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Individualized Dosage Sdjustment of Tacrolimus and Mycophenolate Mofetil in First Human Face Allograft Recipient in China

Author: JiaYanYan
Tutor: LuoXiaoXing;WenAiDong
School: Fourth Military Medical University
Course: Pharmacology
Keywords: Face transplant Facial composite tissue allograft Tacrolimus Mycophenolate mofetil Mycophenolic acid Pharmacokinetics Personalized Medicine
CLC: R96
Type: Master's thesis
Year: 2007
Downloads: 36
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Abstract


Limb allograft, the main obstacle is the reason why a large area of ??skin allografts are not widely carried out successfully postoperative prone to immune rejection, occurrence of rejection of transplanted organs and tissues can not be long-term functional survival, even decay necrosis. Implemented in France in 2005 the world's first facial composite tissue allograft aroused strong social repercussions in the world, but 21 days after the occurrence of acute rejection. In April 2006, Xijing Hospital successfully completed the first case of facial composite tissue allograft transplantation organizations including the skin, the expression of muscle, upper lip, and nose, and fits with the artery, external jugular vein and the facial nerve, the degree of difficulty and complexity is much difficult to France to complete allogeneic facial tissue transplantation. Skin composite tissue transplantation recipients after a high chance of rejection, rejection of the degree and frequency of the transplanted tissue will directly affect the long-term survival and timely recovery, immunosuppressants personalized medicine whether reasonable and direct impact on the frequency and extent of postoperative immune rejection reaction, so recipients \world. To date, allogeneic facial tissue transplantation anti individualized dosing regimen rejection study of the country the first time, abroad no experience can learn, the test will mycophenolate mofetil and tacrolimus in the first case of allogeneic facial tissue transplant recipients in vivo pharmacokinetic characteristics, implemented by individual administration, to avoid serious after transplantation rejection or toxicity. Objective: Based on the immunosuppressant tacrolimus Division and pharmacokinetics of mycophenolate mofetil clinical learning characteristics and distribution of the first case of facial composite tissue allograft recipients implementation of personalized medicine, to ensure the therapeutic window within the range of safe and effective , to avoid rejection and immunosuppressant dosage caused due to insufficient amount of immunosuppressant caused by excessive toxicity. Methods: The test is divided into three parts. Part I: high sensitivity, specificity, accuracy and good immunosuppressant tacrolimus Division and mycophenolic acid detection methods. The test first established specificity, high sensitivity, good accuracy and high stability of microparticle immunoassay (EMIA) method for the determination of whole blood tacrolimus the Secretary (FK506) plasma concentrations of analytical methodology, and through the method specific assessment of the performance indicators, precision, accuracy, linearity range and quantitative detection limit of each other Law for evaluation. Determining step: the precise amount of uniformly mixing 150 ul of whole blood sample, adding precision, 150μL protein precipitating agent (zinc sulfate in methanol, isopropanol solution), and the supernatant 200μL Determination of tacrolimus whole blood concentrations; measured using Mode 1, while adding high, medium and low concentrations of tacrolimus control samples. The second is to establish strong specificity, high sensitivity, good accuracy as well as economic and strong high performance liquid chromatography (HPLC) method for the determination of plasma mycophenolic acid (MPA) concentration analysis methods, and on the method-specific, precision, performance indicators for the assessment of the accuracy, stability, recovery, linear range and quantitative detection limit of each other Law for evaluation. Chromatographic conditions Column: Irregular C18 (250 mm × 4.6 mm, 5μm); guard column: Agilent Eclipse C18 (12.5 mm × 4.6 mm, 5μm); mobile phase: methanol? 10 mmol · L-1 K2HPO4 buffer (68: 32, v / v; 5 mmol · L-1 tetrabutylammonium bromide), a flow rate of 1.0 mL · min-1, detection wavelength: 210 nm; column temperature: 25 ° C. Part II: Research immunosuppressant tacrolimus the Division and mycophenolate mofetil in facial composite tissue allograft recipients in vivo pharmacokinetics, the intention is to reveal tacrolimus the Division and mycophenolate mofetil absorption by the body , metabolism, and excretion characteristics and distribution and as a basis to develop an initial dosing regimen. Tacrolimus the Division pharmacokinetics: microparticle immunoassay (EMIA) method for the determination of whole blood tacrolimus concentration. Tacrolimus (FK506) steady state, before taking after taking 0.25,0.5,0.75,1,1.5,2,2.5,3,4,6,8,12 h was extracted by blood mL, placed in a the EDTA anticoagulant test tube, 4 ° C refrigerator until tested. Mycophenolate mofetil pharmacokinetics: high performance liquid chromatography (HPLC) determination of the concentration of the active metabolite of mycophenolate mofetil plasma mycophenolic acid (MPA). Oral mycophenolate mofetil steady state after heparin tubes placed in 2 mL of medication before and after taking 0.25,0.5,1,1.5,2,2.5,3.5,5.5,7.5,11.5 h was extracted by blood in -20 ° C refrigerator tested. DAS 2.0 software