Plasma Cyclosporine Research Articles

Real-Life Data of Cyclosporine (CsA) Tapering in Patients with Very/ Severe Aplastic Anemia (v/sAA) Treated with Horse Anti-Thymocyte Globulin (hATG/CsA) Suggest Higher Risk of AA Relapse at Cyclosporine Plasma Levels below 100 Nanogram per Milliliter

Introduction: Aplastic anemia (AA) is an acquired bone marrow failure syndrome (BMFS) mediated by autoreactive T-cells. In adults with severe (s) or very severe (vs) AA >40-50 years or ineligible for transplant for other reasons immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), cyclosporine A (CsA) and Eltrombopag (Epag) has recently become the actual standard of care. With CsA treatment maintained for 6 to 24 months followed by CsA tapering hematologic response is achieved in 60-70 % of AA patients (pts.), while 30-40 % are primary refractory. Approximately 40% of pts. relapse during CsA tapering and most relapsed AA pts. remain CsA dependent. In vitro data indicate a dose dependent inhibition of T cell activity induced by CsA, suggesting the presence of a therapeutic CsA threshold around 100 ng/mL (Flores et al. Front Immunol 2019). Pts. with CsA related side effects such as renal insufficiency would benefit from an established lowest efficient CsA plasma level preventing relapse and reducing CsA related toxicity. As data about correlation of CsA plasma levels and the occurrence of relapse during tapering are sparse, we analyzed data from our registries including CsA plasma levels of 20 s/vsAA pts. with and without relapse during CsA tapering after treatment with horse ATG/CsA. Methods: Descriptive retrospective analysis of 20 AA pts. (17 sAA/ 3 vsAA) from the AA-BMF/Basel AA registry treated with horse ATG/CsA and sufficient clinical data during CsA tapering. Results are given as mean ± standard deviation. Mean age of the 13 female and 7 male pts. was 53 ± 19 years. Follow-up data over 59 ±17 months were compiled between 2010 and 2023. Results: All 20 pts. achieved a hematological response i.e. partial (PR) or complete remission (CR) (as defined in Peffault de Latour et al., 2022) at 3/6/9 months after ATG as follows: PR 90%/ 75%/ 55% and CR 0%/ 20%/ 45%. Relapse of AA occurred in 60 % (12 pts.) at 24 ± 11 months after ATG, while 40 % (8 pts.) remained relapse-free during a follow up period of 59 ±17 months. In the 8 pts. without relapse, dose reduction was initiated 14 ± 6 months after ATG at a hematological response of CR in 4 pts. and PR in 4 pts. In two pts. with PR, early decrease of CsA was required due to renal insufficiency (1 month after ATG) or CsA related adverse drug reaction (4 months after ATG), respectively. The average time of CsA maintenance was 32 ± 13 months. In pts. with relapse (60%, 12 pts.), dose reduction was started after reaching best hematological response i.e. CR (9 pts.) or PR (3 pts.) at 11 ± 7 months after ATG. Relapse i.e. recurrent thrombocytopenia occurred 12 ± 9 months after start of tapering at CsA plasma levels of 44.0 ± 29.2 ng/mL and a daily CsA dosage of 1.01 ± 0.70 mg/kg. In one case, relapse occurred one month after stopping CsA. No patient with CsA levels continuously > 100 ng/mL relapsed, whereas thrombocytopenia was observed with a latency of 2.8 ± 1.6 months after first decrease below 100 ng/mL CsA in pts. with relapse. While 58% (7 pts.) of the relapsed pts. responded to salvage-therapy with CsA+Epag (age 58 ± 16 years), 42 % (5 pts.) required a second course of ATG/CsA, or transplant (age 44 ± 22 years). Conclusion: In s/vsAA pts. with hematological response to ATG/CsA, closer monitoring for relapse is recommended reaching CsA plasma levels <100 ng/mL, as CsA <100 ng/mL was associated with higher risk of relapse during CsA tapering in line with previous reported in vitro data. Pending prospective validation, CsA plasma levels >100 ng/mL might serve as threshold in pts. requiring accelerated tapering due to renal insufficiency or CsA related side effects.

