1,720,994 research outputs found
A pharmacokinetic/statistical modelling approach to improve dosage individualization after renal transplantation
No full textImprovement is still needed to improve the patient outcome after kidney transplantation and the biggest challenge is now extending the half-life of the allograft and the prognosis of patient survival long term after transplantation.
The survival of the allograft after transplantation depends on several factors including the immunosuppressive (IS) therapy. Not only the most efficient IS drug or combinations of drugs must be chosen, but also effective and non-toxic levels must be reached in the patients as soon as possible after starting the therapy.
This has become a big challenge since most of the IS drugs are characterized but a high pharmacokinetic (PK) and pharmacodynamic (PD) variability making the use of a standard dosage regimen inappropriate.
The aim of the present thesis is to manage the unexplained variability in the PK of IS drugs (particularly mycophenolic acid (MPA) and tacrolimus (TAC) with the ultimate objective to contribute to a safer and more efficient use of these drugs.
To achieve these objectives, two approaches have been used:
1. The population PK (POP PK) analysis approach that models the time course of drug concentrations in a group of patients after administration of the drug of interest and aims to explain and therefore reduce at least partly the unexplained PK variability by taking into account certain patient characteristics (covariates). This would allow group dosing or improve therapeutic drug monitoring (TDM).
2. Limited sampling strategies (LSS) that allow patient dosage individualization based not only on his/her individual characteristics but also on the characteristics of the population to which he/she belong.
First, we present the results of the validation of a UPLC analytical method for simultaneous quantification of MPA and its metabolites in human plasma. This method is one of the fastest used to date for determination of MPA and its metabolites as part of clinical trial and TDM.
A POP PK modelling study on TAC to identify covariates that could explain its inter- and intra-individual variability is presented. Time of drug administration, analytical method, CYP3A5 and ABCB1 genotypes were found to be significant covariates.
We have also developed and validated MLR-based and Bayesian estimators based LSS for MPA and TAC TDM early and long tem after renal transplantation. Patients were co-medicated with cyclosporine or sirolimus and corticosteroids.
Lastly, we show that Bayesian estimation approach is better than MLR and trough level based approaches for TDM of MPA and TAC when only trough levels are available.(SBIM 3) -- UCL, 201
Pharmacokinetics and dosage adjustment in patients with renal dysfunction
No full textINTRODUCTION: Chronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment. METHODS: Inappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft-Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required. DISCUSSION: According to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drug's pharmacokinetics and pharmacodynamics. CONCLUSION: In conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common
Model-based Strategies of Drug Dosing for Pharmacokinetic Systems
Full text linkThe aim of this paper is to report analytical and individual-based methods forantibiotic dose selection, that are based on tools from system and control theory. A brief system analysis of standard population pharmacokinetic models proves that such models are nonnegative and stable. Then, an input-output analysis leads to an open-loop control law which yields a dosing for the "average" patient, based on the equilibrium trajectory of the system. This approach is then incorporated into a "worst-case" analysis based on the monotony of the statetrajectories with respect to the clearance (model parameter). Finally, an heuristic method of an estimated state feedback is presented. Thanks to numerical simulations, these methods were successively illustrated on a model describing the pharmacokinetic of meropenem, an intravenous antibiotic for treatment of severe sepsis.The aim of this paper is to report analytical and individual-based methods for antibiotic dose selection, that are based on tools from system and control theory. A brief system analysis of standard population pharmacokinetic models proves that such models are nonnegative and stable. Then, an input-output analysis leads to an open-loop control law which yields a dosing for the "average" patient, based on the equilibrium trajectory of the system. This approach is then incorporated into a "worst-case" analysis based on the monotony of the state trajectories with respect to the clearance (model parameter). Finally, an heuristic method of an estimated state feedback is presented. Thanks to numerical simulations, these methods were successively illustrated on a model describing the pharmacokinetic of meropenem, an intravenous antibiotic for treatment of severe sepsis.</p
