Blood Cyclosporine Concentrations Research Articles

Rapid Decline in Glomerular Filtration Rate during the First Weeks Following Heart Transplantation

We hypothesized that a decrease in renal function is seen immediately after heart transplantation (HTX) with little recovery over time. Twelve consecutive patients had their glomerular filtration rate (GFR) measured using 51Cr-ethylenediaminetetraacetic acid (EDTA) measured GFR (mGFR) before transplantation and at 1, 2, 3, and 26 weeks after transplantation. The mGFR decreased by 28% and 24% during the first 3 and 26 weeks, respectively, with mean blood cyclosporine concentration as an independent risk factor for the decrease in mGFR. The identification of cyclosporine A (CsA) as the most important risk factor for the rapid and sustained decrease in renal function supports the need for more studies on renoprotective strategies immediately after HTX.

The clinical value of enzyme-multiplied immunoassay technique monitoring the plasma concentrations of cyclosporine A after renal transplantation

The feasibility and the clinical value of the enzyme-multiplied immunoassay technique (EMIT) monitoring of blood concentrations of cyclosporine A (CsA) in patients treated with CsA were investigated after kidney transplantation. The validation method was performed to the EMIT determination of CsA blood concentration, the CsA whole blood ‘trough concentrations (C0) of patients in different time periods after renal transplantation were monitored, and combined with the clinical complications, the statistical results were analyzed and compared. EMIT was precise, accurate and stable, also with a high quality control. The mean postoperative blood concentration of CsA was as follows: <1 month, (281.4±57.9)ng/mL; 2 – 3 months, (264.5±41. 2)ng/mL; 4 – 5 months, (236.4±38. 9)ng/mL; 6 – 12 months, (206.5±32.6)ng/mL; >12 months, (185.6±28.1)ng/mL. The toxic reaction rate of CsA blood concentration within the recommended therapeutic concentration was 14. 1%, significantly lower than that of the none-recommended dose group (37.2%) (P<0.05); the transplantation rejection rate was 4.4%, significantly lower than that of the none-recommended dose group (22.5%) (P<0.05). Using EMIT to monitor the blood concentration of CsA as the routine laboratory method is feasible, and is able to reduce the CsA toxicity and rejection significantly, leading to achieving the desired therapeutic effect.

Pharmacokinetics and absolute bioavailability of cyclosporin following intravenous and abomasal administration to sheep.

Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0.45 +/- 0.05 L h-1 kg-1), distribution volume (4.4 +/- 2.0 L kg-1), mean residence time (9.6 +/- 4.1 h) and half-life (12.1 +/- 3.1 h) were calculated cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26.3 mg kg-1, but was curvilinear above this dose. Abomasal bioavailability at 6.4 mg kg-1 was 0.26 +/- 0.09, and mean absorption time was 4.7 +/- 11.1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.

Effect of oral adsorbent AST-120 on cyclosporin absorption in rats.

The oral adsorbent AST-120 is used to inhibit the progression of renal failure by adsorbing uraemic toxins in the gastrointestinal tract. When AST-120 is administered to patients receiving immunosuppressive medicines, it is important to study the effect of AST-120 on the amount of these and other drugs absorbed. We have, therefore, studied the in-vitro adsorption of cyclosporin by AST-120 and investigated the effect of oral administration of AST-120 on the absorption of cyclosporin in rats. The in-vitro adsorption ratios of AST-120 for cyclosporin were more than 80%. When pure cyclosporin powder was administered with AST-120, blood cyclosporin concentrations were significantly higher than when cyclosporin was administered alone. When cyclosporin dissolved in medium-chain triglyceride was administered to rats by intramuscular injection there was no significant difference in the blood cyclosporin concentration of rats given combined AST-120 and cyclosporin and those given cyclosporin alone. There was no significant difference between the serum concentration of total bile acids, in rats receiving combined oral AST-120 and cyclosporin dissolved in olive oil, and those receiving orally solely a solution of cyclosporin dissolved in olive oil. These results suggest that oral administration of AST-120 accelerates the absorption of orally administered cyclosporin from the gastrointestinal tract and does not affect the metabolism of cyclosporin. When a solution of cyclosporin in olive oil is administered orally, however, oral administration of AST-120 has no influence on cyclosporin absorption and does not affect the enterohepatic circulation of bile acids.

Decreased cyclosporin A absorption after treatment with GoLytely lavage solution in rats.

