Ácido micofenólico en trasplante renal ¿El problema es la selección de la dosis o su alta variabilidad farmacocinética?

2019 ◽  
Vol 1 (1) ◽  
pp. 84-88
Author(s):  
Pilar García Roca ◽  
Ana María Hernández ◽  
Saúl Valverde ◽  
Rodrigo González Ramírez ◽  
Mara Medeiros
Keyword(s):  
Mycophenolate Mofetil ◽  
Plasma Concentration ◽  
Mycophenolic Acid ◽  
Plasma Concentrations ◽  
High Variability ◽  
Gastrointestinal Disorders ◽  
Pharmacokinetic Variability ◽  
Linear Pharmacokinetics ◽  
Case Presentation ◽  
Drug Pharmacokinetic

Introduction. Mycophenolic acid, in combination with tacrolimus, is the cornerstone of the immunosuppressive therapy in transplants. Nevertheless, its use is controversial because it is associated with adverse events, high variability in plasma concentrations, and because monitoring it in plasma levels is still debatable. Case presentation. A female sixteen-year-old patient with kidney transplant and with maintenance immunosup-pressive therapy. She had been treated with mycophenolate mofetil, tacrolimus, and prednisone according to her size and weight, but she presented recurrent gastrointestinal disorders associated with the administration of mycophenolate mofetil and with overexposure to the drug. Pharmacokinetic monitoring of mycophenolate mofetil was performed and the findings showed high levels of the drug (double concentration); then the dose was reduced. Nevertheless, after two attempts to adjust the levels (and the corresponding monitoring), the goal levels were not achieved; she passed from overexposure to underexposure; there was no relationship among doses adjustments. Based on the risk of graft rejection due to plasma concentration variability, azathioprine was used as an antimetabolite drug instead of mycophenolic acid and the outcomes were good. Conclusions. The pharmacokinetic monitoring was useful to identify overexposure to mycophenolic acid, but it was not possible to properly adjust the dose regimen due to the pharmacokinetic variability, even though the literature claims that mycophenolic acid shows linear pharmacokinetics.

scholarly journals Mycophenolic acid exposure and complement fraction C3 influence inosine 5′-monophosphate dehydrogenase activity in systemic lupus erythematosus

2016 ◽  
Vol 54 (4) ◽  
pp. 490-494
Author(s):  
Yasuaki Mino ◽  
Takafumi Naito ◽  
Kumiko Shimoyama ◽  
Noriyoshi Ogawa ◽  
Junichi Kawakami
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Mycophenolate Mofetil ◽  
Dehydrogenase Activity ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Plasma Concentrations ◽  
Interquartile Range ◽  
Acid Exposure ◽  
Systemic Lupus ◽  
Monophosphate Dehydrogenase

Background Mycophenolate mofetil has recently been reported to be effective against systemic lupus erythematosus. The influence of the pharmacokinetics of mycophenolic acid, the active form of mycophenolate mofetil and the major inactive mycophenolic acid phenolic glucuronide on the activity of the target enzyme inosine 5′-monophosphate dehydrogenase, is expected to be revealed. The aim of this study was to identify the factors associated with inosine 5′-monophosphate dehydrogenase activity in systemic lupus erythematosus patients. Methods Fifty systemic lupus erythematosus patients in remission maintenance phase (29 received mycophenolate mofetil [MMF+] and 21 did not [MMF−]) were enrolled. Median and interquartile range of dose of mycophenolate mofetil were 1500 and 1000–1500 mg/day, respectively. Stepwise multiple linear regression analysis was performed to assess the dependence between inosine 5′-monophosphate dehydrogenase activity and 25 predictor values including predose plasma concentrations of free mycophenolic acid and mycophenolic acid phenolic glucuronide. Results Median and interquartile range of predose total plasma concentrations of mycophenolic acid and mycophenolic acid phenolic glucuronide were 2.73 and 1.43–5.73 and 25.5 and 13.1–54.7  µg/mL, respectively. Predose inosine 5′-monophosphate dehydrogenase activity was significantly higher in MMF+ than MMF− patients (median 38.3 and 20.6 nmoL xanthosine 5′-monophosphate/g haemoglobin/h, P<0.01). The plasma concentration of free mycophenolic acid phenolic glucuronide, complement fraction C3 and body weight were significant predictors accounting for interindividual variability in the inosine 5′-monophosphate dehydrogenase activity (adjusted R2 = 0.52, P < 0.01) in a multivariate analysis. Conclusions Predose inosine 5′-monophosphate dehydrogenase activity was higher in systemic lupus erythematosus patients receiving mycophenolate mofetil therapy. Inosine 5′-monophosphate dehydrogenase activity may be determined by mycophenolic acid exposure and complement fraction C3 in systemic lupus erythematosus patients.

