Cyclosporine Monitoring and Pharmacokinetics in Pediatrie Liver Transplant Patients (original) (raw)
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Age-Related Distribution of Cyclosporine Concentrations in Liver Transplant Patients - Comparative Population Pharmacokinetic Retrospective Observation, 2018
Abstract Immunosuppression following solid organ transplantation is important therapy for the survival of both allograft and patient. After Orthotopic Liver Transplantation (OLT) many patients are treated by emulsified cyclosporine (Neoral ® ). 20 patients (8 adults and 12 children) who were on Neoral ® postorthotopic liver transplantation over a 5 year period were studied (2004-2009). All patients received Neoral ® twice daily orally at 08:00 AM and at 08:00 PM. C 0 drug concentrations were recorded in morning (C 0 AM) and in evening before each dosing (C 0 PM) and C 2 concentrations - in morning and in evening 2 hours post- dosing (C 2 AM and C 2 PM). A total of 323 CsA C 0 in children group and 242 C 0 in adult group and a set of 117 CsA C 2 in children group and a set of 133 C 2 in adult group were analyzed. Population Pharmacokinetic (PK) analysis was performed with dose normalized to 1 mg/kg cyclosporine concentrations in order to avoid Body Weight (BW) differences between the two age groups. Statistical distributions of CsA blood concentrations at the end of each dose interval and 2 hrs after each oral dose are characterized by non-Gaussian distributions skewed to the right. Normalized C 0(trough) and C 2 CsA concentrations were significantly lower in liver transplant children than in adults. The probit analysis confirmed the non-Gaussian distributions and revealed well-distinguishable subgroups of CsA C 0(trough) and C 2 levels deviating from linearity and suggestive of non-Gaussian clearance distributions in both age groups of liver transplant patients. Blood concentrations of CsA at the end of each dose interval and 2 hours after each oral dose demonstrated significantly higher variability in liver transplant children, which identifies them as a higher risk group when using standardized dose regimens and draws attention to the need for strictly individualized CsA therapy in this age population. Statistically significant correlation was observed between serum creatinine(Scr) and the normalized CsA C 0(trough) concentrations measured on the second day after liver transplantationin adult patients. The applicability of C 2 monitoring to paediatric patients is still being debated given the age-specific properties of CsA. While C 0 monitoring frequently results in overdosing and renal dysfunction, C 2 monitoring may lead to episodes of under dosing and rejection. Therefore better ways of monitoring cyclosporine dosing need to be devised. The statistically significant correlation between Scr and the normalized CsA C 0(trough) concentrations in adult patients on the second day after liver transplantation, if confirmed on a larger sample of liver transplanted patients, points to the possibility of Scr being used as a biomarker for individualization of CsA therapy in these transplanted patients. Keywords: Liver Transplantation; Cyclosporine; TDM; C 0 And C 2 Cyclsporine Concentrations; Serum Creatinine
Liver Transplantation, 2004
It has been demonstrated that achieving therapeutic levels of cyclosporine (CsA) exposure in the first days posttransplant is critical for effective prevention of rejection. In patients receiving oral CsA, it has been shown that C(2)-monitoring is superior to trough (trough level [C(0)]) measurement. Intravenous administration may overcome the problem of CsA absorption dysfunction seen in some patients. Currently, little evidence is available concerning CsA exposure after intravenous application. Twenty de novo liver transplant recipients were given twice-daily 4-hour infusions of intravenous CsA, with full pharmacokinetic profiles undertaken during the first postoperative week. The greatest CsA exposure occurred during the period 2 to 4 hours after the start of infusion. The correlation between C(0) and area under the curve (AUC(0-12)) was r(2) = 0.18; the correlation between C(2) and AUC(0-12) was r(2) = 0.82. The best 2-point predictive model included both C(2) and C(4) (r(2) = 0.90). There was a poor correlation between CsA dose per kilogram of body weight and AUC(0-12) (r(2) = 0.19); total CsA dose also showed a weak relationship to exposure (r(2) = 0.37). When patients were divided according to initial or delayed graft function, there was good correlation between total CsA dose and AUC(0-12) (initial function, r(2) = 0.71; delayed function, r(2) = 0.86). In conclusion, previous discouraging results with intravenous CsA in liver transplant patients may have been due to a limited understanding of CsA pharmacokinetics. Our results show that C(2)-monitoring during 4 hour infusion provides a reliable indication of CsA exposure. Calculation of starting dose based on initial graft function is more precise than use of body weight. Using C(2)-monitoring to individualize dosing and function-based calculations of starting dose could be expected to improve clinical outcomes in patients receiving intravenous CsA.
C2 monitoring of cyclosporine in de novo liver transplant recipients: The clinician's perspective
Liver Transplantation, 2004
Adjusting cyclosporine (CsA) dose based on blood concentration at 2 hours after dose (C 2) has been shown in prospective clinical trials to reduce the risk of rejection compared with conventional trough monitoring. In addition, it provides equivalent efficacy to tacrolimus in liver transplant patients, with a favorable safety profile. Target C 2 should be defined on an individual basis depending on adjunctive therapy and the level of exposure required. It appears less critical to achieve target C 2 in the first few days after liver transplantation than was previously believed. Achieving target C 2 exposure in the initial period after transplant requires that changes in the proportion of cyclosporine absorbed from the gut be taken into account to avoid risk of overexposure. In addition, if a starting dose of 10-15 mg/day is used, it is advisable to delay increasing the dose until a trend in C 2 level indicates this to be necessary. Immediate dose reduction is required if C 2 exceeds target range. In patients with low C 2 values, cyclosporine concentration at a later time point should be measured to establish whether the patient is a poor absorber or a delayed absorber of C 2 , and dose adjustments should be undertaken accordingly. In conclusion, this more flexible approach to C 2 monitoring allows the dose of cyclosporine to be individualized effectively for each patient, which results in significant efficacy benefits while minimizing the risk of toxicity. (Liver Transpl 2004;10:577-583.) Abbreviations: AUC 0-6 , area under the curve for the first six hours post-dose; AUC 0-12 , area under the curve for the first twelve hours post-dose; C 0, trough blood concentration; C 2, blood concentration at 2 hours after dose; C 4 , blood concentration at 4 hours after dose; C 6 , blood concentration at 6 hours after dose; CsA, cyclosporine; ME, microemulsion; MMF, mycophenolate mofetil.
