Diagnostic Accuracy of a Novel Chromogenic Direct Thrombin Inhibitor Assay: Clinical Experiences for Dabigatran Monitoring

Background Direct oral anticoagulants (DOACs) are increasingly replacing vitamin K antagonists (VKA) for clinical indications requiring long-term oral anticoagulation. In contrast to VKA, treatment with DOAC including dabigatran—the only direct thrombin inhibitor amongst them—does not require therapeutic drug monitoring. However, in case of treatment complications (e.g., major haemorrhage) and conditions requiring urgent surgery or thrombolytic therapy, information about actual DOAC plasma levels is needed to guide treatment decisions. Due to short reagent stability, limited accuracy at low dabigatran levels and high heparin sensitivity, the applicability of the widely used Hemoclot thrombin inhibitor (HTI) coagulation assay is limited in the emergency setting. Methods Dabigatran concentrations of 288 citrated plasma samples taken from 48 dabigatran-treated patients with drug concentrations of up to 300 ng/mL were measured with the chromogenic anti-IIa Biophen direct thrombin inhibitor (BDTI) assay and results compared with HTI using ultra performance liquid chromatography—tandem mass spectrometry as the reference method for measuring dabigatran plasma concentrations. Results BDTI results showed a very strong correlation with dabigatran concentrations (r = 0.965, p < 0.0001) as well as a low intra- and inter-assay variation of <5%. Compared with HTI, BDTI provides an improved on-board reagent stability of 72 hours, rapid turnaround times comparable to routine coagulation assays, high accuracy at low drug levels and reduced heparin sensitivity. Conclusion The BDTI is an ideal coagulation assay for the around-the-clock determination of dabigatran plasma levels in clinical routine including emergency situations.

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Clozapine and desmethylclozapine: correlation with neutrophils and leucocytes counting in Mexican patients with schizophrenia

BMC Psychiatry ◽

10.1186/s12888-019-2286-1 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Mayela Vaquero-Baez ◽

Araceli Díaz-Ruíz ◽

Luis Tristán-López ◽

Carlos Aviña-Cervantes ◽

Carlos Torner ◽

...

Keyword(s):

Plasma Levels ◽

High Performance ◽

Adverse Reactions ◽

Plasma Concentrations ◽

High Performance Liquid Chromatographic ◽

Analysis Model ◽

Ultraviolet Detector ◽

Drug Concentrations ◽

Blood Neutrophils ◽

Schizophrenic Patients

Abstract Purpose The aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects. Methods A high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions. Results The analytical method employed was linear, reproducible, and stable to measure concentrations of CLZ between 30 and 1000 ng/mL, while 12.5–560 ng/mL of the metabolite. The method allowed us to correlate CLZ plasma concentrations, the time taking CLZ and CLZ dose as determinants of neutrophils’ counting with a R2 = 0.447, using a multiple regression analysis model. Likewise, the correlation of leucocyte counting vs CLZ plasma levels and CLZ time, showed a R2 = 0.461. DMC correlated significantly with both neutrophils and leucocytes counting, but was excluded from the regression when CLZ concentration was included in the model. Finally, no other hematological adverse reactions were recorded. One patient presented a cardiovascular complication. The negative correlation between clozapine and neutrophil count observed in patients, suggest that CLZ itself, but not DMC, could be related to hematologic side-effects. Conclusion The findings of this study, demonstrate for the first time, that plasma levels of CLZ and time taking the drug are independent determinants of blood neutrophils and leucocytes, so the monitoring of plasma CLZ may be useful in the clinic practice to determine safe dosing of the drug.

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Therapeutic Drug Monitoring of Imatinib and Impact on Clinical Decision Making.

Blood ◽

10.1182/blood.v108.11.4820.4820 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4820-4820 ◽

Cited By ~ 3

Author(s):

Carolyn Blasdel ◽

Yanfeng Wang ◽

Theodore Lagattuta ◽

Brian Druker ◽

Laurie Letvak ◽

...

