scholarly journals Streptococcal and enterococcal endocarditis: time for individualized antibiotherapy?

2021 ◽  
Author(s):  
Clara Flateau ◽  
Adélie Riazi ◽  
Bruno Cassard ◽  
Maryse Camus ◽  
Sylvain Diamantis
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Oral Medication ◽  
Antibiotic Concentration ◽  
Crucial Question ◽  
Serious Infections ◽  
Data Point ◽  
Efficacy Studies ◽  
The Way

Abstract Recommendations for the treatment of streptococcal and enterococcal endocarditis are based on old efficacy studies, but the starting doses have never been reassessed and are associated with significant adverse events. Based on data from other serious infections, we suggest that maintaining a concentration of β-lactams higher than 4–6 times the responsible bacteria MIC 100% of the time in the heart of the vegetation would be a pertinent therapeutic objective. The data point to a diffusion gradient of β-lactams in the vegetation. Yet, so far as is known, the ratio of antibiotic concentration at steady state between plasma and vegetation cannot be completely determined. Answering this crucial question would make it possible for each patient to have a targeted β-lactam plasma concentration, according to the MIC for the responsible bacteria. This would lead the way to personalized antibiotherapy and allow a safe switch to oral medication.

scholarly journals Exposure-Response Relationship of the Bruton Tyrosine Kinase Inhibitor, Zanubrutinib (BGB-3111) in Patients with Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5063-5063
Author(s):  
Ying Ou ◽  
Kun Wang ◽  
Lucy Liu ◽  
Ashutosh Jindal ◽  
Yuying Gao ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Adverse Events ◽  
B Cell ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Bleeding Events ◽  
B Cell Malignancies ◽  
Exposure Response ◽  
Bruton Tyrosine Kinase

Background: Zanubrutinib (BGB-3111) is a highly selective, potent, irreversible inhibitor of Bruton tyrosine kinase (BTK), currently in phase 3 development for the treatment of hematologic malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM). In a dose escalation study evaluating doses of 40, 80, 160, and 320 mg once daily and 160 mg twice daily, no dose limiting toxicities were observed and maximum tolerated dose (MTD) was not established. Objective responses have been observed in patients with various B-cell malignancies (including CLL, MCL, WM) at all tested dose levels. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (Tam et al. Blood 2016;128:642). To support dose selection, this exposure-response (E-R) analysis evaluated exposure-safety and exposure-efficacy (in MCL) relationships in patients with B-cell malignancies receiving zanubrutinib monotherapy. Methods: A population pharmacokinetic (PopPK) model was developed from 600 subjects enrolled in 9 clinical studies in patients with B-cell malignancies and healthy volunteers. Exposure data such as steady-state area under the plasma concentration time curve (AUC0-24,ss), maximum observed plasma concentration (Cmax ) or steady state trough concentration (Cmin) derived from the PopPK analysis were used in the E-R analysis. Exposure-efficacy analyses were performed using exposure metrics and overall response rate (ORR) data from two studies in patients with relapsed/refractory (R/R) MCL (n=51), including Study 206, a pivotal Phase 2 study conducted in China and study AU-003, a global Phase 1, dose escalation/cohort expansion study. The efficacy endpoint evaluated was ORR, as assessed by an independent review committee (IRC) as well as by investigators, according to 2014 Lugano Classification. Exposure-safety analyses were conducted using data from 4 studies in patients with B-cell malignancies (n=372) receiving zanubrutinib as monotherapy at a total daily dose from 40 mg to 320 mg. The safety endpoints evaluated included Grade ≥ 3 adverse events (AE) and AEs of interests, including neutropenia, thrombocytopenia, anemia, infections/infestations, all events of secondary primary malignancies, all events of atrial fibrillation and flutter, major bleeding events, and any bleeding events. Results: PopPK analysis demonstrated that race, body weight, age, CrCL, sex, tumor type, and use of acid-reducing agents did not show a statistically significant impact on the PK of zanubrutinib. The PK profile of zanubrutinib was comparable between Asians and non-Asians, which allows for bridging of clinical efficacy and safety data across the pivotal studies conducted globally (AU-003) and in China (206). The analysis showed that the median AUC0-24,ss and Cmax values were 1736 ng·h/mL and 275 ng/mL in responders compared with 1326 ng·h/mL and 175 ng/mL in nonresponders, respectively. Although overall median exposure (AUC0-24,ss, Cmax) was higher in responders compared with nonresponders, no significant E-R relationship was identified for efficacy based on probability of observing ORR and logistic regression model (Fig 1). The E-R relationships based on investigator assessments were consistent with those based on IRC assessments. For the exposure-safety analysis, the exposure ranges were similar in patients experiencing adverse events of interests relative to those who were not. There were no evident E-R relationships between PK exposure (AUC0-24,ss, Cmax, or Cmin) and the probability to have adverse events of interest (eg., Fig. 2). Conclusion: E-R analyses indicate that higher plasma exposures of zanubrutinib were not associated with higher probability to have adverse events across the dose range of 40 mg to 320 mg in patients with B-cell malignancies. This result supports the recommended dose of 160 mg twice daily in patients with MCL, based on high rates of objective response in patients with R/R MCL, generally favorable safety and tolerability profiles, and complete and sustained BTK occupancy in PBMCs and target tissues at this dose. Disclosures Ou: BeiGene: Employment. Jindal:BeiGene: Employment. Sahasranaman:BeiGene: Employment, Equity Ownership.

scholarly journals Metabolism of inorganic sulphate in the isolated perfused rat liver. Effect of sulphate concentration on the rate of sulphation by phenol sulphotransferase