Bimetallic metal–organic framework as an efficient sorbent for the extraction of tacrolimus and cyclosporine from plasma before HPLC-MS/MS analysis

This study investigated the application of pores-size protocols into metal–organic frameworks that can lead to improved adsorption capacity of sorbents. A selective, fast, and sensitive analytical procedure based on dispersive solid phase extraction using a bimetallic metal organic framework named ZrZnMOF coupled with high-performance liquid chromatography-tandem mass spectrometry was established for the simultaneous quantification of tacrolimus and cyclosporine in plasma. The effects of several parameters, such as the dosage of sorbent, separation and elution times, volume and type of elution solvent, were investigated. Under optimal conditions, high extraction recovery (70 and 89 for tacrolimus and cyclosporine, respectively), low limits of detection (0.15 and 0.31 μg L-1 for tacrolimus and cyclosporine, respectively) and quantification (1.0 and 0.51 μg L-1 for tacrolimus and cyclosporine, respectively) wide linearity (1.0–1000 and 0.51–500 μg L-1 for tacrolimus and cyclosporine, respectively), and acceptable repeatability (n = 5, relative standard deviation less than 5.6 %) were attained. The validated method was successfully applied to quantify tacrolimus and cyclosporine A in plasma samples obtained from different volunteers.

Advanced oxidation protein products upregulate ABCB1 expression and activity via HDAC2-Foxo3α-mediated signaling in vitro and in vivo

The unpredictable pharmacokinetics of non-renal cleared drugs in chronic kidney disease (CKD) patients is associated with the activity of drug transporters. However, the mechanisms underlying regulation of drug transporters are yet to be established. In this study, we demonstrated the involvement of a HDAC2-Foxo3α pathway in advanced oxidation protein products (AOPPs)-induced ATP-binding cassette subfamily B member 1 (ABCB1) expression and activity. The correlation of AOPPs accumulation with concentration of cyclosporine in plasma was evaluated in 194 patients with transplantation. Molecular changes in acetylation of various histones and related regulatory molecules were examined in HepG2 cell cultures treated with AOPPs. Accumulation of AOPPs in serum in relation to molecular changes in HDAC2-Foxo3α in vivo were evaluated in 5/6 nephrectomy (5/6 nx) and oral adenine (Adenine) CKD rat models. Interestingly, the cyclosporine level was negatively correlated with AOPPs in plasma. In addition, AOPPs markedly suppressed the expression of histone deacetylase 2 (HDAC2), inducing ABCB1 expression and activity in vitro and in vivo. Importantly, AOPPs modulated phosphorylation of Foxo3α and the upstream Akt protein. Our findings indicate that AOPPs regulate the expression and activity of ABCB1 via reducing HDAC2 expression and activating Foxo3α-dependent signaling. The collective results support the utility of AOPPs as a potential target for drug and/or dosage adjustment in CKD patients. Targeting of AOPPs presents a novel approach to regulate non-renal clearance.

First known case of catatonia due to cyclosporine A-related neurotoxicity in a pediatric patient with steroid-resistant nephrotic syndrome

BackgroundCatatonia is a neuropsychiatric syndrome characterized by diverse psychomotor abnormalities, including motor dysregulation and behavioral and affective disturbances. Once thought to occur primarily in the context of schizophrenia, recent data suggest most cases of catatonia develop in individuals with depressive or bipolar disorders. Moreover, catatonia may ensue in general medical and neurological conditions, as well as due to a variety of pharmaceuticals, drugs of abuse, and toxic agents. At one time considered rare in pediatric patients, evidence now suggests catatonia is both underrecognized and undertreated in this population, where it carries an elevated risk of morbidity and mortality. Here we present the case of a child with steroid-resistant nephrotic syndrome who developed catatonia due to cyclosporine A-related neurotoxicity.Case presentationA 9-year-old African-American boy with no psychiatric history and a 9-month history of nephrotic syndrome due to focal segmental glomerulosclerosis was admitted to the local children’s hospital for management of mutism, posturing, insomnia, gait abnormalities, and somatic delusions. Seven days prior to admission, his cyclosporine plasma concentration was elevated at 1224 ng/mL (therapeutic range: 100–200 ng/mL). Upon admission, cyclosporine was discontinued and psychiatry was consulted, diagnosing catatonia. The patient subsequently received propofol 80 mg IV resulting in a transient lysis of catatonia. Over a lengthy hospitalization, the patient’s catatonia was initially treated with lorazepam, quetiapine being added later to target psychosis. All signs and symptoms of catatonia resolved, and the patient was eventually tapered off both lorazepam and quetiapine with no return of symptoms more than 6 months later.ConclusionsTo our knowledge, this case represents the first reported instance of cyclosporine A-induced catatonia in a patient with steroid-resistant nephrotic syndrome. It illustrates the importance of maintaining vigilance for signs and symptoms of cyclosporine A-related neurotoxicity (including catatonia) in patients with steroid-resistant nephrotic syndrome. In addition, it highlights the challenges faced by clinicians in jurisdictions that prohibit the use of electroconvulsive therapy in pediatric patients.