Pharmacogenetics of Mycophenolate Mofetil in Patients Undergoing Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3010-3010
Author(s):  
Janel Long ◽  
William S. Oetting ◽  
Wang Xinjing ◽  
Xianghua Luo ◽  
Marcie Tomblyn ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Kidney Transplant ◽  
Mycophenolic Acid ◽  
Hematopoietic Cell Transplantation ◽  
Univariate Analysis ◽  
Plasma Concentrations ◽  
Hematopoietic Cell ◽  
Pharmacokinetic Parameters ◽  
Published Data ◽  
Kidney Transplant Recipients

Abstract Mycophenolate mofetil (MMF) is commonly used to provide host immunosuppression for hematopoietic cell engraftment and prevention of acute graft vs host disease (GVHD) in recipients of nonmyeloablative allogeneic HCT. There is wide variability in plasma concentrations of mycophenolic acid (MPA), the active metabolite of mycophenolate. Low MPA exposure is associated with poorer rates of engraftment and development of acute GVHD. This variability is not satisfactorily explained by hepatic or renal function suggesting variability may be due to genetic factors involved in drug metabolism or transport. MPA is glucuronidated by UDP glucuronosyltransferase enzymes UGT1A8, 1A9, and 1A10 to the primary metabolite, mycophenolic acid glucuronide (MPAG). MPAG is excreted into the urine and bile through multidrug resistant protein (MRP2) transporters. Several genetic variants of UGT enzymes and MRP2 are known to modify MPA pharmacokinetic parameters in kidney transplant recipients but have not been evaluated in HCT. We hypothesized that these variants are associated with systemic MPA and MPAG concentrations in HCT recipients. Recipient pretransplant DNA was obtained in 133 patients and evaluated for UGT1A8*2, UGT1A8*3, UGT1A9*2, UGT1A9*3, UGT1A9 T-275A, UGT1A9 C-2152T, UGT1A10*2, UGT2B7*2, MRP2 C-24T, MRP2 C-3972T, and MRP2 G-1249A. Patients received MMF at 1–1.5 gm IV or PO every 8–12 hours along with cyclosporine. Each subject had steady-state pharmacokinetics studied once or twice within the first 15 days of transplant for a total of 118 pharmacokinetic profiles. Frequencies of all variants were consistent with published data. Thirty three (24.8%) subjects were heterozygous (CT) and 3 (2.26%) were homozygous (TT) for the MRP2 C-24T variant. MRP2 C-3972T was heterozygous (CT) and homozygous (TT) in 56(42.2%) and 7(5.3%) individuals, respectively. In univariate analysis, there was no association between UGT variants and MPA IV or PO pharmacokinetics. Patients receiving oral MMF and carrying at least one MRP2 C-24T variant had significantly higher median (range) total dose adjusted MPAG Cmax 90.8ug/ml(40.0–164.8) vs 63.3(30.8–202.7), p= 0.02, trough 54.5ug/ml(16.1–99.6) vs 39.7(11.9–173.5), p=0.01 and MPAG Css 71.5ug/ml(28.9–123.0) vs 51.0(19.9–175.6), p=0.01. Similar results were observed for the C-3972T. These data suggest that single UGT variants do not significantly alter MPA exposure but MRP2 variants influence MPAG exposure. Reasons for observed UGT effects on MPA exposure in kidney transplant and not HCT remain unclear but may be due to bioavailability, lack of enterohepatic recycling due to gut decontamination, chemotherapy-induced mucosal and subclinical hepatic damage, and unidentified drug interactions. MRP2 variants may have an impact on other MRP2 substrates such as cyclophosphamide or inhibitors such as cyclosporine. A single UGT genotype to assist in dose selection is unlikely to be of clinical benefit; therefore the effect of combined variants should be explored.

