Is Dilute Russell’s Viper Venom Time a Useful Assay To Monitor Patients Treated By Rivaroxaban Or Dabigatran Etexilate?

Abstract Introduction There is still a need for a general test easily implementable and widely available that may be used to screen all patients on DOACs. A recent study has suggested that the dilute Russell Viper Venom Time (DRVV-T) could be used for the monitoring of DOACs but these results have been generated in vitro. The primary objective of this study is to analyse and compare the results obtained with the DRVV Screen and Confirm tests to the plasma drug levels measured by LC-MS/MS. We also aimed at proposing specific cut-off associated with supratherapeutic levels at Ctrough. Finally, a comparison of our results with those obtained with PT for rivaroxaban and aPTT for dabigatran is also provided. Methods Thirty-two rivaroxaban and 31 dabigatran platelet poor plasma samples from real-life patients were included in the study. Dilute Russell's Viper Venom time was measured using STA®-Staclot®DRVV Screen and Confirm reagents. Prothrombin Time and aPTT have been performed with Triniclot PT Excel S® and RecombiPlastin 2G® and with STA®C.K. Prest and SynthasIL®, respectively. The Hemoclot Thrombin Inhibitor® and the Biophen DiXaI® have been performed to estimate plasma concentration of dabigatran and rivaroxaban, respectively. All methodologies were performed on a STA-R Evolution® analyser according with the recommendation of the manufacturer, except for RecombiPlastin 2G® which were performed on an ACL-TOP®. All of these tests have been performed according to the recommendations of the manufacturer. The reference LC-MS/MS measurement of plasma drug concentrations were validated according to FDA Guidelines for Industry for Bioanalytical Method (for rivaroxaban) and to the Validation European Medicines Agency guidelines (for dabigatran). Results The plasma concentrations range from 6 to 426ng/mL for rivaroxaban and from 0 to 386ng/mL for dabigatran as determined by LC-MS/MS. Tables 1 and 2 summarize Spearman correlations and Bland-Atlman analyses for rivaroxaban and dabigatran, respectively. Figures 1 and 2 provide the results of STA®-Staclot®DRVV Screen and Confirm versus LC-MS/MS measurements. Bland-Altman graphs are also provided. Discussion STA®-Staclot®DRVV-Screen and Confirm shows a better correlation than PT or aPTT. Bland-Altman analyses reveal an overestimation of approximately 40ng/mL and large 5th-95th limits of agreement with both STA®-Staclot®DRVV-Screen and Confirm. Specific cut-offs associated with supratherapeutic level (>200ng/mL) at Ctrough have been defined. For STA®-Staclot®DRVV-Screen, results below 125 seconds or below a ratio of 3 could exclude plasma concentrations >200ng/mL for rivaroxaban and dabigatran (Figure 1 - A and B). For STA®-Staclot®DRVV-Confirm, cut-offs must be adapted independently (Figure 2 - A and B). Results below 75 seconds or below a ratio of 2, could exclude rivaroxaban plasma concentrations >200ng/mL. For dabigatran, the threshold could be defined at 90 seconds or at a ratio of 2.5. Conclusion Thanks to its good correlation with plasma drug level, DRVVT can be more informative than PT and aPTT, to exclude supra-therapeutic level of rivaroxaban and dabigatran at Ctrough. However, due to overestimations in plasma drug level, it cannot be recommended to accurately estimate plasma drug concentrations which require more specific coagulation assays or LC-MS/MS measurements. Disclosures: No relevant conflicts of interest to declare.

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Plasma Drug Level Validates Self-Reported Adherence but Predicts Limited Specificity for Nonadherence to Antiretroviral Therapy

ISRN Pharmacology ◽

10.5402/2012/274978 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Robert Balikuddembe ◽

