A Population Pharmacokinetic Model and Dosing Algorithm to Guide the Tacrolimus Starting and Follow-Up Dose in Living and Deceased Donor Kidney Transplant Recipients.

Introduction: Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to predict an individual's dose requirement following living and deceased donor kidney transplantation.

Methods: In this international, multicenter, retrospective study, data was collected from patients who had received a living or a deceased donor kidney and received tacrolimus twice daily.

Population pharmacokinetics of levetiracetam in patients diagnosed with refractory epilepsy: A real-world study.

Objectives: Levetiracetam is a widely used antiseizure drug in patients with refractory epilepsy due to its specific mechanism of action. This study aimed to develop and validate a population pharmacokinetic model (PopPK) to optimize levetiracetam dosing in patients with refractory epilepsy.

Methods: A total of 256 plasma concentrations of levetiracetam, obtained from 135 patients, were employed for PopPK model development, applying a nonlinear mixed-effects modeling methodology.

A new population pharmacokinetic model for dosing optimization of zonisamide in patients with refractory epilepsy.

Zonisamide exhibits significant pharmacokinetic variability, demanding for the development of population pharmacokinetic (PopPK) models to identify key factors influencing drug disposition. This study aimed to develop and validate a PopPK model to optimize zonisamide posology in patients with refractory epilepsy. A total of 114 plasma concentrations of zonisamide, obtained from 64 patients, were used for PopPK model development, employing the nonlinear mixed-effects modelling approach.

Customizing Tacrolimus Dosing in Kidney Transplantation: Focus on Pharmacogenetics.

Different polymorphisms in genes encoding metabolizing enzymes and drug transporters have been associated with tacrolimus pharmacokinetics. In particular, studies on CYP3A4 and CYP3A5, and their combined cluster have demonstrated their significance in adjusting tacrolimus dosing to minimize under- and overexposure thereby increasing the proportion of patients who achieve tacrolimus therapeutic target. Many factors influence the pharmacokinetics of tacrolimus, contributing to inter-patient variability affecting individual dosing requirements.

Guiding the starting dose of the once-daily formulation of tacrolimus in " adult renal transplant patients: a population approach.

Aims: The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period.

Methods: A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed.

Tools for a personalized tacrolimus dose adjustment in the follow-up of renal transplant recipients. Metabolizing phenotype according to CYP3A genetic polymorphisms versus concentration-dose ratio.

Background And Justification: The strategy of the concentration-dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile.

Materials And Methods: 425 kidney transplant patients who received Tac as immunosuppressive treatment have been included.

The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model.

Background: Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing.

Objective: The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance.

Pharmacokinetics of Hydroxytyrosol and Its Sulfate and Glucuronide Metabolites after the Oral Administration of Table Olives to Sprague-Dawley Rats.

The pharmacokinetics (PK) of hydroxytyrosol and its metabolites were characterized following oral administration to Sprague-Dawley rats of 3.85 and 7.70 g of destoned Arbequina table olives/kg.

and Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach.

The aim of the study is to develop a population pharmacokinetic (PopPK) model and to investigate the influence of CYP3A5/CYP3A4 and ABCB1 single nucleotide polymorphisms (SNPs) on the Tacrolimus PK parameters after LCP-Tac formulation in stable adult renal transplant patients. The model was developed, using NONMEM v7.5, from full PK profiles from a clinical study (n = 30) and trough concentrations (C) from patient follow-up (n = 68).

Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study.

Voriconazole, an antifungal agent, displays high intra- and inter-individual variability. The predictive pharmacokinetic (PK) index requires a minimum plasma concentration (C) in patient serum of between 1-5.5 mg/L.

A prospective controlled, randomized clinical trial of kidney transplant recipients developed personalized tacrolimus dosing using model-based Bayesian Prediction.

For three decades, tacrolimus (Tac) dose adjustment in clinical practice has been calculated empirically according to the manufacturer's labeling based on a patient's body weight. Here, we developed and validated a Population pharmacokinetic (PPK) model including pharmacogenetics (cluster CYP3A4/CYP3A5), age, and hematocrit. Our study aimed to assess the clinical applicability of this PPK model in the achievement of Tac Co (therapeutic trough Tac concentration) compared to the manufacturer's labelling dosage.

Population Pharmacokinetic Analysis of Perampanel in Portuguese Patients Diagnosed with Refractory Epilepsy.

Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM).

In Vitro Approaches to Explore the Anticancer Potential of One Natural Flavanone and Four Derivatives Loaded in Biopolymeric Nanoparticles for Application in Topical Delivery Treatments.

The increasing number of skin cancer cases worldwide and the adverse side effects of current treatments have led to the search for new anticancer agents. In this present work, the anticancer potential of the natural flavanone 1, extracted from , and four flavanone derivatives 1a-d obtained by different reactions from 1 was investigated by an in silico study and through cytotoxicity assays in melanoma (M21), cervical cancer (HeLa) cell lines and in a non-tumor cell line (HEK-293). The free compounds and compounds loaded in biopolymeric nanoparticles (PLGA NPs 1, 1a-d) were assayed.

Baricitinib Lipid-Based Nanosystems as a Topical Alternative for Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a chronic autoimmune inflammatory skin disorder which causes a significant clinical problem due to its prevalence. The ongoing treatment for AD is aimed at improving the patient's quality of life. Additionally, glucocorticoids or immunosuppressants are being used in systemic therapy.