scholarly journals P108 Pharmacokinetics of mycophenolic acid for systemic lupus erythematosus in children

2019 ◽  
Vol 104 (6) ◽  
pp. e63.1-e63
Author(s):  
D Zhang ◽  
V Elie ◽  
S Magreault ◽  
I Melki ◽  
V Baudouin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Plasma Concentration ◽  
Lupus Nephritis ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Interindividual Variability ◽  
Plasma Concentrations ◽  
Systemic Lupus ◽  
Time Curve ◽  
Concentration Time

BackgroundMycophenolate mofetil (MMF) is increasingly used in children with systemic lupus erythematosus (SLE). Monitoring of its active metabolite, mycophenolic acid (MPA), is performed for individual dosage adjustment of MMF and is based on determination of area under the plasma concentration-time curve (AUC12h) of MPA. The objective of this monocentric study is to describe the pharmacokinetics (PK) of MPA in paediatric patients with SLE or lupus nephritis.MethodsPatients with lupus treated by MMF between January 2009 and July 2018 were included. MPA plasma concentrations (T0, T0.5h, T1h, T2h, T3h, T8h and T12h) were determined by EMIT (enzyme-multiplied immunotechnique) and MPA AUC12h calculated according to trapezoid rule.ResultsTwenty-two patients were diagnosed with lupus at 11.5 ± 2.9 years. Clinical presentation was SLE (n=18) or isolated lupus nephritis (n=4). Treatments prior to MMF were steroids and/or immunosuppressants (endoxan, rituximab). Age at initiation of MMF (Cellcept®n=20, Myfortic®n=2) was 12.9 ± 2.6 years.PK of MPA was performed after 8.2 ± 14.8 months of treatment, under MMF dose of 840 ± 218 mg (577 ± 98 mg/m2). A large interindividual variability in MPA concentration-time profiles was observed with the following mean parameters: Cmax=4.60 ± 11.70 µg/mL, tmax=80 ± 77 min, trough plasma concentration (C0) = 2.30 ± 1.60 µg/mL and AUC0-12h=46.29 ± 17.39 µg*h/mL.ConclusionData on the PK of MPA in lupus children are limited. Our results show the high interindividual variability in MPA exposure after oral administration of MMF. Monitoring of exposure based on AUC in combination with immunological disease parameters will allow to individualise treatment to optimiseDisclosure(s)Nothing to disclose

Clinical Impact of Co-medication of Levetiracetam and Clobazam with Proton Pump Inhibitors: A Drug Interaction Study

2020 ◽  
Vol 21 (2) ◽  
pp. 126-131
Author(s):  
Bhuvanachandra Pasupuleti ◽  
Vamshikrishna Gone ◽  
Ravali Baddam ◽  
Raj Kumar Venisetty ◽  
Om Prakash Prasad
Keyword(s):  
Plasma Concentration ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Plasma Concentrations ◽  
Control Group ◽  
Drug Concentrations ◽  
Significant Difference ◽  
Post Hoc ◽  
Hydrolysis Of ◽  
Cytochrome P 450

