 L; sRaw: +0.35 kPa s.). The new liposomal CsA PARI formulation can be deposited to the peripheral lung using the PARI eFlow nebulizer. The treatment was well tolerated, and no drug-related side effects were observed. Once or twice daily dosing of 10 mg CsA A PARI would result in a sufficient peripheral lung deposition of approximately 14 and 28 mg/week, respectively.

Simultaneous PET Imaging of P-Glycoprotein Inhibition in Multiple Tissues in the Pregnant Nonhuman Primate

Studies in rodents indicate that the disruption of P-glycoprotein (P-gp) function increases drug distribution into the developing fetus and organs such as the brain. To simultaneously and serially evaluate the effect of P-gp activity and inhibition on the tissue distribution of drugs in a more representative animal model, we tested the feasibility of conducting whole-body PET of the pregnant nonhuman primate (Macaca nemestrina). We used (11)C-verapamil as the prototypic P-gp substrate and cyclosporine A (CsA) as the prototypic inhibitor. Four pregnant macaques (gestational age, 145-159 d; gestational term, 172 d) were imaged after the intravenous administration of (11)C-verapamil (30-72 MBq/kg) before and during intravenous infusion of CsA (12 or 24 mg/kg/h, n = 2 each). The content of verapamil and its metabolites in plasma samples was determined using a rapid solid-phase extraction method. The plasma and tissue time-radioactivity concentration curves of (11)C were integrated over 0-9 min after each verapamil injection. The tissue or arterial plasma area under the time-concentration curve (AUC(tissue)/AUC(plasma)) served as a measure of the tissue distribution of (11)C radioactivity. CsA effect on (11)C radioactivity distribution was interpreted as P-gp inhibition. The change in the fetal liver AUC ratio served as a reporter of placental P-gp inhibition. CsA effect on tissue distribution of (11)C radioactivity (AUC ratios) did not increase with the mean blood concentration of CsA, indicating a near-maximal P-gp inhibition. CsA increased maternal brain and fetal liver distribution of (11)C radioactivity by 276% +/- 88% (P < 0.05) and 122% +/- 75% (P < 0.05), respectively. Changes in other measured tissues were not statistically significant. These data demonstrate for the first time, to our knowledge, the feasibility of simultaneous, serial, noninvasive imaging of P-gp activity and inhibition in multiple maternal organs and the placenta in the nonhuman primate. Our findings, consistent with previous data in rodents, indicate that the activity of P-gp in the placenta and the blood-brain barrier is high and that the inhibition of P-gp facilitates drug distribution across these barriers.

Relative Bioavailability and Pharmacokinetics of Newly Designed Cyclosporin A Self-microemulsifying Formulation after Single and Multiple Doses to Dogs

The pharmacokinetics of cyclosporin A (CsA) after single and multiple oral dosing of new CsA self-micro-emulsifying drug delivery system (SMEDDS) in dogs were estimated. A single dose study was performed following a two-way crossover design against six dogs with reference SMEDDS. For a multiple dose study, three dogs were allocated for each drug, and 100 mg of drug was administered daily for 6 days. Whole blood concentration of CsA was analyzed by radio-immunoassay. Both drug showed identical blood concentration profiles in both studies, and no statistical difference was detected in pharmacokinetic parameters. The relative bioavailabilities of test SMEDDS were 91.4% and 89.1%, respectively, in the single dose study and the last day of multiple dose study. Especially, multiple dose study proved the good relationship between C-0/C-2 and AUC for reference SMEDDS, which is an indispensable part of therapeutic drug monitoring. These results suggest newly formulated CsA SMEDDS possibly shows identical pharmacokinetics and pharmacodynamic behaviors in clinical trials.

Individual Differences in Cyclosporine A Pharmacokinetics and Its Association with Acute Renal Function Following Heart Transplantation

Background: The secondary metabolites of cyclosporine A (CsA), AM19, AM1c and AM1c9, have been indi- cated to be nephrotoxic. The aim of the present pilot study was to investigate the relationship between acute renal failure and CsA metabolite levels, including relevant pharmacokinetic genotypes, following heart transplantation. Methods: Whole-blood samples were drawn the first posttransplant week in 22 patients (median 54 years, range from 27 to 65). Whole blood concentrations of CsA and its six main metabolites were analyzed with a validated HPLC-MS/MS method, and relevant CYP3A5 and ABCB1 genotypes determined. Renal function was monitored daily during the first posttransplant month and also at months 3, 6 and 12. Results: One patient died early posttransplant. Six patients were in need of dialysis directly after transplantation. Nine pa- tients developed sustained impaired renal function, while six had stable renal function. Sustained renal impairment tended to be associated with high levels of toxic metabolites (P=0.08). Six of the patients with possible ABCB1 TTT-haplotype developed renal impairment (P=0.12). Conclusion: The present study indicates that toxic CsA metabolites seems to be associated with development of impaired renal function and together with ABCB1 genotyping they might be promising biomarkers for optimalization of immuno- suppressive drug treatment in future studies.

