Factors Influencing Cyclosporine Blood Concentration–Dose Ratio

Universidad de Cantabria, Santander, Cantabria, Spain
Annals of Pharmacotherapy (Impact Factor: 2.06). 03/2002; 36(2):193-9. DOI: 10.1345/aph.10380
Source: PubMed


To analyze the trough cyclosporine concentration-dose ratio (CDR) and its relationship to some commonly available factors such as cyclosporine dosage, patient age, grade of obesity, posttransplant days, serum creatinine, serum bilirubin, and serum cholesterol by multiple linear regression.
The study was performed on 866 samples from 90 transplant recipients (25 kidney, 25 heart, 17 bone marrow, 13 liver, 10 simultaneous pancreas-kidney).
The results show differences between transplants both in cyclosporine CDR variability (expressed by the coefficients of variation) and in the capability of those factors to explain this variability (expressed by the coefficient of determination). Coefficients of variation were 41% for the 866 samples (from 34% in heart to 55% in pancreas-kidney transplantation) and 28% for the 90 patients' CDR mean values (from 24% in heart to 32% in pancreas-kidney transplantation). All factors, except for the grade of obesity, were related to the cyclosporine CDR for all transplants as a whole. However, differences in the influence of each factor on each transplant were observed. The coefficient of determination based on significant factors was R2 = 0.25 for all samples (from 0.18 in pancreas-kidney to 0.52 in liver transplantation) and R2 = 0.53 for the patients' CDR means (from 0.39 in heart to 0.83 in kidney transplantation).
We have quantified the cyclosporine CDR, its variability, and its relationship with some commonly available factors and found significant differences between transplant types. The equations of regression obtained might improve trough cyclosporine CDR estimation as a first step in cyclosporine dosage adjustment in kidney and liver transplant recipients.