to calculate the pharmacokinetic parameters, Tmax, Cmax use of the measured values ??obtained using the trapezoidal method under the curve area AUC. Part III: evaluation, adjustment and optimization of the Division and mycophenolate mofetil, tacrolimus dosing regimen, summarized a safe and effective treatment of facial composite tissue allograft transplant recipients immunosuppressant window. Combined with tacrolimus and mycophenolate mofetil in facial composite tissue allograft recipients pharmacokinetic characteristics, laboratory parameters, biopsy and the recipients transplanted tissue recovery of evaluation, adjustment and optimization of immunosuppressant dosing regimen , the implementation of personalized medicine, to explore different periods after Tacrolimus safe and effective therapeutic window to avoid the occurrence of immune rejection and toxicity caused by improper due to the amount of immunosuppressant. Results: 1 In this test, The EMIA method for the determination of whole blood tacrolimus the Secretary concentration, the detection limit was 3 ng · mL-1, the linear range of 3 to 30 ng · mL-1 within the linear range box precision (RSD) were less than 12.7% accuracy in the range of 94.3 to 100.8%; different kit precision (RSD) were less than 11.1% accuracy in the range of 92.2% to 101.7%. (2) This test uses HPLC method for the determination of the active metabolite of mycophenolate mofetil, mycophenolic acid plasma concentration of mycophenolic acid peak shape, retention time 7.45 min, baseline separation. The detection limit was 0.5 mg · L-1, the linear range of 0.5 to 32 mg · L-1, within the linear range of batch, inter-assay precision (RSD) were less than 10% accuracy in the range of 94.8 to 109.0% ; recoveries were between 79.72 to 84.89%; stability RSD were less than 4.6%. Facial composite tissue allograft recipients tacrolimus Secretary pharmacokinetic profile: oral tacrolimus the Secretary of the steady-state, the main pharmacokinetic parameters: Tmax for 1.5 h, Cmax to 51.4 ng · mL- 1, T1 / 2 for 13.4 h, AUC0 ~ 12 600.58 ng · mL-1 · h-1, 4 facial composite tissue allograft recipients mycophenolic acid pharmacokinetic profile: oral mycophenolate mofetil steady state , the main pharmacokinetic parameters: Tmax for 0.5 h, Cmax to 12.42 mg · L-1, T1 / 2 for 0.51 h, AUC0 ~ 11.5 to 13.31 mg · L-1 · h-1. 5 facial composite tissue allograft \Intraoperative intravenous infusion of tacrolimus the injections and methylprednisolone (MP) impact to achieve the desired concentration as soon as possible, to avoid postoperative hyperacute rejection. The first day after surgery to give the MP 250 mg, diminishing from 40 mg to 130 mg per day, 5 day to change clothes prednisone 80 mg, gradually decreasing to 15 mg daily, maintained at 25 mg / d; 3 d after he g Secretary Mo starting dose of 13 mg / d orally 2 times, according to his later tacrolimus Division plasma concentration, clinical diagnosis and biopsy timely adjust the dose from 13 mg / d reduced to 11 mg / d, and then down to 8 mg / d, and then down to 4 mg / d, and finally transferred to 1 mg / d; mycophenolate mofetil (MMF), a starting dose of 1000 mg / d, gradually increasing the dose to 1500 mg / d last less amount to 750 mg / d; Seney piperazine postoperative adjuvant. Tacrolimus Division therapeutic window after a month was 20.12 ± 4.77 ng · mL-1; after 2 to 3 months was 20.17 ± 4.02 ng · mL-1; after the first 4 to 6 months for the 22.82 ± 7.10 ng · mL-1; after the first 7 to 12 months was 27.88 ± 5.68 ng · mL-1. Biopsy and laboratory test results show that tacrolimus Division and mycophenolate mofetil dose control in a safe and effective treatment window, after transplantation does not appear serious rejection and the immunosuppressant side effects. Conclusions: 1. Establish a high sensitivity, specificity, accuracy and stability of EMIA law determination in whole blood tacrolimus the Secretary concentration analytical methodology. Mycophenolic acid specificity, accuracy, stability, and good recovery in plasma were determined by HPLC analysis methodology. Established tacrolimus in the first allogeneic facial tissue transplant recipients in vivo pharmacokinetic model: the peak time Tmax of 1.5 h, elimination half-life T1 / 2 for 13.4 h, with the general population of drug The dynamic characteristics in line. Tacrolimus recipient body belongs to the slow elimination of the types of drugs, according to its biological half-life T1 / 2 13.4 h design dosing regimens: twice a day, morning and evening administration. Established mycophenolate mofetil in the first allogeneic facial tissue transplant recipients in vivo pharmacokinetic model: the peak time Tmax = 0.5 h, the elimination half-life T1 / 2 for 0.51 h, and the general population pharmacokinetic characteristics in line. Mycophenolic acid in the body of the recipient rapid elimination, are ultra rapid elimination of the types of medication dosing regimens, designed according to the characteristics of its high therapeutic index. 4 established a practical suitable for China's first facial composite tissue allograft recipients individualized dosing regimen. The clinical diagnosis of the indicators show the recipients face transplant tissue function partially restored. Morphology, the recipient facial skin surface smooth, good color, swelling, congestion, ulcers and other clinical manifestations disease does not appear; functional learning composite tissue transplantation for the outside world to stimulate the function of the reaction partially restored.

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