Keyword(s):

Decision Making ◽

Drug Monitoring ◽

Dose Adjustment ◽

Clinical Decision Making ◽

Plasma Concentrations ◽

Clinical Decision ◽

Therapeutic Drug ◽

Dose Increase ◽

Qrt Pcr ◽

Drug Concentrations

Abstract OBJECTIVES: Imatinib (IM) has demonstrated durable clinical efficacy in the majority of chronic myeloid leukemia (CML) patients. Optimal response may be influenced by multiple innate and external factors, some of which may be controlled by monitoring plasma concentrations of the drug. This abstract reports 6 cases where analyzing plasma IM trough concentrations (Cmin) in patients treated with three commonly used IM doses (400, 600, and 800 mg daily) influenced clinical decision making. METHODS: IM trough blood samples were collected at a time before that day’s IM dosing. Plasma concentrations of IM were determined by a validated LC/MS/MS method. RESULTS: In large population studies of CML patients enrolled in Phase I, II, and III clinical trials, the mean Cmin levels of IM at 400 mg qd, 600 mg qd, and 400 mg bid doses were: 981 (±543, 55%, n=394), 1572 (±1032, 66%, n=14), and 3479 (±1264, 36%, n=14) ng/mL, respectively. Large inter-patient variability was shown at all three doses. Of the 6 cases detailed in the table below, 4 (ID 1, 3, 4, and 5) had dose reduction due to tolerability concerns with subsequent improvement of symptoms following dose adjustment. One patient (ID 2) had a dose increase because of a poor qRT-PCR response. Another (ID 6) had a dose increase due to low plasma IM exposure resulting from drug-drug interaction with phenytoin, a known inducer of CYP3A4 (the major metabolizing isozyme for IM). After dose adjustment, all six patients showed good clinical response to IM treatment. The new mean Cmin value in these patients was 2000 (±471) ng/mL, representing a 24% coefficient of variability. CONCLUSIONS: Although the data is limited, IM drug monitoring proved useful in managing tolerability, lack of efficacy, adherence or potential drug interactions that modulate imatinib drug concentrations. More prospective studies are needed to demonstrate the value of IM drug monitoring in routine clinical practice. Patient ID Age, Sex CML Stage IM Daily Dose 1st Cmin (ng/mL) Reason for Dose Change New Dosing Regimen New Cmin (ng/mL) CP, chronic phase1 1 54, f CP 200 mg bid, Jan 03 3048, Sep 05 transfusion-dependent, anemia, Sep 05 300 mg, Oct 05 2130, Jan 06 2 9, f CP 300 mg, Jan 05 not done qRT-PCR 0.016, Jan 06 400 mg, Jan 06 2341, Jul 06 3 13, f CP 300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 05 1966, Feb 06 nausea, fatigue, arthralgias, myalgia, ongoing 400 mg, Mar 06 1222, May 06 4 67, f CP 400 mg, Feb 05 not done myelosuppression, Mar 05 200 mg, Mar 05 1928, May 06 5 53, f CP 400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04 not done inflammatory pulmonary reaction with shortness of breath; dose held, Mar 05 400 mg, Oct 05 2378, May 06 6 73, m CP 350 mg, on phenytoin, Apr 99 35, Jun 99 stopped phenytoin, Jul 99 500 mg, Jul 99 not done; qRT-PCR negative, Jul 06

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Effect of AR-H067637, the Active Metabolite of the Oral Anticoagulant AZD0837, on Thrombus Formation Using Human Whole Blood in an In Vitro Flow Chamber Model

Blood ◽

10.1182/blood.v112.11.4049.4049 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4049-4049

Author(s):

Margareta Elg ◽

Helen Zachrisson

Keyword(s):