Evaluation of Cyclosporine Pharmacokinetic, Monitoring, and Dosing Parameters for GVHD Prophylaxis in Hematopoietic Stem Cell Transplant (HSCT) Recipients.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a major method of treatment for different hematologic and congenital disease. Graft versus host disease (GvHD) is a life-threatening adverse effect of AHSCT. Cyclosporine is the most important and common agent for GvHD prophylaxis. Because of variable and unpredictable pharmacokinetics of cyclosporine that produces different responses in each patients group and clinical setting, there are still lots of uncertainties about its optimal method of administration and monitoring of this drug. Frequent blood samples in eight different times were taken for cyclosporine quantification in twenty AHSCT recipients and pharmacokinetic parameters determined in both intravenous (IV) and oral administration and monitoring parameters assessed accordingly. Of pharmacokinetic parameters mean ± SD area under concentration – time curve (AUC), clearance, and half-life were estimated to be 5492 ± 1596 ng.h/mL, 19.44 ± 6.61 L/h, and 11.8 ± 5.4 h for IV and 7637.7 ± 2739.8 ng.h/mL, 19.42 ± 6.62 L/h, and 11.16 ± 5.9 h for oral administration, respectively. Appropriate oral to intravenous dosing ratio found to be about 1.6. Of monitoring parameters, C0.5 h and C6 showed the highest coefficient of determination for regression between single points and total area under curve. Evaluation of pharmacokinetic parameters derived from concentration versus time curve showed that the appropriate oral/IV is 1.6 for maintenance GvHD prophylaxis for outpatients could be helpful. Cyclosporine plasma concentration at 0.5 and 6 h after IV administration showed the highest correlation with AUC of this drug.

Comparison of three estimators for determining cyclosporine dosing in infants after liver transplantation .

To compare and analyze how allometrically- and linearly-scaled daily doses of cyclosporine could affect the therapeutic drug monitoring concentrations when applied to 8 infants with liver transplants. Eight infants who underwent liver transplantations were put on twice-daily oral cyclosporine immunosuppressive regimens. After starting therapy, the adjustments of individual daily doses were determined by using therapeutic monitoring of plasma cyclosporine levels by measuring trough concentrations (C₀) and concentrations at 2 hours after drug administration (C₂). These doses were analyzed and compared with the hypothetical doses estimated by allometric and linear scaling in order to compare which of the two methods would yield closer estimates to the actual doses applied. The median therapeutic drug monitoring (TDM)-based dose (n=53) was 70.00 mg (10.9 mg/kg/day) (5.00-190.00 mg), whereas the median allometric (n=53) and linear (n=53) doses were 65.21 mg (10.11 mg/kg/day) (57.17-79.25 mg) and 35.63 mg (5.52 mg/kg/day) (29.89-46.20 mg), respectively. The median allometric dose was significantly different than the median linear dose (p<0.0001), whereas there was no statistical difference between the median TDM-based dose and median allometric dose (p=0.72). The allometric approach, when used to estimate cyclosporine doses in this cohort of liver transplant infants, yielded closer estimates to actually applied daily doses in comparison to linear scaling. Allometric scaling could be employed in calculating starting doses for drugs that lack specific dosing recommendations for infants, in order to achieve therapeutic levels faster, lowering the need for constant monitoring and dose adjustment. .

Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I

Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer≤3200 after 24weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20mg/kg/day), azathioprine (initial dose: 2.5 or 5mg/kg/day) and low-dose laronidase infusions (0.058–0.29mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58mg/kg/week) for 24weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment. Clinical Trial Registration: NCT00741338.

