Xavier Delavenne

A Pharmacokinetic-Pharmacodynamic Model for Predicting the Impact of CYP2C9 and VKORC1 Polymorphisms on Fluindione and Acenocoumarol During Induction Therapy

Background and ObjectiveVitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to fluindione and acenocoumarol. The aims of this study were to characterize the relationship between fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization.MethodsFluindione concentrations, S- and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3.ResultsA two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity.ConclusionDuring initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of fluindione therapy, in addition to genetic factors.

In Vitro Comparison of the Role of P-Glycoprotein and Breast Cancer Resistance Protein on Direct Oral Anticoagulants Disposition

BackgroundPharmacokinetics of direct oral anticoagulants (DOACs) are influenced by ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).ObjectivesTo better understand the role of transporters in DOAC disposition, we evaluated and compared the permeabilities and transport properties of these drugs.MethodsBidirectional permeabilities of DOACs were investigated across Caco-2 cells monolayer. Transport assays were performed using different concentrations of DOAC and specific inhibitors of ABC transporters. Cell model functionality was evaluated by transport assay of two positive control substrates.ResultsThe results of transport assays suggest a concentration-dependent efflux of apixaban, dabigatran etexilate and edoxaban, whereas the efflux transport of rivaroxaban did not seem to depend on concentration. Verapamil, a strong inhibitor of P-gp, decreased DOAC efflux in the Caco-2 cell model by 12–87%, depending on the drug tested. Ko143 reduced BCRP-mediated DOAC efflux in Caco-2 cells by 46–76%.ConclusionThis study allowed identification of three different profiles of ABC carrier-mediated transport: predominantly P-gp-dependent transport (dabigatran), preferential BCRP-dependent transport (apixaban) and approximately equivalent P-gp and BCRP-mediated transport (edoxaban and rivaroxaban).

Antithrombotics in pulmonary hypertension: more work needed before we turn to newer agents!

Therapeutic research is particularly dynamic in the setting of pulmonary arterial hypertension (PAH). Despite the low prevalence of this rare disease, the efficacy and safety of targeted PAH therapies have been evaluated in randomised controlled trials, providing important data for clinicians, health authorities and patients. Beside these well-studied targeted therapies, “supportive therapy” is also recommended. This includes antithrombotic therapy with vitamin-K antagonists (VKAs) [1]. The background for the use of these agents is principally supported by findings in histopathological and biological studies [2, 3], as well as their potential indirect clinical consequences which may present as perfusion defects evaluated by ventilation/perfusion ( V ′/ Q ′) scan [4]. Clinical studies evaluating VKAs in the setting of PAH are, however, lacking. In the prospective study published by Rich et al. [5], VKA use improved prognosis, but the allocation to VKA treatment followed the demonstration of perfusion defects on V ′/ Q ′ scan, and not from proper randomisation. This explains the low level of the related recommendation in the guidelines from the European Respiratory Society and European Society of Cardiology [1], that being a class IIa recommendation for idiopathic or heritable PAH and for PAH due to anorexigens, and an even lower level of recommendation in patients with associated PAH. By extension, anticoagulant therapy has been proposed in other groups of pulmonary hypertension (groups 2, 3 or 5) despite the absence of specific studies. Paradoxically, whereas only half of patients with a certain indication for VKA therapy (for example, atrial fibrillation) receive VKA [6], most PAH patients are anticoagulated with VKA (90% of the patients included in the French registry) [7]. Conversely, antithrombotic therapy with VKA is the cornerstone of medical therapy in the case of …

Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism

Graphical abstract Figure. No caption available. &NA; The treatment of acute venous thromboembolism (VTE) is being completely modified with the development of direct oral anticoagulants (DOACs). Rivaroxaban, apixaban and edoxaban directly inhibit factor Xa, whereas dabigatran inhibits factor IIa. All these drugs are proposed orally, and share pharmacological similarities: fixed doses without any therapeutic drug monitoring, key role of the transporter proteins P‐glycoprotein for all of them and metabolism mediated by CYP3A4 for the anti‐Xa, short half‐life with variable rate of renal elimination. More than 25 000 patients with acute VTE were included in phase‐III studies. Rivaroxaban and apixaban challenged all the conventional therapy (parenteral heparins followed by anti‐vitamin K antagonists) whereas edoxaban and dabigatran challenged only anti‐vitamin K antagonists. All the DOACs met the non‐inferiority efficacy endpoint (recurrent VTE during treatment), whereas the large non‐inferiority margin was debated for dabigatran. However, they were associated with better safety and a decreased risk of major bleeding. According to indirect comparisons, there were no statistically significant differences between DOACs in terms of efficacy but some differences are not excluded in term of safety. Although DOACs allow for simplification of treatment in the majority of patients with acute VTE, their risk/benefit ratio is questioned in elderly patients, patients with mild‐to‐severe renal impairment, and in some clinical subgroups such as cancer or chronic thromboembolic pulmonary hypertension. Validated reversal strategies (potentially based on laboratory monitoring) are expected for patients with major bleeding, overdose or with a need for surgery.