Active Metabolite ◽

Thrombus Formation ◽

Plasma Concentrations ◽

Flow Chamber ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor ◽

Antithrombotic Effect ◽

Chamber Model ◽

Platelet Content ◽

D Dimer

Abstract AR-H067637 is a direct thrombin inhibitor derived in vivo from the orally available prodrug AZD0837. AR-H067637 is a reversible and selective direct thrombin inhibitor, which has an inhibition constant, Ki, of 2–4 nmol/L against human alpha-thrombin. During early development of a new anticoagulant drug, data on antithrombotic doses from animal studies may help guide selection of the dose to use in initial human studies. In the present study, using a flow chamber model developed by Badimon and colleagues (Badimon L, et al. J Lab Clin Med1987;110:706–718), the antithrombotic effect of AR-H067637 was evaluated using pig aorta and human whole blood. Following collection of informed consent, blood was taken from 11 healthy subjects into citrate-containing (10%, 0.109 M) tubes. Subjects were not permitted to receive medication for 7 days prior to blood collection. Blood was also collected in EDTA-containing tubes for cell counting. Denuded pig aorta pieces were used as the thrombogenic surface in the flow chamber. AR-H067637 was added to the blood at final blood concentrations ranging from 0.01 to 10 μmol/L, corresponding to plasma concentrations of 0.02 to 16 μmol/L. The blood was drawn for 5 minutes through the flow chamber with a shear of 220−s which is comparable with venous flow rate. The thrombus formed inside the chamber was degraded by plasmin, and platelets attached to the thrombus were lysed. The degradation product of fibrin, D-dimer, and the expression of the platelet cell adhesion molecule P-selectin were used as indirect measures of fibrin and platelet content in the thrombus, respectively. The anticoagulant effect of AR-H067637 was determined using the activated partial thromboplastin time (APTT) and prothrombin time (PT) assays. When using D-dimer levels as a measure of thrombus size, 25%, 50% and 75% thrombus inhibition was estimated to occur at AR-H067637 plasma concentrations of 0.21, 0.48 and 1.32 μmol/L, respectively. A significant inhibition of P-selectin expression by AR-H067637 was seen only at the highest concentration. APTT and PT were shown to be prolonged in a concentration-dependent manner; 50% inhibition of thrombus formation on the pig aorta was obtained at 1.8 and 1.2 times prolongations of APTT and PT, respectively. Hematological parameters such as WBC, RBC, HCT and platelets were all within the normal range. In conclusion, this study demonstrates that AR-H067637, the active metabolite of the oral prodrug AZD0837, has antithrombotic effects, causing concentration-dependent inhibition of thrombus formation measured as fibrin degradation products on the denuded pig aorta. Only a small effect at the highest concentration was observed on inhibition of platelet content in the thrombus, measured by P-selectin. This is in accordance with thrombin being a very potent platelet agonist. Therefore, higher concentrations of a thrombin inhibitor are needed to totally prevent platelet activation and aggregation, compared to those needed to prevent fibrin formation. APTT and PT prolongation correlated with the antithrombotic effect of AR-H067637 with >75% inhibition of fibrin formation at APTT and PT prolongations of 2.4 and 1.7, respectively.

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Pharmacokinetics (PK) and Pharmacodynamics (PD) of a New Direct Thrombin Inhibitor (DPOC-4088) After Single Oral Doses of Two Prolonged Release Formulations in Healthy Male Subjects,

Blood ◽

10.1182/blood.v118.21.3351.3351 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3351-3351

Author(s):

Luc M Van Bortel ◽

Griet Van Lancker ◽

Henri Vanden Bavière ◽

Willem Hettema ◽

Edwin Spaans ◽

...

Keyword(s):

Venous Thromboembolism ◽

Plasma Concentrations ◽

Cervical Lymphadenopathy ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor ◽