The effect of CYP3A5 polymorphism on cyclosporine plasma level in Egyptian renal transplant recipients

Cyclosporine (CsA) and tacrolimus are immunosuppressants used for the prevention of rejection of transplanted organs. The genes encoding cytochrome (CYP) P450 enzymes, CYP3A4, and CYP3A5 are the main ones involved in the pharmacokinetics of calcinurin inhibitors (CNI). Several single nucleotide polymorphisms were identified in these genes such as CYP3A5*3 (6986A>G). The association of the CYP3A5*3/*3 genotype with decreased clearance of its substrates was reported among different ethnic populations. This study aims to evaluate the effect of CYP3A5*3 polymorphism on CsA plasma levels in Egyptian renal transplant patients at the first week and first month of transplantation. A total of 44 renal transplant recipients receiving CsA were genotyped for CYP3A5*3 polymorphism. The C0 and C2 of CsA were measured and their relationships with CYP3A5*3 genotypes were investigated. CYP3A5*3 allele was present in six patients and the CsA level didn’t differ significantly between the CYP3A5*3 the CYP3A5*1 allele carriers at the first week and the first month post transplantation. Large-scale studies with the involvement of multiple genetic markers claimed to affect the CsA pharmacokinetics are highly recommended to elucidate their pharmacogenetic role in renal transplant patients.

Oral Cyclosporine Treatment in Dogs: A Review of the Literature

Cyclosporine is an immunomodulatory drug used to treat an increasing spectrum of diseases in dogs. Cyclosporine is a calcineurin inhibitor, ultimately exerting its inhibitory effects on T‐lymphocytes by decreasing production of cytokines, such as interleukin‐2. Although, in the United States, oral cyclosporine is approved in dogs only for treatment of atopic dermatitis, there are many other indications for its use. Cyclosporine is available in 2 oral formulations: the original oil‐based formulation and the more commonly used ultramicronized emulsion that facilitates oral absorption. Ultramicronized cyclosporine is available as an approved animal product, and human proprietary and generic preparations are also available. Bioavailability of the different formulations in dogs is likely to vary among the preparations. Cyclosporine is associated with a large number of drug interactions that can also influence blood cyclosporine concentrations. Therapeutic drug monitoring (TDM) can be used to assist in attaining consistent plasma cyclosporine concentrations despite the effects of varying bioavailability and drug interactions. TDM can facilitate therapeutic success by guiding dose adjustments on an individualized basis, and is recommended in cases that do not respond to initial oral dosing, or during treatment of severe, life‐threatening diseases for which a trial‐and‐error approach to dose adjustment is too risky. Pharmacodynamic assays that evaluate individual patient immune responses to cyclosporine can be used to augment information provided by TDM.

Pharmacokinetic Characterization of Intravenous Cyclosporine Treatment for Cardioprotection During Resuscitation of Asphyxiated Newborn Piglets

Cyclosporine treatment, as a single intravenous bolus, during resuscitation has been shown to attenuate myocardial injury in asphyxiated newborn piglets. However, the pharmacokinetics of cyclosporine treatment for cardioprotection in newborns has not been studied. We aimed to assess the pharmacokinetics of a single intravenous cyclosporine treatment during resuscitation of asphyxiated newborn piglets and compare these parameters with healthy newborn piglets. Newborn piglets were acutely instrumented and normocapnic alveolar hypoxia was induced for 2 hours followed by 4 hours of reoxygenation. Piglets were block-randomized to receive a single intravenous bolus of cyclosporine (2.5-25 mg/kg) (n = 8 per group). Eight piglets underwent no hypoxia-reoxygenation and received 10 mg/kg cyclosporine at the corresponding time point. Plasma cyclosporine and troponin concentrations during reoxygenation period were determined by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. Noncompartmental methods were used to calculate the pharmacokinetic parameters. Cyclosporine concentrations and pharmacokinetic parameters were analyzed by one-way analysis of variance. University animal laboratory. Piglets (1-4 days old, weighing 1.4-2.5 kg). Intravenous cyclosporine (2.5, 10, or 25 mg/kg) given during resuscitation. In the hypoxic-reoxygenated piglets, the plasma AUC(0-4 hrs) and C(max) of cyclosporine at reoxygenation were in the following rank order: 25 > 10 > 2.5 mg/kg treatment (p < 0.001 between groups, analysis of variance). Plasma AUC(0-4 hrs) and C(max) in piglets treated with cyclosporine at 25 mg/kg was associated with increased plasma troponin levels, a marker of myocardial injury, relative to piglets treated with 2.5 and 10 mg/kg. Asphyxiated newborn piglets had higher clearance and lower AUC(0-∞), but similar AUC(0-4 hrs), steady-state volume of distribution, and mean residence time compared with those of healthy newborn piglets. This is the first study to demonstrate the pharmacokinetics of intravenous cyclosporine treatment during resuscitation of asphyxiated newborn piglets, which did not appear to different from that of healthy piglets.

