miRNAs, dd-cf-DNA, and Chemokines as Potential Noninvasive Biomarkers for the Assessment of Clinical Graft Evolution and Personalized Immunosuppression Requirement in Solid Organ Transplantation.

The use of noninvasive biomarkers may reduce the need for biopsy and guide immunosuppression adjustments during transplantation. The scientific community in solid organ transplantation currently considers that chemokines, T- and B-cell immunophenotypes, and gene expression, among other molecular biomarkers, have great potential as diagnostic and predictive biomarkers for graft evolution; however, in clinical practice, few valid early biomarkers have emerged. This review focuses on the most relevant scientific advances in this field in the last 5 years regarding the role of 3 biomarkers: miRNAs, chemokines, and ddcf-DNA, in both adult and pediatric populations.

Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document.

Calculation of reference intervals for the concentrations of α-tocopherol and retinol in serum using indirect data-mining procedures.

Background: Establishing adequate reference intervals (RIs) for vitamins A and E is essential for diagnosing and preventing deficiencies. Due to the current boom in data mining and its easy applicability, more laboratories are establishing RIs using indirect methods. Our study aims to obtain RIs using four indirect data-mining procedures (Bhattacharya, Hoffmann, Kosmic, and RefineR) for vitamins A and E.

Focusing on Ischemic Reperfusion Injury in the New Era of Dynamic Machine Perfusion in Liver Transplantation.

Liver transplantation is the most effective treatment for end-stage liver disease. Transplant indications have been progressively increasing, with a huge discrepancy between the supply and demand of optimal organs. In this context, the use of extended criteria donor grafts has gained importance, even though these grafts are more susceptible to ischemic reperfusion injury (IRI).

A plasmatic score using a miRNA signature and CXCL-10 for accurate prediction and diagnosis of liver allograft rejection.

Introduction: The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort.

Methods: A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT.

Genotype and Phenotype Influence the Personal Response to Prostaglandin Analogues and Beta-Blockers in Spanish Glaucoma and Ocular Hypertension Patients.

Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714).

Drug-drug interactions of ritonavir-boosted SARS-CoV-2 protease inhibitors in solid organ transplant recipients: experience from the initial use of lopinavir-ritonavir.

Objectives: To review the drug-drug interactions between tacrolimus and lopinavir/ritonavir in 23 patients who received solid organ transplant during the first wave of COVID-19 and to determine the efficacy as well as safety of prednisone monotherapy.

Methods: Observational study performed between March and June 2020 in solid organ transplant recipients admitted with an established diagnosis of SARS-CoV-2 infection who received lopinavir/ritonavir (≥2 doses). Once lopinavir/ritonavir therapy was initiated, calcineurin inhibitor treatment was temporarily switched to prednisone monotherapy (15-20 mg/d) to avoid drug-drug interactions and toxicity.

Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide.

Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined.

Dried Blood Spot (DBS) as a useful tool to improve clozapine, aripiprazole and paliperidone treatment: From adherence to efficiency.

Introduction: Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety.

Methods: 31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11).

Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics.

The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C0/D < 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections.

Therapeutic Drug Monitoring and Dosage Adjustments of Immunosuppressive Drugs When Combined With Nirmatrelvir/Ritonavir in Patients With COVID-19.

Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component.

Polyethylene Glycol Drug-Eluting Embolic Microspheres Loaded with Doxorubicin for the Treatment of Hepatocellular Carcinoma: Feasibility, Safety, and Pharmacokinetic Study.

Purpose: Polyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC).

Materials And Methods: The current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0.

Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections.

Objectives: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target.

Methods: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment.

Getting immunosuppression just right: the role of clinical biomarkers in predicting patient response post solid organ transplantation.

Introduction: Actually, immunosuppression selection isn't based on individual immune alloreactivity, and immunosuppressive drug dosing is mainly based on the development of toxicity and the achievement of specific target concentrations. Since a successful outcome requires optimal patient risk stratification and treatment, several groups have evaluated candidate biomarkers that have shown promise in the assessment of individual immune responses, the prediction of personal pharmacodynamic effects of immunosuppressive drugs and the prognosis and diagnosis of graft outcomes..

Monitoring of Donor-Derived Cell-Free DNA by Short Tandem Repeats: Concentration of Total Cell-Free DNA and Fragment Size for Acute Rejection Risk Assessment in Liver Transplantation.

Monitoring of graft function is essential during the first months after liver transplantation (LT), but current liver function tests (LFTs) lack the specificity and sensitivity to ensure an efficient diagnosis of acute rejection (AR). Recently, donor-derived cell-free DNA (ddcfDNA) has emerged as a noninvasive biomarker to assess graft integrity. This study evaluated the feasibility of measuring the ddcfDNA through short tandem repeat (STR) analysis by quantitative fluorescent-polymerase chain reaction (QF-PCR) and to assess the role of the concentration and fragment size of total cfDNA as AR biomarkers.

Advantages of plasmatic CXCL-10 as a prognostic and diagnostic biomarker for the risk of rejection and subclinical rejection in kidney transplantation.

This study evaluate the potential of plasmatic CXCL-10 (pCXCL-10) as a pre&post transplantation prognostic and diagnostic biomarker of T-cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR) and subclinical rejection (SCR) risk in adult kidney recipients considering BKV and CMV infections as possible clinical confounder factors. Twenty-eight of 100 patients included experienced rejection (TCMR:14; ABMR:14); 8 SCR; 13 and 16 were diagnosed with BKV and CMV infection, respectively. Pre-transplantation pCXCL-10 was significantly increased in TCMR and ABMR and post-transplantation in TCMR, ABMR and SCR compared with nonrejectors.

Tacrolimus, Sirolimus and Everolimus Doses in HIV-Infected Solid-Organ Recipients, Requiring a Cobicistat-Based Antiretroviral Regimen: Report of Three Cases and Review.

People living with HIV should be considered candidates for solid-organ transplantation (SOT). However, managing HIV-infected patients undergoing SOT represents a major challenge due to the potential drug-drug interactions between antiretroviral drugs and immunosuppressive agents, particularly when resorting to antiretroviral drugs that require pharmacokinetic enhancers. We report three cases of cobicistat-tacrolimus co-administration, two of which also include the co-administration of mTOR inhibitors, in HIV-positive patients undergoing SOT (2 kidney and 1 liver recipient).

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome.

Monitoring of gene expression in tacrolimus-treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study.

Aims: Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy.

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.

Tetracaine from urethral ointment causes false positive amphetamine results by immunoassay.

Background: Amphetamine urine drug screening by immunoassay is prone to cross-react with other compounds leading to false positive results. Tetracaine is a local anesthetic drug used in the clinical setting as an ointment during urinary catheterization. In our laboratory, tetracaine is often detected by gas chromatography-mass spectrometry in the urine of patients admitted in the emergency department with false positive amphetamine results.