Recently we observed a case in which the cyclosporin A absorption decreased after treatment with GoLytely lavage solution in a kidney transplant patient. In this study, we confirmed the decrease of the blood concentration of cyclosporin A after oral administration by GoLytely (Macrogol 3350) based on experiments with rats. The peak blood cyclosporin A concentration, and the area under the blood drug concentration-time curve from 0 to 24 h in the GoLytely-administered group were significantly lower than the control group. In the case of gastrointestinal dysfunction such as diarrhoea, or in treatment with laxatives such as GoLytely lavage solution, whole blood cyclosporin levels must be carefully monitored, and intravenous cyclosporin A may be more suitable for providing adequate immunosuppression.

Effect of the number of samples on Bayesian and non-linear least-squares individualization: a study of cyclosporin treatment of haematological patients with multidrug resistance.

We have studied whether the prediction of drug concentrations improves as the number of samples used for individualization is increased, and whether the Bayesian method of individualization is superior to the non-linear least-squares method. Data were obtained from ten adult haematological patients with multidrug resistance who were treated with cyclosporin. The predictions of blood-cyclosporin concentrations were made using the Abbott PKS program. The number of samples used for individualization was increased from 1 to 30 for the Bayesian method and from 4 to 30 for the non-linear least-squares method. Linear regression, percentage prediction error, and absolute and relative predictive performance were used to evaluate the predictions. The results show that the Bayesian method affords greater precision than the non-linear least-squares method, but that the non-linear least-squares method is more accurate and results in less bias. Whereas for linear regression predictions improve as the number of samples is increased, other evaluations show improvement in the range from 5 to 11 samples; linear regression, percentage prediction errors and prediction bias support the opinion that the Bayesian method progressively becomes the non-linear least-squares method as the number of samples used for individualization is increased, but the accuracy and precision of prediction do not support this opinion. The study supports the statement that Bayes' law requires parameters from an infinite population, otherwise the advantage of the Bayesian method might be marginal.

Quercetin and Rutin Reduced the Bioavailability of Cyclosporine from Neoral, an Immunosuppressant, through Activating P-Glycoprotein and CYP 3A4

Quercetin and rutin are popular flavonoids in plant foods, herbs, and dietary supplements. Cyclosporine (CSP), an immunosuppressant with a narrow therapeutic window, is a substrate of P-glycoprotein (P-gp) and cytochrome P-450 3A4 (CYP3A4). This study investigated the effects of quercetin and rutin on CSP pharmacokinetics from Neoral and relevant mechanisms. Rats were orally administered Neoral with and without quercetin or rutin. The blood CSP concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. The results showed that quercetin and rutin significantly decreased the C(max) of CSP by 67.8 and 63.2% and reduced the AUC(0-540) by 43.3 and 57.2%, respectively. The in vitro studies indicated that the quercetin and rutin induced the functions of P-gp and CYP3A4. In conclusion, quercetin and rutin decreased the bioavailability of CSP through activating P-gp and CYP3A. Transplant patients treated with Neoral should avoid concurrent consumption of quercetin or rutin to minimize the risk of allograft rejection.

Cyclosporine and Lactation: When the Mother Is Willing to Breastfeed

We describe a woman treated with cyclosporine after renal transplantation who commenced breastfeeding of her newborn infant. The child had no apparent clinical adverse effects to cyclosporine. To confirm the safety of breastfeeding and guide the patient and her clinician, cyclosporine concentrations in maternal blood, breast milk, and infant blood were measured. Maternal cyclosporine concentration (1-hour postdose) was 49 μg/L, and the breast milk cyclosporine concentration (2-hour postdose) was 46 μg/L. Infant cyclosporine blood concentration shortly after breastfeeding was undetectable (<10 μg/L). Analysis revealed that the estimated infant exposure to cyclosporine via breast milk was minimal and provided reassurance to continue breastfeeding in this case.

Is the Lower Cyclosporine Concentration at 2 Hours After Dosing Safe in Kidney Transplant Recipients?