Joshua Kayiwa ◽

David Musoke ◽

Muhammad Ntale ◽

Steven Baveewo ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Low Income ◽

Plasma Levels ◽

Plasma Concentrations ◽

Drug Level ◽

Low Income Countries ◽

Plasma Drug ◽

Cross Sectional ◽

Drug Concentrations ◽

Emergence Of Resistance

Introduction. Adherence to antiretroviral therapy (ART) in low-income countries is mainly assessed by self-reported adherence (S-RA) without drug level determination. Nonadherence is an important factor in the emergence of resistance to ART, presenting a need for drug level determination. Objective. We set out to establish the relationship between plasma stavudine levels and S-RA and validate S-RA against the actual plasma drug concentrations. Methods. A cross-sectional investigation involving 234 patients in Uganda. Stavudine plasma levels were determined using high-performance liquid chromatography. We compared categories of plasma levels of stavudine with S-RA using multivariable logistic regression models. Results. Overall, 194/234 patients had S-RA ≥ 95% (good adherence) and 166/234 had stavudine plasma concentrations ≥ 36 nmol/L (therapeuticconcentration). Patients with good S-RA were eight times more likely to have stavudine levels within therapeutic concentration (Adjusted Odds Ratio: 7.7, 95% Confidence Interval: 3.5–7.0). However, of the 194 patients with good S-RA, 21.7% had below therapeutic concentrations. S-RA had high sensitivity for adherence (91.6%), but limited specificity for intrinsic poor adherence (38.2%). Conclusions. S-RA is a good tool for assessing adherence, but has low specificity in detecting nonadherence, which has implications for emergence of resistance.

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Interest of Dosing of Ibrutinib in B-Cell Lymphoid Malignancies: Data from a Real-Life, Phase 4 Study

Blood ◽

10.1182/blood-2018-99-116532 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3960-3960

Author(s):

Anne Calleja ◽

Sandra De Barros ◽

Camille Vinson ◽

Caroline Protin ◽

Lucie Oberic ◽

...

Keyword(s):

Adverse Events ◽

B Cell ◽

Conflicts Of Interest ◽

Plasma Concentrations ◽

Real Life ◽

Therapeutic Drug ◽

Therapeutic Effects ◽

Lymphoid Malignancies ◽

Oncology Nurse ◽

Drug Concentrations

Abstract Introduction: Therapeutic drug monitoring (TDM) entails the measurement of drug concentrations and the individualization of drug dosages or schedules to maximize therapeutic effects and minimize toxicity. Ibrutinib (IBR), the first-in-class inhibitor of BTK (Bruton tyrosine kinase) is approved for the therapy of relapsed/refractory chronic lymphocytic leukemia (R/R CLL), mantle cell lymphoma (MCL) and Waldenström's disease (WM), at the dose of 420-560mg/d. Drug-drug interactions (DDI), older age, liver diseases have been reported to impact PK parameters of ibrutinib, but dosing is not yet part of clinical practice, despite TDM of imatinib and other kinase inhibitors is routinely used in chronic myeloid leukemia. In this study, we sought to determine whether TDM of ibrutinib should be proposed for patients, in a preliminary cohort of 73 patients included in the PK-e3i trial (NCT02824159). Methods: Serial plasma PK samples were collected at steady-state after one month of therapy in 73 patients: before intake (residual concentration), and then at time 0.5-1-2-4-6h. Key PK parameters for ibrutinib and its metabolite DHD-ibrutinib were calculated: Cmax, Cmin, tmax,AUC24h. Analysis of DDI was made by an oncology pharmacist in 49/73 patients. Treatment-related adverse events were monitored by phonecalls given by an oncology nurse (AMA procedure) and during consultations with hematologist (at least twice a month the first 6 months, then monthly until 12 months, then every 3 months), and severity graded according CTCAE version 4 scale. Efficacy of therapy in CLL patients was assessed with an "effect marker" to demonstrate biological efficacy, the redistribution hyperlymphocytosis seen in 70% of patients the first month of therapy. Results: we reported very similar PK results for ibrutinib as compared to pivotal phase 1 trials in CLL and other B-cell lymphoid malignancies (Advani RH, J Clin Oncol 2013, Byrd JC, New Engl J Med 2013). Mean peak plasma concentrations were observed 1-2h after dosing, Cmax and AUC results showing an important inter-patient heterogeneity. Median Cmax was 150ng/ml (8.2-596ng/ml), and median AUC24h was 412.4 ng h/mL ((32.2-2906 ng h/mL). According to published phase I trials, complete or near complete BTK occupancy was observed in patients with AUCs exceeding 160 ng h/mL, suggesting ibrutinib dose might have been supramaximal in 67 of our patients. Adverse events the first 3 months were seen in 96% (grade 1), 63% (grade 2), 25% (grade 3) and 6.5% (grade 4), respectively. We plotted AUC results for the total cohort of 73 patients (Figure 1), and for 49 patients with adverse events monitoring available at 3 months (9/49 needed drug dose reduction due to toxicity) (Figure 2), both emphasizing the absence of correlations between AUC levels and toxicities. We next splited up toxicities into 10 sub-groups (bleeding, cardiac, liver, muscle, joint, skin, infection, gastro-intestinal, hematologic, neurologic disorders). Again, we could not identify a specific organ toxicity associated with a significant increase of Cmax or AUC24h, nor we could identify a specific DDI signature explaining side effects in our patents (data not shown: 13/49 had CYP3A4 inhibitors, 25/49 had pgp inhibitors). In 45 CLL patients with PK parameters and lymphocyte counts available after one month of therapy, we made the intriguing observation that lower Cmax correlated with the lack of observable, transient hyperlymphocytosis (a class-effect of ibrutinib, correlating with PFS in the Resonate trial) (Figure 3). Altogether, our data did not find any positive correlation between high ibrutinib exposure and efficacy or safety profile. Conclusions: our preliminary results suggested that higher Cmax and AUC24h did not correlate neither to efficacy nor to classical toxicities reported with ibrutinib intake. On one hand, we think that dosing intra-cellular concentrations could be more reliable than in plasma. On the other hand, we could consider TDM of ibrutinib in the context of a clinical trial reducing the doses of drug over time, to limit clinical and financial toxicity of this highly efficient drug. Disclosures No relevant conflicts of interest to declare.