Prolonged Release ◽

Thrombin Time ◽

Healthy Male ◽

Thrombin Inhibition ◽

Oral Doses

Abstract Abstract 3351 Background: DPOC-4088 is an orally active, potent, rapidly binding, reversible direct thrombin inhibitor (DTI) being developed as a once-a-day alternative to warfarin for primary prevention of venous thromboembolism. Objectives: This Phase I study was designed to: (1) compare plasma concentration-ratios (Cmax/C12 hr and Cmax/C24 hr) and other standard PK parameters (Tmax, AUC0-∞, T1/2 terminal) following single oral dosing with 100 mg and 200 mg DPOC-4088 tablets in two prolonged release formulations (16 and 20 hr); (2) determine the extent of thrombin inhibition of these formulations as measured by activated partial thromboplastin time [aPTT], ecarin clotting time [ECT], thrombin time [TT] and prothrombin time [PT] (reported as the international normalized ratio [INR]); and (3) assess the safety of DPOC-4088 in healthy male volunteers. Methods: Randomized, open-label, 4-period crossover design. Subjects were dosed in 4 periods after an overnight fast and had blood drawn for PK/PD determinations immediately prior to dosing and at specified time intervals for 48 hrs post-dosing. Each dosing period was separated by a ≥5-day washout. Results: Twelve subjects aged 21 to 45 (mean 32.9 ± 8.55) years were enrolled and completed all 4 dosing periods. Increases in Cmax and AUC were dose proportional for both formulations, with the 20 hr-release formulation exhibiting slightly lower Cmax, and Cmax/C12 hr and Cmax/C24 hr ratios for a given dose compared to the 16 hr formulation (Table). Median tmax was 3–4 hrs. Geometric means of T1/2 terminal ranged from 4.0 to 5.8 hrs. Compared to pre-dose values, increases in all PD clotting parameters (aPTT, ECT, TT, and INR) closely followed the shape of the PK profile, were dose-dependent, and exhibited no lag time in response, suggesting a direct effect of DPOC-4088. Changes in aPTT, ECT, TT, and INR were correlated with peak DPOC-4088 concentrations. At 24 hrs post-dose, mean aPTT remained 12–15% above the pre-dose aPTT after 100 mg DPOC-4088 and 21–24% above pre-dose after 200 mg. The mean 24 hr ECT remained 21–23% and 35–36% above the pre-dose ECT for the 100 and 200 mg doses, respectively. Mean TT returned to within 1–15% of pre-dosing TT by 48 hrs. After single doses of 100 or 200 mg DPOC-4088, mean peak INRs were reached at 4 hrs for both the 100 mg (1.15–1.17) and 200 mg (1.28–1.30) formulations, returning to pre-dose INRs by 48 hrs. DPOC-4088 at both doses and release formulations was well-tolerated. Adverse events (AEs) occurred in 9/12 subjects; most were grade 1, unrelated or unlikely to be related to DPOC-4088, and resolved within hours without sequelae (headache, oropharyngeal pain, nausea, cervical lymphadenopathy, neck pain, fatigue). Among the AEs considered at least possibly related to DPOC-4088 administration, only grade 1 epistaxis (n=1) and blood in stools (n=1) were potentially linked to the PD activity of DPOC-4088. Conclusions: Following administration of single oral doses of DPOC-4088, a new once-daily DTI, dose proportionality was observed in the PK parameters for two prolonged release formulations. Evidence of anticoagulation efficacy by direct thrombin inhibition was reflected in key PD clotting parameters. The PD parameters were well-correlated with DPOC-4088 plasma concentrations and other PK parameters. At 100 and 200 mg doses, DPOC-4088 was safe and well-tolerated. Given the slightly lower Cmax/C24 hr and corresponding peak/trough PD ratios, the 20 hr release tablet is the preferred candidate formulation for further testing of DPOC-4088 in multiple-dose studies and for continued clinical development of DPOC-4088 for prevention of venous thromboembolism. PK/PD Parameters of Two Doses and Two Prolonged Release Formulations of DPOC-4088 Disclosures: Van Bortel: Diakron, GSK, JNJ, Merck, Menarini, Novartis, Nycomed, Recordati, Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hettema:Kinesis Pharma, BV: Employment. Spaans:Kinesis Pharma, BV: Employment. Ramakrishnan:Orchid Healthcare: Employment. Elumalai:Orchid Healthcare: Employment. Jayanthi:Orchid Healthcare: Employment. Allard:Diakron Pharmaceuticals: Employment.

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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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Real-life isoniazid and rifampicin plasma concentrations in children: a tool for therapeutic drug monitoring of tuberculosis

BMC Infectious Diseases ◽

10.1186/s12879-021-06764-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chiara Tersigni ◽

Giulia Boiardi ◽

Lorenzo Tofani ◽

Elisabetta Venturini ◽

Carlotta Montagnani ◽

...

Keyword(s):

Plasma Concentration ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Venous Blood ◽

Plasma Concentrations ◽

Age Groups ◽

Real Life ◽

Therapeutic Drug ◽

Blood Samples ◽

Drug Concentrations

Abstract Background Low plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages. Methods Children with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method. Results In all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (≤ 2 years, 2–12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range. Conclusions Based on our findings, monitoring patients’ drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.

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Current therapeutic applications and pharmacokinetic modulations of ivermectin

Veterinary World ◽

10.14202/vetworld.2019.1204-1211 ◽

2019 ◽

Vol 12 (8) ◽

pp. 1204-1211 ◽

Cited By ~ 6

Author(s):

Khan Sharun ◽

T. S. Shyamkumar ◽

V. A. Aneesha ◽

Kuldeep Dhama ◽

Abhijit Motiram Pawde ◽

...

