French-Speaking Network of Pharmacogenetics (RNPGx) Recommendations for Clinical Use of Mavacamten.

Mavacamten, the first drug in the class of β-cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 poor metabolizers have increased exposure and are at increased risk of reduced cardiac hypercontractility.

Physicochemical and microbiological stability of 40 mg/mL amiodarone hydrochloride oral suspension.

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Development of an Oral Liquid Formulation of Nicardipine Hydrochloride Compounded with Simple Excipients for the Treatment of Pediatric Hypertension.

Nicardipine hydrochloride is an anti-hypertensive drug that is used off-label to treat hypertension in children. A previous oral formulation of nicardipine hydrochloride was developed using a commercial vehicle as an excipient. However, ready-to-use vehicles are prone to supply shortages, and their composition may undergo substantial modifications.

Population Pharmacokinetics of Levosimendan and its Metabolites in Critically Ill Neonates and Children Supported or Not by Extracorporeal Membrane Oxygenation.

Background: Levosimendan (LVSMD) is a calcium-sensitizer inotropic and vasodilator agent whose use might have a beneficial effect on the weaning of venoarterial extracorporeal membrane oxygenation (VA-ECMO). In light of LVSMD pharmacological characteristics, we hypothesized that ECMO may induce major pharmacokinetic (PK) modifications for LVSMD and its metabolites.

Objective: The aim of this study was to investigate the PK of LVSMD and its metabolites, and to assess the effects of ECMO on PK parameters.

Therapeutic Drug Monitoring of Sputum Voriconazole in Pulmonary Aspergillosis.

Voriconazole is one of the most used antifungal azoles against pulmonary aspergillosis. Therapeutic drug monitoring (TDM) of the voriconazole concentration in plasma is recommended in clinical practice guidelines to prevent treatment failure and toxicity. The aim of this study was to evaluate the feasibility and utility of TDM of the voriconazole concentration in the sputum of patients treated for pulmonary aspergillosis.

Evidence of pharmacogenetics-based fluvoxamine use as an add-on to clozapine treatment in psychiatry.

Pharmacological treatments used for psychiatric disorders, such as clozapine, demonstrate large interindividual variability in terms of possible adverse effects and therapeutic benefit. This variability can be explained by multiple factors, including pharmacogenetic factors. Clozapine efficacy can be impacted by CYP polymorphisms.

Reliability of the Minto model for target-controlled infusion of remifentanil during cardiac surgery with cardiopulmonary bypass.

Background: The Minto pharmacokinetic model is used for target-controlled infusion of remifentanil. The reliability of this model has never been evaluated during normothermic cardiac surgery with cardiopulmonary bypass (CPB). The aim of this study was to assess the predictive performance of the model during CPB to determine its reliability during cardiac surgery.

Ultrafast Measurement of Metformin in the Clinical Setting Using Probe Electrospray Ionization Mass Spectrometry.

Metformin (MtF) is a treatment used for type 2 diabetes. Lactic acidosis (LA) is a frequent complication that can be either induced by or associated with elevated MtF plasma concentrations. When coupled with a mass spectrometry (MS) system, the probe electrospray ionization (PESI) method allows direct and rapid analysis of different types of matrices without pretreatment.

A Robust and Fast/Multiplex Pharmacogenetics Assay to Simultaneously Analyze 17 Clinically Relevant Genetic Polymorphisms in , , , , , , and Genes.

In the field of pharmacogenetics, the trend is to analyze a panel of several actionable genetic polymorphisms. It may require the use of high-throughput sequencing which demands expensive reagents/instruments and specific skills to interpret results. As an alternative, the aim of this work was to validate an easy, fast, and inexpensive multiplex pharmacogenetics assay to simultaneously genotype a panel of 17 clinically actionable variants involved in drug pharmacokinetics/pharmacodynamics.

Proposals for a standardized procedure of validation of DNA extraction and allelic discrimination assays in pharmacogenomics according to ISO15189 requirements.

Objectives: In the era of quality management in clinical laboratories, method validation can be a challenge without appropriate guidelines, such as in the field of pharmacogenetics. The present work describes a method validation for DNA extraction and CYP3A5*3 genotyping, which would meet ISO15189:2012 requirements.

Methods: DNA extraction was performed using a QIAamp DSP DNA Blood kit, DNA purity and concentration were determined using a Nanodrop, and the genotyping assay was a real-rime PCR using TaqMan reagents.

Pharmacokinetic modeling of morphine and its glucuronides: Comparison of nebulization versus intravenous route in healthy volunteers.

Intravenous (i.v.) morphine is a safe, robust, and recommended treatment for severe pain using the titration principle.

Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series.