Effects of powdered whole grapefruit and metoclopramide on the pharmacokinetics of cyclosporine in dogs

To determine whether oral administration of metoclopramide or a commercially available powdered whole grapefruit (PWG) nutraceutical in combination with cyclosporine enhances systemic availability of cyclosporine in dogs. 8 healthy mixed-breed dogs in part 1 and 6 of these 8 dogs in part 2. Cyclosporine pharmacokinetics were determined over the course of 24 hours after oral administration of cyclosporine (5 mg/kg) alone, cyclosporine with metoclopramide (0.3 to 0.5 mg/kg), cyclosporine with 2 g of PWG, or cyclosporine combined with both metoclopramide and 2 g of PWG by use of a Latin square crossover study with a 14-day washout period between treatments. Sixty days later, 6 of the 8 dogs were given 10 g of PWG followed by cyclosporine, and pharmacokinetic parameters were compared with those previously obtained after administration of cyclosporine alone. Although metoclopramide or coadministration of metoclopramide and 2 g of PWG had no effect on the pharmacokinetic parameters of cyclosporine, compared with results for cyclosporine alone, the higher (10-g) dose of PWG resulted in 29% faster mean time to maximal plasma cyclosporine concentration, 54% larger area under the curve, and 38% lower apparent oral clearance. Adjustment of the cyclosporine dose may not be needed when metoclopramide is coadministered orally to prevent common adverse effects of cyclosporine. Powdered whole grapefruit has the potential to reduce the required orally administered dose of cyclosporine but only when PWG is used in an amount (at least 10 g) that is currently not cost-effective.

A new method for measuring the free fraction of cyclosporin in plasma by equilibrium dialysis.

The free fraction of cyclosporin in plasma has been measured by equilibrium dialysis in steel chambers. Equilibration time was 16 h. The intra-assay coefficient of variation was 7%. The free fraction remained constant in plasma samples frozen for up to 6 months, and was independent of the total concentration within the therapeutic range.

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Intrarenal activation of renin angiotensin system in the development of cyclosporine A induced chronic nephrotoxicity

The relationship between cyclosporine-induced chronic nephrotoxicity (CAN) and renin-angiotensin II in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin II (ANGII) both in renal tissue and plasma from kidney transplantation patients suffering from CAN. Twenty-six patients with allograft biopsy-proven CsA-related chronic nephrotoxicity (CAN group) and chronic rejection (control group) were enrolled in this study. Renal tissues were subjected to immunohistochemical staining with renin and ANGII antibodies. Renin and ANGII plasma levels were measured when the biopsy was performed. The relationship between expression of renin or ANGII and clinicopathological manifestations were also investigated. The cyclosporine plasma level was obtained 2 hours after morning dose (C2). In vitro, human umbilical vein endothelial cells (HUVEC) and rat mesangial cells (MC) were incubated with different concentrations of CsA (0, 250, 500, 1000 microg/L) for 24 hours. Secretion and expression of renin and ANGII was measured by radioimmunoassay or immunohistochemical staining. Renal pathological scores for renin and ANGII expression were significantly higher in specimens of CAN than in controls (P < 0.05). The plasma levels of renin, ANGII and C(2) in the CAN group were higher than the control group, but no significant difference was found ((0.37 +/- 0.12) ng x ml(-1)x h(-1) vs (0.20 +/- 0.10) ng x ml(-1) x h(-1), P = 0.076; (122.69 +/- 26.73) pg/ml vs (121.88 +/- 36.35) pg/ml, P = 0.977; (719.04 +/- 55.89) ng/ml vs (658.80 +/- 90.78) ng/ml, P = 0.196, respectively). In vitro, renin as well as ANGII expression increased significantly in both HUVEC and MC after the cells were incubated with CsA for 24 hours (P < 0.05). CsA also stimulated the secretion of ANGII in HUVEC and MC in a dose-dependent manner. Renal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The intrarenal renin angiotensin system plays an important role in CsA-related chronic nephropathy. The histological lesions of CsA nephrotoxicity fail to correspond spontaneously to either the change of C2 level or the change of renin and ANGII plasma level. CsA stimulates the secretion of ANGII and the expression of renin and ANGII in HUVEC and MC. Blockage of RAS may be helpful for therapeutic intervention in the progression of CsA-related chronic nephropathy.