Objective To determine the correlation between cyclosporine blood concentration at 2 hours after dosing (C2) and renal allograft function. Materials and Methods From 2008 to 2010, 1191 kidney transplant recipients (718 male and 473 female patients) were studied. The correlation between serum creatinine concentration and C2 blood concentration was stratified as 400, 600, 800, and 1000 ng/mL. Results The mean (SD) C2 was 620 (235) ng/mL, and serum creatinine concentration was 1.49 (0.68) mg/dL. At multivariate regression analysis, no significant correlation was observed between serum creatinine concentration and C2 blood concentrations of 600, 800, or 1000 ng/mL ( P = .18, .57, and .76, respectively); however, it was associated at 400 ng/mL ( P = .03). Moreover, 36.1% of 3159 samples demonstrated satisfactory renal allograft function despite low C2 blood concentration between 400 and 600 ng/mL. Conclusion During maintenance therapy, C2 blood concentration between 400 and 600 ng/mL is effective and safe for providing prophylaxis against rejection, and can improve long-term survival by decreasing cyclosporine toxicity.

CALCINEURIN INHIBITOR-INDUCED RENAL ALLOGRAFT NEPHROTOXICITY

The introduction of the calcineurin inhibitors (CI) cyclosporine and tacrolimus into immunosuppressive protocols initiated a new era in organ transplantation with excellent short-term graft survival. Nevertheless, the chronic nephrotoxicity of these drugs represents a significant adverse factor limiting their long-term use. Patients treated with a CI can be at risk for developing renal failure and this problem is especially pronounced in patients after renal transplantation. In a review paper we summarize the clinical aspects, histological manifestations and pitfalls of diagnostics of acute and chronic CI nephrotoxicity in patients after kidney transplantation. We look in detail at the disputed relationship between blood concentrations of cyclosporine and tacrolimus and histological manifestation of toxicity and summarize data showing that for toxic effects, local renal exposure to CI and their metabolites can play a more significant role than systemic exposure. We also include recent views on the pathophysiologic and molecular mechanisms underlying these changes; factors influencing local susceptibility to CI nephrotoxicity are discussed, including variability of expression and activity of P-glycoprotein and cytochrome P450. Last but not least we summarize our own experience with clinically manifest and subclinical forms of nephrotoxicity and their impact on the progression of chronic graft changes. Owing to their unique effects, CI remain the cornerstone of most immunosuppressive protocols for renal transplantation. Together with optimization of local kidney exposure to CI and their metabolites, efforts to reduce systemic levels as much as possible are the most important preventive measure for reducing toxic renal graft damage.

Falsely Elevated Whole Blood Cyclosporine Concentrations Measured by an Immunoassay With Automated Pretreatment

Falsely Elevated Whole Blood Cyclosporine Concentrations Measured by an Immunoassay With Automated Pretreatment

Apparent Elevation of Cyclosporine Whole Blood Concentrations in a Renal Allograft Recipient

We describe a 77-year-old cyclosporine-treated renal allograft recipient in whom falsely elevated whole blood cyclosporine concentrations were encountered using the antibody conjugated magnetic immunoassay (ACMIA) for therapeutic drug monitoring.

Changes in blood concentrations of cyclosporine after combination with azoles in bone marrow transplant recipients

Changes in blood concentrations of cyclosporine after combination with azoles in bone marrow transplant recipients

Monitoring of C0 and C2 Blood Concentrations of Cyclosporine on the Roche Hitachi 902 Analyzer

This work provided parameters to perform the widely used enzyme multiplied immunoassay technique (Emit) cyclosporine assay on a Hitachi 902 analyzer. Instrument settings were optimized to arrive at assay characteristics regarding precision, linearity, and lower limit of quantitation among 105 samples from renal transplant recipients receiving cyclosporine. We compared successive results with Emit on a Cobas Integra 400 analyzer with HPLC-UV. We validated a quantitation range of 20–500 ng/mL. For all parameters tested total imprecision <5%. Calibration stability was at least 30 days. The reagent cartridge in the instrument was stable for 2 months between runs. We observed good correlations with other analytical methods. The following equations were obtained: Hitachi 902 = 0.984 Cobas Integra + 2.097; r = 0.998 and Hitachi 902 = 1.019 LC-UV + 3.143; r = 0.974. The mean bias was 1.68% for C0 and 0.02% for C2 concentrations between Hitachi 902 and Cobas Integra 400. Overestimations of 5.61% for C0 and 8.81% for C2 levels assayed with Emit Hitachi 902 were observed compared with LC-UV. The proposed, validated protocol enhanced the versatility of the Emit assay for routine therapeutic drug monitoring. The Hitachi 902 analyzer is an acceptable option for evaluation of C0 and C2 blood cyclosporine concentrations in transplant recipients.

Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations

St John's wort (SJW) extracts, prepared from the aerial parts of Hypericum perforatum, contain numerous pharmacologically active ingredients, including naphthodianthrones (e.g., hypericin and its derivatives), phloroglucinols derivatives (e.g., hyperforin, which inhibits the reuptake of a number of neurotransmitters, including serotonin), and flavonoids. Such extracts are widely used for the treatment of mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, relevant and, in some case, life-threatening interactions have been reported, particularly with drugs which are substrate of cytochrome P450 and/or P-glycoprotein. Well-documented SJW interactions include (1) reduced blood cyclosporin concentration, as suggested by multiple case reports as well as by clinical trials, (2) serotonin syndrome or lethargy when SJW was given with serotonin reuptake inhibitors, (3) unwanted pregnancies in women while using oral contraceptives and SJW, and (4) reduced plasma drug concentration of antiretroviral (e.g., indinavir, nevirapine) and anticancer (i.e., irinotecan, imatinib) drugs. Hyperforin, which is believed to contribute to the antidepressant action of St John's wort, is also strongly suspected to be responsible of most of the described interactions.

Clinical Application of Cordyceps sinensis on Immunosuppressive Therapy in Renal Transplantation

Objective We sought to explore the adjunctive effects of Cordyceps sinensis (CS) in clinical renal transplantation. Materials and Methods Patients (n = 202) were divided randomly by lottery into a treatment (n = 93) and a control group (n = 109). Patients in the treatment group were treated with CS 1.0 g 3 times a day in addition to the immunosuppressive regimen given to the control group. We compared patient and graft survivals, incidence, time and severity of acute rejection episodes, chronic allograft nephropathy (CAN), hepatotoxicity and nephrotoxicity, biochemistry parameters including indicators of liver and kidney functions, fats, proteinuria, dosages, and whole blood concentrations of cyclosporine (CsA). Results Patient and graft survival rates, serum creatinine (SCr), and blood urea nitrogen (BUN) were not significantly different between the 2 groups ( P > .05). Serum uric acid (UA) and 24-hour urinary total protein (24-hour UTP) were significantly lower in the treatment group than in the control group ( P < .05). The incidences (11.83% vs 15.60%) and times to acute renal allograft rejection (23.48 ± 7.22 vs 22.27 ± 8.03 days posttransplantation) were not significantly different between the treated and control groups ( P > .05). Patients receiving thymoglobulin antirejection therapy (3 cases) were fewer in the heated versus control group (13 cases; P = .014). The incidences of hepatotoxicity and nephrotoxicity in the treated group were 12.90% and 19.35%, significantly lower than 24.77% and 33.94% in the control group, respectively ( P < .05). At 2 to 6 months posttransplantation, the CsA dosages in the treated group were significantly lower than those in the control group ( P < .05). The whole blood trough CsA concentrations in the treated group were significantly lower than those in the control group at 3 to 6 months posttransplantation ( P < .05). The decreasing trends of the 2 aforementioned parameters in the treatment group were approximately linear among treated subjects compared with approximately quadratic in the control group ( P < .05). The incidence of CAN in the treated group was 7.53%, which was significantly lower than 18.35% in the control group ( P = .024). The 24-hour UTP level in CAN patients within the treated group was significantly lower than the control group after transplantation ( P = .045). The differences in total bilirubin, SCr, serum UA, and total cholesterol levels among otherwise normal patients in the treated group were significantly lower than those among the control group ( P < .05). Conclusions The use of CS may allow decreased dosages and concentrations of CsA causing fewer side effects without an increased risk of acute rejection. In addition, CS with reduced dose CsA may decrease proteinuria and retard CAN progression.

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.

Cyclosporine-Induced Pain Syndrome in a Child Undergoing Hematopoietic Stem Cell Transplant

