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1.
Clin Lab ; 56(7-8): 345-53, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20857899

RESUMO

BACKGROUND: For mycophenolic acid (MPA), substantial inter- and intra-individual variability and drug interactions have been observed and therapeutic drug monitoring is now recommended. In this study, a MPA commercial Enzyme Multiplied Immunoassay Technique (EMIT) was evaluated and compared with the HPLC-UV reference method which is easily practicable in a routine laboratory. METHODS: Plasma samples (n = 117) were collected from adult renal graft patients treated by mycophenolate in combination with either cyclosporin A (CyA) (n = 32) or tacrolimus (n = 85). RESULTS: Considering all samples, correlation was excellent (p < 0.0001). However, significant MPA overestimation was observed with EMIT in the early post-transplant period (30%, n = 32) or when combined with cyclosporin (45%). CONCLUSIONS: In the early post-transplant period, or in cases where CyA is used in combination with MPA, the EMIT cannot be recommended. HPLC or LC/MS are here the method of choice.


Assuntos
Antibióticos Antineoplásicos/sangue , Monitoramento de Medicamentos/métodos , Técnica de Imunoensaio Enzimático de Multiplicação , Ácido Micofenólico/sangue , Antibióticos Antineoplásicos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Rejeição de Enxerto/sangue , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Tacrolimo/uso terapêutico , Raios Ultravioleta
2.
Clin Pharmacokinet ; 45(9): 905-22, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16928152

RESUMO

BACKGROUND AND OBJECTIVES: Population pharmacokinetic studies of ciclosporin microemulsion are needed to identify the individual factors influencing ciclosporin pharmacokinetic variability in transplant patients and to design efficient tools for the accurate estimation of ciclosporin overall exposure (area under the plasma concentration-time curve from 0 to 12 hours [AUC12]). In the present retrospective study, a large database of heart, lung (with or without cystic fibrosis) and kidney (both adult and paediatric) transplant patients receiving ciclosporin microemulsion was analysed with the aims of (i) building a population pharmacokinetic model and finding the main covariates linked with ciclosporin microemulsion pharmacokinetic parameters; and (ii) developing a maximum a posteriori probability Bayesian estimator (MAP-BE) to estimate ciclosporin microemulsion pharmacokinetic parameters using a limited-sampling strategy. METHODS: 3,072 concentration data from 147 patients (i.e. 309 full pharmacokinetic profiles) were analysed using the nonlinear mixed-effects model program NONMEM. The influence of numerous covariates was tested, and the final model was validated by data splitting. For Bayesian estimation, the best limited-sampling strategy was determined based on the D-optimality criterion, and validation performed in an independent group of 60 patients. RESULTS: The pharmacokinetics of ciclosporin microemulsion were accurately described by a two-compartment model with Erlang distribution for the absorption process. The type of graft and post-transplantation period were identified as significant sources of variability of the absorption parameter. Both apparent volume of the central compartment after oral administration (V1/F) and apparent oral clearance (CL/F) increased with bodyweight. The best limited-sampling strategy for Bayesian estimation was 0 hour, 1 hour and 3 hour post-dose, providing accurate estimation of ciclosporin microemulsion AUC12 in all patients of the test group, with a mean bias of 2.0 +/- 10.5% (range: -19.1% to -21.4% and 95% CI -0.6, +4.7). CONCLUSION: Population pharmacokinetic analysis of ciclosporin microemulsion in allograft transplants resulted in the design of a new pharmacokinetic model for ciclosporin microemulsion, identification of significant covariates and the design of an accurate MAP-BE based on three blood concentrations and these covariates.


Assuntos
Ciclosporina/farmacocinética , Transplante de Coração , Imunossupressores/farmacocinética , Transplante de Rim , Transplante de Pulmão , Modelos Biológicos , Adolescente , Adulto , Idoso , Teorema de Bayes , Criança , Pré-Escolar , Ciclosporina/administração & dosagem , Emulsões , Feminino , Humanos , Imunossupressores/administração & dosagem , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo
3.
Clin Pharmacokinet ; 44(12): 1317-28, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16372829