Pharmacokinetics of cyclosporine in recipients of marginal versus standard liver transplants
Pharmacological Research, 2006
In the field of transplants, the practice of using marginal donor livers has become widely accepted, yielding good clinical results. This study investigated and compared the pharmacokinetics of cyclosporine in marginal and standard liver transplant recipients. Twenty-four de novo liver transplant patients, 12 with marginal and 12 with standard (normal) grafts, were treated with a microemulsion formulation of cyclosporine (capsules 100 mg) as immunosuppressive therapy. Blood concentration profiles were measured, and pharmacokinetic calculations performed at days 3 and 10 after transplantation. Different sampling strategies to predict drug exposure (AUC(0-12 h)) were compared, and the best limited-sampling strategies to monitor the desired blood levels were determined. Marginal and standard patients showed a significant difference in blood concentration and pharmacokinetic profiles of cyclosporine at the day 10 post-transplantation. Blood concentration at 4h (C(4 h)) was the single best timepoint to estimate AUC(0-12 h) in marginal liver transplant (r(2)=0.700), while C(2h) was confirmed to be the optimal choice with standard graft (r2=0.720). Two blood samples at 2 and 6 h significantly improved the prediction model in both groups (r2=0.920). Our data suggest that patients receiving a marginal liver transplant present a different pharmacokinetic profile of cyclosporine from those receiving standard graft, which should be taken into account in dosing the patient to avoid subtherapeutic blood concentrations or toxic effects.
Cyclosporine Absorption Following Orthotopic Liver Transplantation
The Journal of Clinical Pharmacology, 1986
Blood concentrations of cyclosporine were determined in adult and pediatric patients following orthotopic liver transplantation to quantitate cyclosporine blood clearance and oral absorption. Seventeen bioavailability studies were performed following transplantation surgery in nine children and seven adults. The intravenous cyclosporine study was performed following an average dose of 2.1 mg/kg. The patients were again studied when they received the same intravenous dose plus an oral dose of cyclosporine of 8.6 mg/kg or an oral dose alone. Blood samples were collected and analyzed for cyclosporine using high-performance liquid chromatography. Cyclosporine blood clearance ranged from 29 to 203 mL/min (1.9-21.5 mL/min/kg) in children and from 253 to 680 mL/ min (3.2-7.6 mL/min/kg) in adults. The mean cyclosporine clearance value was 9.3 mL/min/kg in the pediatric patients and 5.5 mL/min/kg in the adults. Cyclosporine bioavailability was less than 5% in six studies on five pediatric patients in the immediate postoperative period. The bioavailability varied from 8% to 60% in adult liver transplant patients (mean, 27%). We conclude that: (1) cyclosporine clearance is highly variable between patients, (2) pediatric patients clear the drug more rapidly than adults and therefore need a higher cyclosporine dose on a body weight basis, (3) cyclosporine is poorly and variably absorbed in liver transplant patients, and (4) cyclosporine blood concentration monitoring is essential following orthotopic liver transplantation.
PEAK CYCLOSPORINE LEVELS (Cmax) CORRELATE WITH FREEDOM FROM LIVER GRAFT REJECTION
Transplantation, 1999
Background. Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine (CsA) for liver transplantation. The present study was undertaken (1) to determine whether treatment with a new formulation of CsA, Neoral, would improve the results of liver transplantation; and (2) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation.
American Journal of Clinical Pathology, 2000
Cyclosporine is used in the prevention of allograft rejection. Owing to its narrow therapeutic index, regular monitoring of the whole blood levels of cyclosporine is required. We observed that immunoassays measured significantly higher cyclosporine levels than did high-performance liquid chromatography (HPLC) over time after transplantation. As cyclosporine metabolites crossreact even with immunoassays, this observation might be due to alterations of the cyclosporine metabolism. We analyzed cyclosporine metabolite concentrations in the early and in the late posttransplantation periods in 127 patients after kidney, bone marrow, heart-lung, and liver transplantation by HPLC and determined whole blood levels of cyclosporine by 4 immunoassays (enzyme-multiplied immunoassay [EMIT], cloned enzyme donor immunoassay [CEDIA], AxSYM [Abbott Laboratories, Chicago, IL], and TDx [Abbott Laboratories]). Despite reduced dose, we found significantly higher cyclosporine concentrations measured by the EMIT, AxSYM, and TDx assays in various patient groups. These results are due to the increased metabolite/cyclosporine ratio in the late posttransplantation period. In particular, the metabolites AM1 and AM19 increased significantly over time in bone marrow transplant recipients. Therefore, cyclosporine levels measured by immunoassays should be interpreted with caution.