The Effect of Intracellular Tacrolimus Exposure on Calcineurin Inhibition in Immediate- and Extended-Release Tacrolimus Formulations.

Despite intensive monitoring of whole blood tacrolimus concentrations, acute rejection after kidney transplantation occurs during tacrolimus therapy. Intracellular tacrolimus concentrations could better reflect exposure at the site of action and its pharmacodynamics (PD). Intracellular pharmacokinetic (PK) profile following different tacrolimus formulations (immediate-release (TAC-IR) and extended-release (TAC-LCP)) remains unclear.

Comparison of Three Renal Function Formulas for Ganciclovir/Valganciclovir Dose Individualization in CMV-Infected Solid Organ Transplantation Patients Using a Population Approach.

Background And Objective: The gold standard treatment of established cytomegalovirus infection or prevention in solid organ transplantation is the intravenous administration of ganciclovir (GCV) or oral administration of valganciclovir (VGCV), both adjusted to the renal function. In both instances, there is a high interindividual pharmacokinetic variability, mainly owing to the wide range of variation of both the renal function and body weight. Therefore, accurate estimation of the renal function is crucial for GCV/VGCV dose optimization.

Population pharmacokinetic modelling of fibrinogen in patients with congenital or acquired-chronic or acute-hypofibrinogenaemia.

Aims: Fibrinogen is the key substrate for coagulation. Fibrinogen pharmacokinetics (PK) after single doses of fibrinogen concentrate (FC), using modelling approaches, has only been evaluated in congenital afibrinogenaemic patients. The aims of this study are to characterize the fibrinogen PK in patients with acquired-chronic (cirrhosis) or acute-hypofibrinogenaemia (critical haemorrhage), showing endogenous production.

Baricitinib Liposomes as a New Approach for the Treatment of Sjögren's Syndrome.

Sjögren's syndrome is a chronic systemic autoimmune disease affecting from 0.2 to 3% of the general population. The current treatment for Sjögren's syndrome is aimed at controlling symptoms such as dry eyes and xerostomia.

Swine as the Animal Model for Testing New Formulations of Anti-Inflammatory Drugs: Carprofen Pharmacokinetics and Bioavailability of the Intramuscular Route.

Carprofen (CP) is a non-steroidal anti-inflammatory drug (NSAID) frequently used to treat respiratory diseases in numerous small animals, but also in large species. CP is a formidable candidate for further therapeutic research of human inflammatory diseases using the pig as an animal model. However, CP administration in swine is very uncommon and respective pharmacokinetics/bioavailability studies are scarce.

Enhanced Transdermal Delivery of Pranoprofen Using a Thermo-Reversible Hydrogel Loaded with Lipid Nanocarriers for the Treatment of Local Inflammation.

A biocompatible topical thermo-reversible hydrogel containing Pranoprofen (PF)-loaded nanostructured lipid carriers (NLCs) was studied as an innovative strategy for the topical treatment of skin inflammatory diseases. The PF-NLCs-F127 hydrogel was characterized physiochemically and short-time stability tests were carried out over 60 days. In vitro release and ex vivo human skin permeation studies were carried out in Franz diffusion cells.

Plasma idebenone monitoring in Friedreich's ataxia patients during a long-term follow-up.

Introduction And Objectives: Despite the growing interest and the potential benefits of idebenone as a repurposed drug for different orphan conditions, data regarding its monitoring are scarce. Our main goal was to report plasma idebenone values in a cohort of Friedreich's ataxia (FRDA) patients during a long-term follow-up. Taking advantage of this, we also assessed cardiological and neurological status together with idebenone values and genetic background.

Influence of the Circadian Timing System on Tacrolimus Pharmacokinetics and Pharmacodynamics After Kidney Transplantation.

Tacrolimus is the backbone immunosuppressant after solid organ transplantation. Tacrolimus has a narrow therapeutic window with large intra- and inter-patient pharmacokinetic variability leading to frequent over- and under-immunosuppression. While routine therapeutic drug monitoring (TDM) remains the standard of care, tacrolimus pharmacokinetic variability may be influenced by circadian rhythms.

A first-in-human phase I/Ib dose-escalation clinical trial of the autophagy inducer ABTL0812 in patients with advanced solid tumours.

Background: ABTL0812 is an autophagy inducer that promotes cancer cell death by activation of cytotoxic autophagy selectively in tumour cells. ABTL0812 induces endoplasmic reticulum stress and blocks the Akt-mTOR axis; both actions converge to activate a robust and sustained autophagy leading to cancer cell death. Preclinical data supported the initiation of clinical trials in patients with cancer.

Early prognostic performance of miR155-5p monitoring for the risk of rejection: Logistic regression with a population pharmacokinetic approach in adult kidney transplant patients.

Previous results from our group and others have shown that urinary pellet expression of miR155-5p and urinary CXCL-10 production could play a key role in the prognosis and diagnosis of acute rejection (AR) in kidney transplantation patients. Here, a logistic regression model was developed using NONMEM to quantify the relationships of miR155-5p urinary expression, CXCL-10 urinary concentration and tacrolimus and mycophenolic acid (MPA) exposure with the probability of AR in adult kidney transplant patients during the early post-transplant period. Owing to the contribution of therapeutic drug monitoring to achieving target exposure, neither tacrolimus nor MPA cumulative exposure was identified as a predictor of AR in the studied population.