Effect of Activated Charcoal on Rivaroxaban Complex Absorption

ObjectiveTo quantify the impact of activated charcoal (AC) on rivaroxaban exposure in healthy volunteers.MethodsThis was an open-label study with an incomplete cross-over design of single-dose rivaroxaban (40xa0mg) administered alone or with AC in 12 healthy volunteers. The study comprised three treatment periods in randomised sequence, one with rivaroxaban administered alone and two with AC given at 2, 5 or 8xa0h post-dose. Rivaroxaban plasma concentration was measured in blood samples drawn at 16 time points. The pharmacokinetic model of rivaroxaban alone or with AC administration was built using a non-linear mixed-effect modelling approach.ResultsThe pharmacokinetic model was based on a one-compartment model with an absorption rate described by the sum of three inverse Gaussian densities to reproduce multiphasic and prolonged absorption. The inclusion in the model of each AC administration schedule significantly improved objective function value. AC reduced the area under the rivaroxaban concentration-time curve by 43% when administered 2 h post-dose, by 31% when administered 5xa0h post-dose and by 29% when administered 8xa0h post-dose. Based on the estimated pharmacokinetic model, simulations suggested that AC might have an impact even after 8xa0h post-dose.ConclusionAC administration significantly reduces exposure to rivaroxaban even if AC is administered 8xa0h after rivaroxaban. These results suggest that AC could be used in rivaroxaban overdose and accidental ingestion to antagonise absorption.ClinicalTrial.gov registration no.NCT02657512.

In vitro assessment of pharmacokinetic drug-drug interactions of direct oral anticoagulants: type 5-phosphodiesterase inhibitors are inhibitors of rivaroxaban and apixaban efflux by P-glycoprotein

Because of their lower bleeding risk and simplicity of use, direct oral anticoagulants (DOACs) could represent an interesting alternative to conventional anticoagulant treatment with vitamin K antagonists for patients with pulmonary arterial hypertension (PAH). P-glycoprotein (P-gp) plays a key role in DOAC pharmacokinetics. Type 5-phosphodiesterase inhibitors (PDE5is), a drug class commonly used in the treatment of PAH, have been shown to strongly inhibit P-gp. This work aimed to assess potential P-gp–mediated drug-drug interactions between PDE5is and DOACs using in vitro methods. A cellular model of drug transport assay, using P-gp–overexpressing Madin-Darby canine kidney cells (transfected with the human P-gp gene), was used to determine the bidirectional permeabilities of two DOACs (rivaroxaban and apixaban) in the absence and presence of increasing concentrations (0.5–100 µM) of three PDE5is (sildenafil, tadalafil, and vardenafil). Permeabilities and efflux ratios were calculated from DOAC concentrations, were measured with liquid chromatography coupled with mass spectrometry, and were subsequently used to determine the PDE5i percentage of inhibition and half maximal inhibitory concentration (IC50 ). Rivaroxaban efflux was inhibited by 99%, 66%, and 100% with 100 µM sildenafil, tadalafil, and vardenafil, respectively. Similarly, apixaban efflux was inhibited by 97%, 74%, and 100%, respectively. The IC50 values of the three PDE5is were 8, 28, and 5 µM for rivaroxaban and 23, 15, and 3 µM for apixaban, respectively. This study showed strong in vitro inhibition of DOAC efflux by PDE5is. In vivo studies are required to determine the clinical relevance of these interactions.

Pharmacological Characterization of the RPMI 2650 Model as a Relevant Tool for Assessing the Permeability of Intranasal Drugs

The RPMI 2650 cell line has been described as a potent model of the human nasal mucosa. Nevertheless, pharmacological data are still insufficient, and the role of drug efflux transporters has not been fully elucidated. We therefore pursued the pharmacological characterization of this model, initially investigating the expression of four well-known adenosine triphosphate [ATP]-binding cassette (ABC) transporters (P-glycoprotein (P-gp), multidrug resistance associated protein (MRP)1, MRP2, and breast cancer resistance protein (BCRP)) by means of ELISA and immunofluorescence staining. The functional activity of the selected transporters was assessed by accumulation studies based on specific substrates and inhibitors. We then performed standardized bidirectional transport experiments under air-liquid interface (ALI) culture conditions, using four therapeutic compounds of local intranasal relevance in upper airway diseases. Protein expression of P-gp, MRP1, MRP2, and BCRP was detected at the membrane of the RPMI 2650 cells. In addition, all four transporters exhibited functional activity at the cellular level. In the bidirectional transport experiments, the RPMI 2650 model was able to accurately discriminate the four therapeutic compounds according to their physicochemical properties. The ABC transporters tested did not play a major role in the efflux of these compounds at the barrier level. In conclusion, the RPMI 2650 model represents a promising tool for assessing the nasal absorption of drugs on the basis of preclinical pharmacological data.

Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time‐to‐event analysis

Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20–50 ml min−1).

Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic–pharmacodynamic study

AIMSnTranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10xa0mg l-1 ), and perioperative blood loss.nnnMETHODSnData were obtained from a prospective, double-blind, parallel-arm, randomized superiority study in hip arthroplasty. Patients received a preoperative intravenous bolus of TXA 1xa0g followed by a continuous infusion of either TXA 1xa0g or placebo over 8xa0h. A population pharmacokinetic study was conducted to quantify TXA exposure.nnnRESULTSnIn total, 827 TXA plasma concentrations were measured in 166 patients. A two-compartment model fitted the data best, total body weight determining interpatient variability in the central volume of distribution. Creatinine clearance accounted for interpatient variability in clearance. At the end of surgery, all patients had TXA concentrations above the therapeutic target of 10xa0mg l-1 . The model-estimated time during which the TXA concentration was above 10xa0mg l-1 ranged from 3.3xa0h to 16.3xa0h. No relationship was found between blood loss and either the time during which the TXA concentration exceeded 10xa0mg l-1 or the other exposure markers tested (maximum plasma concentration, area under the concentration-time curve).nnnCONCLUSIONnIn hip arthroplasty, TXA plasma concentrations were maintained above 10xa0mg l-1 during surgery and for a minimum of 3xa0h with a preoperative TXA dose of 1xa0g. Keeping TXA concentrations above this threshold up to 16xa0h conferred no advantage with regard to blood loss.