RESUMO

OBJECTIVES: To: (i) test different pharmacokinetic models to fit full tacrolimus concentration-time profiles; (ii) estimate the tacrolimus pharmacokinetic characteristics in stable lung transplant patients with or without cystic fibrosis (CF); (iii) compare the pharmacokinetic parameters between these two patient groups; and (iv) design maximum a posteriori Bayesian estimators (MAP-BE) for pharmacokinetic forecasting in these patients using a limited sampling strategy. METHODS: Tacrolimus blood concentration-time profiles obtained on three occasions within a 5-day period in 22 adult lung transplant recipients (11 with CF and 11 without CF) were retrospectively studied. Three different one-compartment models with first-order elimination were tested to fit the data: one with first-order absorption, one convoluted with a gamma distribution to describe the absorption phase, and one convoluted with a double gamma distribution able to describe secondary concentration peaks. Finally, Bayesian estimation using the best model and a limited sampling strategy was tested in the two groups of patients for its ability to provide accurate estimates of the main tacrolimus pharmacokinetic parameters and exposure indices. RESULTS: The one-compartment model with first-order elimination convoluted with a double gamma distribution gave the best results in both CF and non-CF lung transplant recipients. The patients with CF required higher doses of tacrolimus than those without CF to achieve similar drug exposure, and population modelling had to be performed in CF and non-CF patients separately. Accurate Bayesian estimates of area under the blood concentration-time curve from 0 to 12 hours (AUC12), AUC from 0 to 4 hours, peak blood concentration (Cmax) and time to reach Cmax were obtained using three blood samples collected at 0, 1 and 3 hours in non-CF patients (correlation coefficient between observed and estimated AUC12, R2 = 0.96), and at 0, 1.5 and 4 hours in CF patients (R2 = 0.91). CONCLUSION: A particular pharmacokinetic model was designed to fit the complex and highly variable tacrolimus blood concentration-time profiles. Moreover, MAP-BE allowing tacrolimus therapeutic drug monitoring based on AUC12 were developed.


Assuntos
Fibrose Cística/metabolismo , Imunossupressores/farmacocinética , Transplante de Pulmão , Modelos Biológicos , Tacrolimo/farmacocinética , Adulto , Área Sob a Curva , Teorema de Bayes , Fibrose Cística/tratamento farmacológico , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Tacrolimo/sangue , Tacrolimo/uso terapêutico
4.
Am J Transplant ; 5(6): 1477-82, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15888057

RESUMO

In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was approximately 50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC(0-12)), but the concentration measured 3 h postdose (C(3)) was tightly correlated with the AUC(0-12) in both CF (r(2)= 0.86) and non-CF (r(2)= 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter- and intrasubject variability of exposure compared to patients without CF. C(3) is tightly correlated with AUC(0-12) in lung transplant recipients with and without CF.


Assuntos
Fibrose Cística/metabolismo , Imunossupressores/farmacocinética , Transplante de Pulmão , Tacrolimo/farmacocinética , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tacrolimo/administração & dosagem
5.
Clin Chem Lab Med ; 42(1): 67-71, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15061383

RESUMO

Polyethylene terephthalate (PET) tubes have several advantages over glass tubes: they are unbreakable, lighter and more easily disposed of. Despite a steady increase in their use and an expansion of the range of available tubes, few studies validating their use have been published in the literature. This paper describes the various studies that have been performed to compare VENOJECT glass, VENOSAFE PET and VENOSAFE PET/heparin tubes for the assay of a panel of analytes in routine clinical chemistry, immunochemistry, hormone and tumor marker analysis and trace metal determination. These studies demonstrate that VENOSAFE PET tubes are a suitable alternative to glass tubes.


Assuntos
Coleta de Amostras Sanguíneas/instrumentação , Coleta de Amostras Sanguíneas/métodos , Testes de Química Clínica/instrumentação , Testes de Química Clínica/métodos , Monitoramento de Medicamentos/instrumentação , Hormônios/sangue , Metais/sangue , Monitoramento de Medicamentos/métodos , Vidro , Heparina , Humanos , Metais/análise , Polietilenotereftalatos/análise , Polietilenotereftalatos/química , Água/química
6.
Transplantation ; 76(4): 683-8, 2003 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-12973109

RESUMO

BACKGROUND: In cystic fibrosis (CF), absorption of cyclosporine A (CsA) through the gastrointestinal tract is often impaired because of fat malabsorption. The aim of this study was to compare the steady-state pharmacokinetics of CsA and the inter- and intrasubject variability of CsA exposure in stable lung transplant recipients with and without CF and to determine the best single-time predictors of the area under the curve (AUC). METHODS: Ten lung transplant recipients without CF and 10 lung transplant recipients with CF were studied. All patients received Neoral twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h postdose on three separate days within a 5-day period. RESULTS: CsA exposure and pharmacokinetic variables were similar in the two groups, although exposure-per-milligram-per-dose was approximately 25% lower in CF patients. Coefficients of intersubject variability were numerically higher in CF patients, but the difference between groups did not reach significance. On the other hand, the maximum concentration (Cmax), the concentration 2 hours after administration (C2), AUC0-12, and AUC0-4 showed a twofold greater intrasubject variability in CF patients. CsA trough concentration did not predict accurately the AUC, but C2 was a good predictor of the AUC0-4 in both CF (r2=0.90) and non-CF (r2=0.78) patients. CONCLUSION: Compared to patients without CF, patients with CF show a lower bioavailability of CsA and a greater intrasubject variability of Cmax, C2, and AUC. C2 is the best single-point predictor of the AUC0-4 in lung transplant recipients with and without CF.


Assuntos
Ciclosporina/farmacocinética , Fibrose Cística/metabolismo , Imunossupressores/farmacocinética , Transplante de Pulmão , Adulto , Área Sob a Curva , Ciclosporina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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