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Very High Concentrations of Active Intracellular Phosphorylated Emtricitabine in Neonates (ANRS 12109 Trial, Step 2)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01376-10 ◽

2011 ◽

Vol 55 (6) ◽

pp. 2953-2960 ◽

Cited By ~ 6

Author(s):

Déborah Hirt ◽

Alain Pruvost ◽

Didier K. Ekouévi ◽

Saïk Urien ◽

Elise Arrivé ◽

...

Keyword(s):

Active Form ◽

Plasma Concentrations ◽

Prospective Trial ◽

Plasma Drug ◽

Serious Adverse Events ◽

Drug Concentrations ◽

Liquid Chromatography Tandem Mass ◽

High Concentrations ◽

Mother To Child ◽

Plasma Drug Concentrations

ABSTRACTOur objective was to investigate neonatal emtricitabine (FTC) plasma and intracellular pharmacokinetics. The study was designed as a phase I/II prospective trial in two sequential steps evaluating the combination of tenofovir disoproxil fumarate (TDF) and FTC for the prevention of mother-to-child-transmission (PMTCT) of HIV. HIV-1-infected pregnant women received two tablets of TDF (300 mg) and FTC (200 mg) at onset of labor and then one tablet daily for 7 days postpartum. Based on the data obtained in the first part of the Tenofovir/Emtricitabine in Africa and Asia (TEmAA) Study, single doses of 2 mg/kg of FTC and 13 mg/kg of TDF were given to the neonates within 12 h after birth. A total of 540 FTC plasma concentrations and 44 active intracellular phosphorylated metabolite FTC-TP concentrations were taken from the 36 enrolled women and their neonates. Concentrations were measured by the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and analyzed by a population approach. The proposed dose obtained by simulations based on plasma drug concentrations was confirmed. However, median FTC-TP exposures were, respectively, 5.9 and 6.8 times higher in the fetus and the neonate than in the adult. High FTC-TP concentrations were observed in the four children who had serious adverse events (SAEs), but the link between FTC-TP concentrations and SAEs in children was not formally identified. The exposure to the active form of FTC was high in neonates despite plasma drug concentrations equivalent to those in adults. Our results are similar to those obtained with zidovudine or lamivudine.

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Impact of hepatitis C and liver fibrosis on antiretroviral plasma drug concentrations in HIV-HCV co-infected patients: the HEPADOSE study

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkq320 ◽

2010 ◽

Vol 65 (11) ◽

pp. 2445-2449 ◽

Cited By ~ 14

Author(s):

S. Dominguez ◽

J. Ghosn ◽

G. Peytavin ◽

M. Guiguet ◽

R. Tubiana ◽

...