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    • "They concluded that the maintenance dosage of CyA should probably be given on the basis of IBW rather than TBW.34,35 In addition, García-Sáiz et al. reported that the trough CyA concentration-dose ratio (CDR) was not correlated with %IBW calculated by TBW/IBW*100, to which the distribution volume of hydrophilic drugs was generally correlated.36 Grevel et al. reported that the height of patients correlated with CLtot after infusion of CyA, whereas TBW, BSA and %IBW were not correlated to CLtot.37 "
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    ABSTRACT: The optimal use and monitoring of cyclosporine A (CyA) have remained unclear and the current strategy of CyA treatment requires frequent dose adjustment following an empirical initial dosage adjusted for total body weight (TBW). The primary aim of this study was to evaluate age and anthropometric parameters as predictors for dose adjustment of CyA; and the secondary aim was to compare the usefulness of the concentration at predose (C0) and 2-hour postdose (C2) monitoring. An open-label, non-randomized, retrospective study was performed in 81 renal transplant patients in Japan during 2001-2010. The relationships between the area under the blood concentration-time curve (AUC0-9) of CyA and its C0 or C2 level were assessed with a linear regression analysis model. In addition to age, 7 anthropometric parameters were tested as predictors for AUC0-9 of CyA: TBW, height (HT), body mass index (BMI), body surface area (BSA), ideal body weight (IBW), lean body weight (LBW), and fat free mass (FFM). Correlations between AUC0-9 of CyA and these parameters were also analyzed with a linear regression model. The rank order of the correlation coefficient was C0 > C2 (C0; r=0.6273, C2; r=0.5562). The linear regression analyses between AUC0-9 of CyA and candidate parameters indicated their potential usefulness from the following rank order: IBW > FFM > HT > BSA > LBW > TBW > BMI > Age. In conclusion, after oral administration, C2 monitoring has a large variation and could be at high risk for overdosing. Therefore, after oral dosing of CyA, it was not considered to be a useful approach for single monitoring, but should rather be used with C0 monitoring. The regression analyses between AUC0-9 of CyA and anthropometric parameters indicated that IBW was potentially the superior predictor for dose adjustment of CyA in an empiric strategy using TBW (IBW; r=0.5181, TBW; r=0.3192); however, this finding seems to lack the pharmacokinetic rationale and thus warrants further basic and clinical investigations.
    Full-text · Article · Sep 2013 · International journal of medical sciences
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    • "This study was not without limitations, partly reflected by the low r2 value in the regression model. We speculate that other factors may affect CsA pharmacokinetics, including methylation, microRNA regulation, and the copy number variations of relevant genes33, as well as serum lipid profiles, hematocrit levels, and comorbidities (eg, diabetes and hypertension)3,18. Concurrently, the medication prednisone was routinely used in renal transplant patients because of its efficacy in reducing AR. "
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    ABSTRACT: Aim: To evaluate retrospectively the association of cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) gene polymorphisms with the pharmacokinetics of cyclosporine A (CsA) in Chinese renal transplant patients. Methods: One hundred and twenty-six renal transplant patients were recruited. Blood samples were collected, and corresponding clinical indices were recorded on the seventh day after the procedure. The patients were genotyped for CYP3A4*1G, CYP3A5*3C, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T polymorphisms. Whole blood trough concentrations of CsA at time zero (C0) were measured before the drug administration. A multiple regression model was developed to analyze the effects of genetic factors on the CsA dose-adjusted C0 (C0/dose) based on several clinical indices. Results: The CYP3A5*3C polymorphism influenced the C0 and C0/dose of CsA, which were significantly higher in patients with the GG genotype than in patients with the AA or GA genotypes. No significant differences were detected for other SNPs (CYP3A4*1G, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T). In a univariate analysis using Pearson's correlation test, age, hemoglobin, blood urea nitrogen and blood creatinine levels were significantly correlated with the log-transformed CsA C0/dose. In the multiple regression model, CYP3A5*3C, age, hemoglobin and blood creatinine level were associated with the log-transformed CsA C0/dose. Conclusion: CYP3A5*3C correlates with the C0/dose of CsA on the seventh day after renal transplantation. The allele is a putative indicator for the optimal CsA dosage in the early phase of renal transplantation in the Chinese population.
    Full-text · Article · Oct 2012 · Acta Pharmacologica Sinica
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    ABSTRACT: Dyslipidaemia is more frequent in solid organ transplant recipients than in the general population, primarily as a result of immunosuppressive drug treatment. Both cyclosporin and corticosteroids are associated with dyslipidaemic adverse effects. In order to reduce the overall cardiovascular risk in these patients, lipid-lowering drugs have become widely used, especially HMG-CoA reductase inhibitors (statins). Cyclosporin, as well as most statins (lovastatin, simvastatin, atorvastatin and pravastatin) are metabolised by cytochrome P450 (CYP)3A4, so a bilateral pharmacokinetic interaction between these drugs is theoretically possible. However, results from several studies show that statins do not induce increased systemic exposure of cyclosporin. A small (but not clinically relevant) reduction in systemic exposure of cyclosporin has actually been shown in many studies. Cyclosporin-treated patients on the other hand show several-fold higher systemic exposure of all statins, both those that are metabolised by CYP3A4 and fluvastatin (metabolised by CYP2C9). Therefore, the mechanism for this interaction does not seem to be solely caused by inhibition of CYP3A4 metabolism, but it is probably also a result of inhibition of statin-transport in the liver, at least in part. Other lipid-lowering drugs, such as fibric acid derivatives, bile acid sequestrants, probucol, fish oils and orlistat are also used in solid organ transplant recipients. Most of them do not interact with cyclosporin, but there are reports indicating that both probucol and orlistat may reduce cyclosporin bioavailablility to a clinically relevant degree. There is no information on possible interaction effects of cyclosporin on the pharmacokinetics of lipid-lowering drugs other than statins, but it is not likely that any clinical relevant interference exists with fish oil, orlistat, probucol or bile acid sequestrants.
    No preview · Article · Feb 2003 · Drugs
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