Cyclosporine-Related Posterior Reversible Encephalopathy Syndrome After Heart Transplantation: Should We Withdraw or Reduce Cyclosporine?: Case Reports

Cyclosporine (CsA) related encephalopathy has not been well documented after heart transplantation. We report 2 cases of posterior reversible encephalopathy syndrome (PRES). The first case was a 68-year-old woman who underwent heart transplantation and received immunosuppression with mycophenolate mofetil, prednisone, and CsA. On day 14, she developed arterial hypertension, headache, visual disturbances, and generalized seizures. Fluid-attenuated inversion recovery magnetic resonance imaging (MRI) of the brain showed diffuse and bilateral high signals in the frontal posterior and the occipital areas. The second case was a 19-year-old man with a heart transplant receiving immunosuppression with prednisone and CsA. On day 44, he developed acute headache and generalized seizures. T2-weighted MRI of the brain showed diffuse high signals in the cerebellum, right lenticular and occipital areas. In both cases blood CsA concentration was therapeutic. Both cases recovered but in the first case neurologic findings were reversed only after CsA withdrawal.

Management of Living Donor Liver Transplant Patients Using Twice-Daily 4-Hour Intravenous Cyclosporine Therapy

Oral administration of cyclosporine (CsA) is the currently favored route in most liver transplant centers. From October 1998 to January 2008, 86 living donor liver transplantations (LDLTs) were performed in 85 patients (46 adults and 39 children) at our institution. Seventy-three patients received tacrolimus (Tac), and 12 intravenous CsA twice daily at a dose of 3 mg/kg/d as a 4-hour continuous infusion. Thirteen of 73 Tac-based patients were switched to CsA because of side effects. Five were switched to intravenous CsA because they were unable to take the drug orally because of severe Tac-related complications. The remaining eight patients switched to oral CsA. We evaluated patients (11 adults and three children), including 12 with induction therapy and two with conversion therapy within 2 weeks of LDLT. The patients were given a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d. Stable and adequate blood CsA concentrations were achieved by 4-hour intravenous CsA administration. Among several factors, only graft-to-recipient weight ratio ( r = .743, P < .0001) showed significant correlations with initial blood CsA concentration. No adverse effects were observed after intravenous CsA. No patients developed biopsy-proven acute cellular rejection (ACR) during intravenous CsA administration, whereas two patients had histopathologically diagnosed episodes of ACR after conversion from intravenous to oral CsA. Our findings suggest that immediate administration of a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d is practical and effective for routine clinical use.

Pharmacokinetics of P‐glycoprotein inhibition in the rat blood‐brain barrier

This article describes the experimental set‐up and pharmacokinetic modeling of P‐glycoprotein function in the rat blood‐brain barrier using [11C]verapamil as the substrate and cyclosporin A as an inhibitor of P‐gp. [11C]verapamil was administered to rats as an i.v. bolus dose followed by graded infusions to obtain steady‐state concentrations in the brain during 70 min. CsA was administered as a bolus followed by a constant infusion 20 min after the start of the [11C]verapamil infusion. The brain uptake of [11C]verapamil over 2 h was portrayed in a sequence of PET scans in parallel with measurement of [11C]verapamil concentrations in blood and plasma and CsA concentrations in blood. Mixed effects modeling in NONMEM was used to build a pharmacokinetic model of CsA‐induced P‐gp inhibition. The brain pharmacokinetics of [11C]verapamil was well described by a two‐compartment model. The effect of CsA on the uptake of [11C]verapamil in the brain was best described by an inhibitory indirect effect model with an effect on the transport of [11C]verapamil out of the brain. The CsA concentration required to obtain 50% of the maximal inhibition was 4.9 µg/mL (4.1 µM). The model parameters indicated that 93% of the outward transport of [11C]verapamil was P‐gp mediated. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5386–5400, 2008

Reduced Elimination of Cyclosporine A in Elderly (&gt;65 Years) Kidney Transplant Recipients

Physiologic functions that may affect pharmacokinetics of drugs are altered in elderly patients. The current study was performed to elucidate the effect of age on cyclosporine A (CsA) pharmacokinetics in renal transplant recipients. Twenty-five renal transplant recipients on CsA treatment were included in the study. CsA doses were adjusted by C2 monitoring. The patients were divided into two groups based on age; elderly: more than 65 years (n=11, mean 73 years) and younger: 18 to 64 years (n=14, mean 43 years). A full 12-hr pharmacokinetic profile was performed during stable phase. CsA whole blood and intracellular T-lymphocytes concentrations (first 6 hr) were measured. Genotyping of the CYP3A5*1/*3 and ABCB1 (C1236T, G2677T, C3435T) polymorphisms and quantification of whole blood mRNA ABCB1 expression were performed in all patients. Elderly patients achieved target C2 levels with lower CsA doses than the younger patients (4.3+/-0.8 vs. 6.1+/-2.1 mg/day/kg, P=0.025) because of lower clearance of CsA (22.7+/-5.1 vs. 30.5+/-11.1 L/hr, P=0.031). Elderly patients also showed 44% higher intracellular-to-whole blood CsA ratio than younger patients (P=0.02). Neither the CYP3A5*1, the ABCB1 genotypes nor mRNA ABCB1 expression revealed any significant influence on CsA pharmacokinetics. The clearance of CsA decreased with increasing age. In addition, elderly patients had a significant larger proportion of the whole blood CsA concentration located at the site of action (within T lymphocytes). This indicates that in elderly recipients it might be safe to aim for an even lower whole blood target levels than current guidelines propose.