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way.

Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data.

Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450.

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients.

This study addressed the hypothesis that epoxyeicosatrienoic acids (EETs) synthesized by CYP450 and catabolized by soluble epoxide hydrolase (sEH) are involved in the maintenance of renal allograft function, either directly or through modulation of cardiovascular function. The impact of single nucleotide polymorphisms (SNPs) in the sEH gene EPHX2 and CYP450 on renal and vascular function, plasma levels of EETs and peripheral blood monuclear cell sEH activity was assessed in 79 kidney transplant recipients explored at least one year after transplantation. Additional experiments in a mouse model mimicking the ischemia-reperfusion (I/R) injury suffered by the transplanted kidney evaluated the cardiovascular and renal effects of the sEH inhibitor t-AUCB administered in drinking water (10 mg/l) during 28 days after surgery.

Stability study of a compounded oral solution of nicardipine for the treatment of hypertension in children.

Nicardipine is an antihypertensive drug that may be used off-label by oral route to treat hypertension in children. Currently commercially available tablets are inappropriate for oral use in children and manufactured hard capsules are not suitable for easy dose individualization to achieve target blood pressure. We aimed to fulfill this lack of appropriate dose forms by developing an oral liquid formulation of nicardipine.

Pharmacogenetics of Direct Oral Anticoagulants: A Systematic Review.

Dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban are direct oral anticoagulants (DOACs). Their inter-individual variability in pharmacodynamics and pharmacokinetics (transport and metabolism) is high, and could result from genetic polymorphisms. As recommended by the French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases (as antiplatelet agents, oral vitamin K antagonists, and statins) can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity.

Corneal Pharmacokinetics of Voriconazole and Posaconazole following Intrastromal Injection and Posaconazole Eye Drops Instillation in Rats.

: Infectious keratitis is a major cause of visual impairment and blindness worldwide. Common difficulties in treating fungal keratitis prompt new therapeutic possibilities. In this study, intrastromal voriconazole and posaconazole, and topical posaconazole were tested for their potential to obtain therapeutic cornea concentrations.

Deleterious impact of a generic temozolomide formulation compared with brand-name product on the kinetic of platelet concentration and survival in newly diagnosed glioblastoma.

Chemo-induced thrombocytopenia is a limiting toxicity among patients receiving temozolomide (TMZ) as first-line treatment for glioblastoma. We aimed to compare early platelet concentration kinetics, hematological safety profile, and impact on survival following the initiation of either the brand-name or a generic TMZ formulation. A retrospective trial was conducted in patients suffering from newly diagnosed glioblastoma.

Efficacy of a ciprofloxacin/amikacin combination against planktonic and biofilm cultures of susceptible and low-level resistant Pseudomonas aeruginosa.

Background: Eradicating bacterial biofilm without mechanical dispersion remains a challenge. Combination therapy has been suggested as a suitable strategy to eradicate biofilm.

Objectives: To evaluate the efficacy of a ciprofloxacin/amikacin combination in a model of in vitro Pseudomonas aeruginosa biofilm.

Interest of adjusting urine cannabinoids to creatinine level to monitor cannabis cessation therapy in heavy smokers with psychiatric disorders.

Up to 25% of hospitalized patients in a psychiatric department exhibit troubles linked to cannabis use. Weaning patients with psychiatric disorders off drugs of abuse requires specific care to improve their clinical outcome. The present study aims to develop a predictive model of urinary excretion of creatinine-normalized cannabinoids (U ) and to determine U thresholds corresponding to the widely used cut-offs of 20 ng/mL and 50 ng/mL for cannabinoids.

Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients.

Background: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.

Methods And Results: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation.

The right blood collection tube for therapeutic drug monitoring and toxicology screening procedures: Standard tubes, gel or mechanical separator?

Stability data of toxics or drugs in gel-based or mechanical separation blood collection tubes are lacking, especially for therapeutic drug monitoring and clinical toxicology procedures. According to ISO 15189 accreditation standard, laboratories need to master the entire preanalytical process including the stability of analytes in a specific tube. Here we explored the impact of BD PST™ II and Barricor™ separator tubes on the stability of 167 therapeutic compounds and common drugs of abuse in plasma samples using LC-MS/MS.

Isavuconazole Kinetic Exploration for Clinical Practice.

Background: Isavuconazole is a new antifungal prodrug for the treatment of invasive aspergillosis and mucormycosis. As no clear pharmacokinetic-pharmacodynamic relationship has been established for patients, therapeutic drug monitoring is not currently required. However, as isavuconazole is a new drug, clinicians are sometimes sceptical about the exposure achieved in their patients and seek pharmacokinetic exploration.