To report a case of calcineurin-induced pain syndrome (CIPS) in a child undergoing his second hematopoietic stem cell transplant (HSCT). A 6.1-year-old child received cyclosporine and methotrexate for acute graft-versus-host disease (aGVHD) prophylaxis after his first HSCT for acute myeloblastic leukemia. Amlodipine was given for the treatment of hypertension. Symptoms of CIPS were not observed. After the second HSCT at the age of 6.7 years, the child received cyclosporine (target trough whole blood cyclosporine concentration range 150-200 microg/L), starting on day -3, and mycophenolate mofetil for aGVHD prophylaxis. With the first cyclosporine dose, the patient complained of leg pain that was most severe during the cyclosporine infusion. Analgesic agents and a change from intravenous to oral administration of cyclosporine were ineffective in controlling the pain. Magnetic resonance imaging findings on day 10 showed periosteal soft tissue changes and mild bone marrow edema of the femora and tibiae. Tacrolimus was substituted for cyclosporine on day 20; on day 21 amlodipine was initiated to manage hypertension. Trough whole blood tacrolimus concentrations ranged from 1.7 to 6.2 microg/L. Pain was reduced in severity by day 29 and completely resolved once tacrolimus was discontinued on day 42. In this case, CIPS was considered to be probably associated with cyclosporine according to the Naranjo probability scale. CIPS is hypothesized to result from calcineurin-induced vascular changes that disturb bone perfusion and permeability, leading to intraosseous vasoconstriction and bone marrow edema. In our patient, symptoms were most acute during the infusion, when whole blood cyclosporine concentrations were likely to be the highest. Our patient's symptoms were resolved when tacrolimus was substituted for cyclosporine and amlodipine was initiated. Interventions aimed at reducing pain associated with CIPS may include the initiation of calcium-channel blocker therapy and conversion to an alternative calcineurin inhibitor.

Tigecycline and cyclosporine interaction—an interesting case of biliary-excreted drug enhancing the oral bioavailability of cyclosporine

To the Editor: Stumpf et al. (2009) have reported an interesting observation of enhanced blood levels of cyclosporine in a renal transplant patient upon co-medication with tigecycline [1]. The interaction between the two agents was found to be acute in nature and necessitated a dose reduction of cyclosporine to avoid safety concerns. Upon the cessation of tigecycline treatment, the dosing of cyclosporine had to be restored to its original level to avoid graft rejection due to lower efficacy [1]. The observations made in this case study are important ones since there is a myth that drugs administered through two different routes are less likely to show a pharmacokinetic interaction. Additionally, it provides rational information in our understanding of the issues associated with an intravenously administered drug (tigecycline) versus an orally administered drug (cyclosporine). While the authors have proposed p-glycoprotein (pgp) effux transporters as possible culprits for this pharmacokinetic interaction [1], this communication attempts to bring in additional views for consideration to explain this intriguing phenomenon. Although Stumpf et al. do not report the route of administration of cyclosporine, it is presumed that the renal transplant patient was on a oral dose of cyclosporine [1]. As described by the authors [1], the oral bioavailability of cyclosporine is highly variable owing to the concomitant effects of cytochrome P450 (CYP) metabolism (CYP3A4/ 3A5) and pgp-related efflux transport activity [2]. Upon the addition of tigecyline treatment, there was an acute increase in the blood concentrations of cyclosporine suggesting an enhanced oral bioavailability of cyclosporine [1]. The altered bioavailability of cyclosporine could have been achieved by two different possibilities. Firstly, as described by Stumpf et al., since tigecycline is excreted in bile (almost 59% of the administered dose [3]), it is likely that tigecycline would have impaired pgp-mediated gut efflux of cyclosporine resulting in an increased oral bioavailability. Secondly, as an alternate possibility, since cyclosporine is also known to undergo biliary excretion, perhaps there was a preferential biliary excretion of tigecycline as opposed to cyclosporine (direct competition) and/or inhibition of the biliary excrection of cyclosporine by tigecycline leading to the increased blood concentrations of cyclosporine. However, paradoxically, cyclosporine has been shown to increase the plasma concentrations of mycophenolic glucuronide due to the direct inhibition of its biliary excretion pathway [4]. While the above speculative possibilities could account for the observed enhanced bioavailability of cyclosporine in the presence of tigecylcline, one has to closely evaluate the recently reported data from the interaction study of tigecycline and digoxin [5]. Interestingly, tigecycline failed to show an interaction with digoxin, a well known and widely used probe substrate for pgp-mediated efflux [5]. Therefore, a key question to ask should be why tigecylcine would preferentially affect the pgp efflux of cyclosporine but not digoxin. A recent work published by Igel et al. (2008) sheds some light on the specificity of the involvement of apically located pgp transporters for the absorption and transport of digoxin [6]. The use of a pgp inhibitor such as quinidine in the study effectively increased the absorption of digoxin [6]. However, the bioavailability and oral absorption of antipyrine, which undergoes paracellular absorption, was Eur J Clin Pharmacol (2009) 65:543–544 DOI 10.1007/s00228-009-0631-x

Ralstonia pickettiiSepticemia in a Dog with Immune‐Mediated Thrombocytopenia

<i>Ralstonia pickettii</i>Septicemia in a Dog with Immune‐Mediated Thrombocytopenia