Background: Clobazam (CLBZ) metabolized primarily by Cytochrome P-450 isoenzyme CYP3A4 than with CYP2C19, Whereas Levetiracetam (LEV) is metabolized by hydrolysis of the acetamide group. Few CYP enzymes are inhibited by Proton Pump Inhibitors (PPIs) Pantoprazole, Esomeprazole, and Rabeprazole in different extents that could affect drug concentrations in blood. The aim of the present study was to evaluate the effect of these PPIs on the plasma concentrations of LEV and CLBZ. Methods: Blood samples from 542 patients were included out of which 343 were male and 199 were female patients and were categorized as control and test. Plasma samples analyzed using an HPLC-UV method. Plasma concentrations were measured and compared to those treated and those not treated with PPIs. One way ANOVA and games Howell post hoc test used by SPSS 20 software. Results: CLBZ concentrations were significantly 10 folds higher in patients treated with Pantoprazole (P=0.000) and 07 folds higher in patients treated with Esmoprazole and Rabeprazole (P=0.00). Whereas plasma concentration of LEV control group has no statistical and significant difference when compared to pantoprazole (P=0.546) and with rabeprazole and esomeprazole was P=0.999. Conclusion: The effect of comedication with PPIs on the plasma concentration of clobazam is more pronounced for pantoprazole to a greater extent when compared to esomeprazole and rabeprazole. When pantoprazole is used in combination with clobazam, dose reduction of clobazam should be considered, or significance of PPIs is seen to avoid adverse effects.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

scholarly journals Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

2013 ◽  
Vol 57 (4) ◽  
pp. 1888-1894 ◽  
Author(s):  
William W. Hope ◽  
Michael VanGuilder ◽  
J. Peter Donnelly ◽  
Nicole M. A. Blijlevens ◽  
Roger J. M. Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Multiple Model ◽  
Pharmacokinetic Variability ◽  
Hematopoietic Stem ◽  
Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

Effects of diltiazem on atrioventricular conduction and arterial blood pressure: correlation with plasma drug concentrations

1984 ◽  
Vol 62 (12) ◽  
pp. 1479-1486 ◽  
Author(s):  
Jean-Paul Clozel ◽  
Jacques Billette ◽  
Gilles Caillé ◽  
Pierre Théroux ◽  
Richard Cartier
Keyword(s):  
Blood Pressure ◽  
Plasma Concentration ◽  
Refractory Period ◽  
Plasma Concentrations ◽  
Atrioventricular Conduction ◽  
Gas Liquid Chromatography ◽  
Conduction Time ◽  
Arterial Blood ◽  
Drug Concentrations ◽  
Atrial Conduction Time

Atrial and atrioventricular conduction variables were studied at control and at the end of each of six consecutive 45-min diltiazem administration periods in eight closed chest-anesthetized dogs. Diltiazem was given as a bolus (50 μg/kg, i.v.) followed by an infusion (0.5 μg∙kg−1∙min−1); doses were doubled in subsequent periods. The plasma concentrations, measured by gas–liquid chromatography, ranged from 8 to 1400 ng/mL and correlated strongly with the doses (r = 0.92; p < 0.01). The Wenckebach cycle length, basic conduction time, and functional refractory period of the atrioventricular (AV) node increased proportionally with plasma concentration (respective r = 0.90, 0.89, 0.80; p < 0.01). The minimum mean plasma concentrations affecting these variables significantly were 37, 83, and 175 ng/mL, respectively. Second or third degree AV blocks developed in all dogs for plasma concentrations between 379 and 1400 ng/mL. In four dogs which were given isoproterenol (0.2 μg∙kg−1∙min−1), these blocks disappeared within 1 min. Atrial conduction time and functional refractory period were slightly but significantly shortened by diltiazem with mean plasma concentrations of 175 ng/mL and over. His–Purkinje intervals were not significantly changed by diltiazem. Systolic and diastolic arterial pressures were decreased by diltiazem (r = −0.64, r = −0.79; p < 0.01) starting with a mean plasma concentration of 83 ng/mL. We conclude that AV nodal conduction variables are progressively prolonged with increasing plasma concentrations of diltiazem; plasma concentrations affecting blood pressure and AV nodal variables overlap; and the AV blocks produced by toxic concentrations of diltiazem can be corrected by isoproterenol.

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