Keyword(s):

Hepatitis C ◽

Liver Fibrosis ◽

Plasma Drug ◽

Drug Concentrations ◽

Plasma Drug Concentrations

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Response to Maprotiline Treatment in Depressive Patients Relationship to Urinary MHPG Excretion and Plasma Drug Level

Pharmacopsychiatry ◽

10.1055/s-2007-1019532 ◽

1982 ◽

Vol 15 (05) ◽

pp. 170-174 ◽

Cited By ~ 9

Author(s):

H.J. Gaertner ◽

G. Golfinopoulos ◽

U. Breyer-Pfaff

Keyword(s):

Drug Level ◽

Plasma Drug Level ◽

Plasma Drug ◽

Depressive Patients

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Clinical responses and plasma drug concentrations associated with different infusions of xylazine and ketamine in horses

Veterinary Anaesthesia and Analgesia ◽

10.1046/j.1467-2995.2000.00008-9.x ◽

2000 ◽

Vol 27 (1) ◽

pp. 58-59

Author(s):

KR Mama ◽

AE Wagner ◽

EP Steffey ◽

C Kollias-Baker ◽

PW Hellyer ◽

...

Keyword(s):

Plasma Drug ◽

Drug Concentrations ◽

Clinical Responses ◽

Plasma Drug Concentrations

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Plasma Drug Level with Erosion-Controlled Dosage Forms

Assessing Bioavailablility of Drug Delivery Systems ◽

10.1201/9780849330445.ch7 ◽

2005 ◽

pp. 125-146

Keyword(s):

Drug Level ◽

Dosage Forms ◽

Plasma Drug Level ◽

Plasma Drug

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Drug plasma trough concentrations during treatment with daclatasvir and sofosbuvir are associated respectively with liver impairment and with renal dysfunction in HIV/HCV co-infected patients

10.21203/rs.2.11151/v1 ◽

2019 ◽

Author(s):

Ilaria Mastrorosa ◽

Massimo Tempestilli ◽

Stefania Notari ◽

Patrizia Lorenzini ◽

Gabriele Fabbri ◽

...

Keyword(s):

Renal Dysfunction ◽

Virologic Response ◽

Patient Treatment ◽

Limited Information ◽

Plasma Drug ◽

Related Factors ◽

Immunological Parameters ◽

Liver Impairment ◽

Drug Concentrations ◽

Plasma Drug Concentrations

Abstract Background Sofosbuvir (SOF) plus daclatasvir (DCV) achieved high rates of sustained virologic response (SVR) with no difference according to HIV serostatus. Only limited information is available on the pharmacokinetics variability of SOF and DCV in HIV/HCV co-infected patients. Aim was to evaluate the association of plasma drug concentrations (Ctrough) of SOF and of DCV with patient-, treatment-, and disease-related factors in the real-world setting of HIV/HCV co-infected persons. Methods HIV/HCV co-infected patients, undergoing SOF plus DCV treatment, were prospectively enrolled. At baseline, week4 (W4), end of treatment (EOT), and after-EOT, biochemical and viro-immunological parameters were assessed. FIB-4 score and CKD-EPI equation were used for estimation of liver disease and glomerular filtration rate (eGFR), respectively. SOF, SOF metabolite (GS-331007), and DCV Ctrough were measured at W4 and week8 (W8), and the mean value (mean-Ctrough) was calculated Results Thirty-five patients were included (SVR 94%). Increasing GS-331007 mean-Ctrough significantly correlated with decreasing eGFR at W4 (rho=-0.36; p=0.037) and EOT (rho=-0.34; p=0.048). Between DCV mean-Ctrough and FIB-4, a significant correlation was observed at all time-points: baseline (rho=-0.35; p=0.037), W4 (rho=-0.44; p=0.008), EOT (rho=-0.40; p=0.023), after-EOT (rho=-0.39; p=0.028). Conclusion In HIV/HCV co-infected patients receiving SOF plus DCV, plasma drug concentrations are associated with renal dysfunction for GS-331007 and with liver impairment for DCV. Though clinical and therapeutically relevance of these findings may apparently be limited, growth of clinicians’ knowledge on DAA exposure in difficult-to-treat patients, as cirrhotic and renal impaired subjects, can be relevant in single cases.

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