Remission of steroid- and CyA-resistant nephrotic syndrome using multiple drug immunosuppression

Nephrotic proteinuria in minimal change disease (MCD) is supposed to be due to a circulating factor of immunologic origin. End-stage renal failure occurs if both steroids and immunosuppressive drugs remain ineffective. Three children (2 years, 3 years, and 6 years of age) with secondary steroid-resistant nephrotic syndrome (NS) were included, as they remained resistant to 30 days of treatment with prednisone (60 mg/m(2) per day), three pulses of methylprednisolone (1 g/1.73 m(2)) followed by oral administration of CyA 7.5 mg/kg per day over 2 months, and 1 month of intravenous (i.v.) administration of cyclosporine (blood level 500-600 ng/ml). All three patients were partially responsive to methylprednisolone pulses, with an increase of serum albumin by 100%. They were treated with plasma exchanges, cyclophosphamide and cyclosporine A, both given orally, pefloxacin and methylprednisolone pulses followed by orally administered prednisone. All three patients went into remission within 2 to 5 weeks. The character of their NS changed to a steroid-sensitive one. There were no significant side effects from the therapy. They had normal renal function, normal blood pressure and no residual proteinuria. A combination of plasmapheresis and multiple immunosuppressive medications was effective in producing remission of minimal change NS in three children who were previously resistant to glucocorticoids and cyclosporine.

No Kinetic Interaction Between Levetiracetam and Cyclosporine: A Case Report

Levetiracetam is a new antiepileptic drug reported to be effective and well-tolerated in adults and children affected by epilepsy. Its lack of hepatic cytochrome metabolism is the theoretic basis for the absence of interactions with other drugs that follow this pathway. We present a 14-year-old girl who underwent orthotopic heart transplantation, followed by antirejection therapy including cyclosporine. Symptomatic occipital lobe epilepsy developed that was successfully treated with oxcarbazepine, but cyclosporine plasma levels decreased to below the antirejection threshold. Oxcarbazepine was replaced by levetiracetam. Levetiracetam did not affect the metabolism of cyclosporine, and cyclosporine plasma levels have remained in the therapeutic range up to now. The patient is still seizure-free and does not complain of any side effects after a 1-year follow-up. Further studies are necessary to confirm the lack of interactions between these drugs, which would make levetiracetam a useful therapeutic option in managing seizure control during antirejection therapy with cyclosporine.

Late Mortality from Thrombotic Microangiopathy After Liver Transplantation: Report of a Case

Thrombotic microangiopathy (TMA) after liver transplantation is thought to be a rare event. We report a case of TMA after living donor liver transplantation for hepatitis C virus-related cirrhosis. The patient was initially placed on a tacrolimus-based immunosuppressive regimen, and received combined ribavirin and interferon treatment as pre-emptive therapy for hepatitis C virus. His post-transplantation course was complicated by cytomegalovirus (CMV) antigenemia, and intra-abdominal hemorrhage after percutaneous liver biopsy, necessitating laparotomy. On postoperative day (POD) 53, we noted a marked thrombocytopenia with a sudden rise in lactate dehydrogenase. Blood smear indicated prominent fractionated erythrocytes. Treatment included immediate conversion from tacrolimus to cyclosporine (CsA) and successive plasma exchange (PE), despite which the TMA progressed. CsA was discontinued 32 days after initiating the PE, and the TMA progression seemed to cease. However, the patient's condition deteriorated and he died of multiple organ failure on POD 119. We report this case to stress that careful management of calcineurin inhibitor administration is critical in TMA.