Keyword(s):

Sustained Release ◽

Plasma Concentrations ◽

Oral Route ◽

Research Trend ◽

Therapeutic Drug ◽

Parasitic Diseases ◽

Therapeutic Applications ◽

Drug Concentrations ◽

Wonder Drug ◽

Long Acting

Ivermectin is considered to be a wonder drug due to its broad-spectrum antiparasitic activity against both ectoparasites and endoparasites (under class of endectocide) and has multiple applications in both veterinary and human medicine. In particular, ivermectin is commonly used in the treatment of different kinds of infections and infestations. By altering the vehicles used in the formulations, the pharmacokinetic properties of different ivermectin preparations can be altered. Since its development, various vehicles have been evaluated to assess the efficacy, safety, and therapeutic systemic concentrations of ivermectin in different species. A subcutaneous route of administration is preferred over a topical or an oral route for ivermectin due to superior bioavailability. Different formulations of ivermectin have been developed over the years, such as stabilized aqueous formulations, osmotic pumps, controlled release capsules, silicone carriers, zein microspheres, biodegradable microparticulate drug delivery systems, lipid nanocapsules, solid lipid nanoparticles, sustained-release ivermectin varnish, sustained-release ivermectin-loaded solid dispersion suspension, and biodegradable subcutaneous implants. However, several reports of ivermectin resistance have been identified in different parts of the world over the past few years. Continuous use of suboptimal formulations or sub-therapeutic plasma concentrations may predispose an individual to resistance toward ivermectin. The current research trend is focused toward the need for developing ivermectin formulations that are stable, effective, and safe and that reduce the number of doses required for complete clinical cure in different parasitic diseases. Therefore, single-dose long-acting preparations of ivermectin that provide effective therapeutic drug concentrations need to be developed and commercialized, which may revolutionize drug therapy and prophylaxis against various parasitic diseases in the near future. The present review highlights the current advances in pharmacokinetic modulation of ivermectin formulations and their potent therapeutic applications, issues related to emergence of ivermectin resistance, and future trends of ivermectin usage. Keywords: ivermectin, ivermectin resistance, pharmacokinetic modulation, therapeutic applications.

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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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Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Cancers ◽

10.3390/cancers13246281 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6281

Author(s):

Anna Mc Laughlin ◽

Eduard Schmulenson ◽

Olga Teplytska ◽

Sebastian Zimmermann ◽

Patrick Opitz ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Anticancer Drugs ◽

Drug Monitoring ◽

Drug Exposure ◽

Plasma Concentrations ◽

Blood Sampling ◽

Therapeutic Drug ◽

Study Phase ◽

Blood Samples ◽

Drug Concentrations

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs.

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Plasma concentrations resulting from continuous infusion of meropenem in a community-based outpatient program: A case series

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxaa319 ◽

2020 ◽

Vol 77 (24) ◽

pp. 2074-2080

Author(s):

Amy Legg ◽

Melanie Halford ◽

Kate McCarthy

Keyword(s):

Continuous Infusion ◽

Drug Exposure ◽

Plasma Concentrations ◽

Case Series ◽

Infectious Complications ◽

Antimicrobial Treatment ◽

Therapeutic Drug ◽

Community Based ◽

Drug Concentrations ◽

Tertiary Center

Abstract Purpose Traditionally meropenem has been considered too unstable in solution for continuous infusion. However, in the era of increasing antimicrobial resistance, use of meropenem is becoming more frequently required, and the ability to facilitate its administration via community-based programs would be beneficial. There are some reassuring data about meropenem stability in solution, but data about actual drug exposure in patients and subsequent clinical outcomes are lacking. Summary Here we present a case series of 4 patients at a single tertiary center who received meropenem via continuous infusion coordinated through an outpatient parenteral antimicrobial treatment (OPAT) program. We provide plasma drug concentrations achieved and report on the patients’ clinical progress. All patients achieved drug concentrations of at least 2 times the minimum inhibitory concentration (MIC) while receiving meropenem via continuous infusion and had resolution of their infectious complications. No adverse effects of meropenem continuous infusion were noted. Conclusion Meropenem continuous infusion along with therapeutic drug monitoring was used successfully in a community-based program. Due to interpatient pharmacokinetic variability, we consider meropenem concentration monitoring compulsory during continuous-infusion meropenem therapy.

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