Model informed drug development and CAR-T cells:A review of their use and credibility assessment in the context of EMA centralized procedures
No full textModel informed drug development and CAR-T cells:A review of their use and credibility assessment in the context of EMA centralized procedures
No full textTowards a Generic Tool for Prediction of Meropenem Systemic and Infection-Site Exposure:A Physiologically Based Pharmacokinetic Model for Adult Patients with Pneumonia
No full textObjective: The objective of this study was to develop a physiologically based pharmacokinetic model for meropenem using a retrograde approach, which could serve as a basis for prediction of the systemic and infection-site drug exposures in different populations and indications. We intended this model to be a useful tool to inform (local) pharmacokinetic-based optimal dosing of meropenem in different settings. Methods: We developed a reduced physiologically based pharmacokinetic model with NONMEM software using a top-down approach. We used historical (previously published) data for model development and qualification. We used steady-state systemic and infection-site concentrations from 60 adult patients diagnosed with severe lung infection for model development and internal evaluation. The data included rich plasma and sparse epithelial lining fluid samples. We based the internal validation of the model on successful numerical convergence, adequate precision in parameter estimation, acceptable goodness-of-fit plot with no indication of bias, and acceptable performance of visual predictive checks. We performed external validation by fitting the model to independent data from five previously published studies: four studies in patients with pneumonia, with different grades of renal impairment, and one study in morbidly obese patients. Results: We successfully fitted a reduced physiologically based pharmacokinetic model with six compartments (arterial and venous pools, infection site [lungs], liver, kidneys and rest of the body) to the data and adequately estimated model parameters. We successfully qualified the model (internally and externally) using established methods. Estimated values for tissue-to-plasma partition coefficients were 0.2629 and 0.1946 for lungs and non-fat tissues (kidneys and liver), respectively. Estimated total clearance was 8.174 L/h for a typical patient with a glomerular filtration rate of 65 mL/min. Consistent with the known mechanism of meropenem elimination and previously published models, renal clearance accounted for 70% of total clearance. The model had good predictive performances on data from five different sources including populations with different characteristics with regard to body size, renal function and morbidity. Conclusions: We successfully developed a physiologically based pharmacokinetic model for meropenem in adult patients to be used as a basis for prediction of concentrations in different groups of patients, and eventually for effective dose individualisation in different subgroups of the population.</p
THE USE OF MODELING AND SIMULATION TO INFORM HAEMOGLOBINOPATHIES DRUG DEVELOPMENT – A REVIEW OF SCIENTIFIC ADVICES FROM JANUARY 2014 TO DECEMBER 2024
No full textA Fast Ultra-Performance Liquid Chromatography Method for Simultaneous Quantification of Mycophenolic Acid and Its Phenol- and Acyl-Glucuronides in Human Plasma.
No full textSeveral studies have demonstrated a close relationship between mycophenolic acid (MPA) exposure and the risk for graft rejection or side effects. Measurements of MPA and its metabolites plasma levels are therefore recommended. A new chromatographic method has been developed using ultra-performance liquid chromatography (UPLC) to improve both analytical throughput and sensitivity. MPA and its phenol-glucuronide and acyl-glucuronide were extracted from plasma using Isolute C2 solid phase extraction (SPE) cartridges (100 mg, 3 mL). UPLC separations were performed with a Waters BEH C18 column (50 x 2.1 mm, 1.7 mum) maintained at 65 degrees C on a Waters Acquity instrument equipped with a photodiode array detector. The total UPLC run time was 3.5 minutes. The method was linear in the range of 0.1-40 mug/mL for MPA and acyl-glucuronide, and 1-400 mug/mL for phenol-glucuronide. Relative standard error and mean relative prediction error were 10 to 3.5 minutes) was obtained using UPLC for MPA analyses. This retention time reduction was accompanied by an improvement of other analytical performances such as sensitivity
Model informed drug development and CAR-T cells:A review of their use and credibility assessment in the context of EMA centralized procedures
No full textUse of modeling and simulation to inform the development of monoclonal antibodies to treat moderate-to-severe asthma: a review of EMA centralized procedure from 2014 to 2024.
No full text- …