TPMT genotype and its clinical implication in renal transplant recipients with azathioprine treatment

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. Patients with intermediate or deficient TPMT activity are at risk of toxicity after receiving standard doses of these drugs. This study determined the frequencies of TPMT alleles (TPMT*2, *3A, *3B and *3C) and explored the association between TPMT genetic polymorphism and the development of adverse drug reactions in Chinese renal transplant patients receiving azathioprine (AZA). TPMT genotypes were determined using polymerase chain reaction-based assays in 122 renal transplant patients and 210 healthy subjects. Biochemical and clinical data were retrospectively evaluated after renal transplantation. Of 122 patients, eight (allele frequency 3.28%) were heterozygous for TPMT*3C and no TPMT*2, *3A or *3B or homozygous TPMT*3C subjects were identified. The pattern and frequency of the main mutant TPMT alleles were similar in patients and healthy subjects. Four of five patients (80%) with haematopoietic toxicity were heterozygotes. TPMT heterozygosity was associated with significant reductions in haematological indices and a significant decrease in cyclosporine plasma concentrations in the first year after renal transplantation. No association between TPMT genotype and renal rejection was identified. Our results, together with those of others pointing in the same direction, suggest that genotyping the major TPMT variant alleles may be a valuable tool in preventing AZA toxicity and optimization of immunosuppressive therapy.

Cyclosporine-Induced Nephrotoxicity and Dose Adjustments in Bone Marrow Transplantation.

Background and hypothesis: Cyclosporine is administered to all patients undergoing allogeneic bone marrow transplantation in Hamilton. It is given intravenously at first then orally after engraftment. The manufacturer's recommendation is to use a dose ratio of 1:3, IV to oral; the Hamilton unit uses a ratio of 1:2, yet has observed frequent rises of cyclosporine to toxic levels. We wished to confirm that the dose conversion ratio of 1:2 is associated with significantly high cyclosporine levels and nephrotoxicity.Methods and Results: Thirty-five consecutive patients undergoing allogeneic bone marrow transplantation at McMaster University Medical Centre were studied. We included patients who were diagnosed with a hematological cancer i.e. leukemia (76%), lymphoma (18%), or myelodysplastic syndrome (6%), and who underwent chemotherapy. The patients' plasma cyclosporine levels were measured 4–5 days after its initiation and with every dose adjustment, and serum creatinine levels were measured daily. Forty four percent of the patients were males. In 53% of the patients 1:2 IV to oral conversion ratio caused elevation of plasma cyclosporine levels to the toxic range (p<0.001). The toxic cyclosporine levels were seen 5+/−2 days post IV to oral dose adjustment. Furthermore, 43% of these patients developed acute renal failure and significant elevation of their serum creatinine levels (p<0.001).Conclusion: The traditional conversion rate of 1:2–3 for intravenous to oral cyclosporine is associated with rises in plasma cyclosporine to toxic levels and significant rises in serum creatinine level. We recommend that this conversion rate be lowered to 1:4/3 and further studied.

Drug‐Drug Interaction After Single Oral Doses of the Furanocoumarin Methoxsalen and Cyclosporine

Furanocoumarins increase the bioavailability of drugs that are CYP3A4 substrates. A possible interaction of methoxsalen with cyclosporine was evaluated in 12 healthy volunteers following oral administration of 40 mg methoxsalen, 200 mg cyclosporine, or a combination of both in a randomized crossover study. Methoxsalen increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of cyclosporine by 29% (range, -20% to 172%; P < .05) and 8% (range, -10% to 26%; P < .05), respectively, compared to cyclosporine alone. The AUC geometric means ratio (95% confidence interval) for cyclosporine plus methoxsalen/cyclosporine alone was 1.14 (1.02, 1.27), and treatments were therefore not bioequivalent. Methoxsalen causes a clinically significant interaction with cyclosporine in some susceptible individuals. The reasons for susceptibility and the clinical implications for chronic cyclosporine administration have not been established. Caution is recommended in combination therapy, and more frequent monitoring of cyclosporine plasma levels and clinical monitoring is advised.