1978 ◽  
Vol 176 (3) ◽  
pp. 959-965 ◽  
Author(s):  
Gerard J. Mulder ◽  
Katja Keulemans
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Rat Liver ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver ◽  
Perfusion Medium ◽  
Physiological Concentration ◽  
Sulphate Concentration ◽  
Inorganic Sulphate

1. The metabolism of inorganic [35S]sulphate (Na235SO4) was studied in the isolated perfused rat liver at three initial concentrations of inorganic sulphate in the perfusion medium (0, 0.65 and 1.30mm), in relation to sulphation and glucuronidation of a phenolic drug, harmol (7-hydroxy-1-methyl-9H-pyrido[3,4-b]indole). 2. [35S]Sulphate rapidly equilibrated with endogenous sulphate in the liver. It was excreted in bile and reached, at the lowest concentration in the perfusion medium, concentrations in bile that were much higher than those in the perfusion medium; at the higher sulphate concentrations, these concentrations were equal. The physiological concentration of inorganic sulphate in the liver, available for sulphation of drugs, is similar to the plasma concentration. 3. At zero initial inorganic sulphate in the perfusion medium, the rate of sulphation was very low and harmol was mainly glucuronidated. At 0.65mm-sulphate glucuronidation was much decreased and considerable sulphation took place, indicating efficient competition of conjugation by sulphation. At 1.30mm-sulphate the sulphation increased still further. 4. The results suggest that an important factor in sulphation is the relatively high Km of synthesis of adenosine 3′-phosphate 5′-sulphatophosphate (the co-substrate of sulphation) for inorganic sulphate, which is of the order of the plasma concentration of inorganic sulphate. The steady-state adenosine 3′-phosphate 5′-sulphatophosphate concentration may determine the rate of sulphate conjugation of drugs in the rat in vivo.

Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5600-TPS5600
Author(s):  
Ramaswamy Govindan ◽  
Amanda Rose Townsend ◽  
Kathy D. Miller ◽  
Inderjit Mehmi ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Solid Tumors ◽  
Triple Negative ◽  
Phase 1 ◽  
Locally Advanced ◽  
Maximum Plasma ◽  
High Grade ◽  
Serous Ovarian Cancer

TPS5600 Background: KIF18A is a mitotic kinesin motor protein that regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. TP53 mutant unstable aneuploid cancer cells with chromosomal instability (CIN) features are dependent on KIF18A motor activity to prevent lethal multipolar cell division. Preclinical data demonstrate that treatment with AMG 650; an oral, first in class, selective small molecule inhibitor of KIF18A may be safe and tolerable. We are conducting a first-in-human phase 1 study with AMG 650 in adult subjects with locally advanced or metastatic solid tumors with TP53MUT, triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC) or serous like endometrial cancers and other solid tumors. Methods: In this phase 1, multicentric, dose escalation and dose expansion study we evaluate the safety and tolerability of AMG 650 monotherapy in patients with advanced/metastatic solid tumors (NCT04293094). The main objective is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) based on emerging safety, efficacy, and pharmacodynamics (PD) data prior to reaching the MTD. Key inclusion criteria include the presence of measurable disease and diagnosis of advanced/metastatic triple negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC), serous-like endometrial cancer or other solid tumors with documented TP53 mutations. In the dose expansion phase, participants with locally advanced or metastatic TNBC or HGSOC will be treated with the preliminary RP2D identified from the dose exploration part of the study. Primary endpoints include the incidence of Dose Limiting Toxicities (DLTs),Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment-related Adverse Events and the evaluation of the number of participants who experience a clinically significant change from baseline in vital signs, electrocardiogram and laboratory tests parameters. Secondary endpoints include Objective Response Rate, Duration of Response, Progression-free Survival, Clinical Benefit Rate, Time to Response, Time to Progression, Overall Survival (OS), Maximum Plasma Concentration (Cmax) of AMG 650, Time to Maximum Plasma Concentration (Tmax) of AMG 650 as well as Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval for AMG 650. Continuous monitoring of toxicity is conducted. The study began enrolling pts in March 2020 and is ongoing. For more information, please contact Amgen Medical Information: [email protected] Clinical trial information: NCT04293094.

A pharmacist-managed virtual consult service to improve tuberculosis screening

2021 ◽  
Author(s):  
Veranika Sasnovskaya ◽  
Lisa M Kumor ◽  
JoAnn Stubbings ◽  
Aimee Chevalier
Keyword(s):  
Adverse Events ◽  
Safety Management ◽  
Consult Service ◽  
Practice Model ◽  
Tuberculosis Screening ◽  
Serious Adverse Events ◽  
Pharmacy Benefit ◽  
Serious Infections ◽  
Biologic Response ◽  
Specialty Pharmacy

Abstract Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these 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. Purpose To describe a pharmacist-managed virtual consult service practice model to improve medication safety in a population of rheumatology patients and evaluate its initial impact on guideline compliance. Summary Optimal pharmacologic care of patients with rheumatologic conditions often revolves around the use of specialty medications such as self-injectable biologics and infused therapies, including biologic response modifiers (BRMs), nearly all of which carry risks of serious adverse events due to their immune-suppressive properties. Possible adverse events include serious infections such as reactivation of tuberculosis (TB) and viral hepatitis B (HBV). This articles describes a pharmacist-managed virtual consult service introduced by a large university-affiliated health system in 2018 to integrate clinical, specialty pharmacy, and therapeutic infusion services for proactive medication and safety management for patients with rheumatologic conditions requiring specialty or infused medications. During a 4-month evaluation period, 157 referrals were sent to the consult service; of 137 consults included in the analysis, 42% were for self-injectable biologic medications, 28% were for intra-articular injections, 26% were for infusions, and 4% were for oral specialty medications. Forty-one percent of the pharmacy benefit consult orders required an intervention prior to submission of prior authorization requests. Most interventions (61%) were clinical in nature and involved the pharmacists ensuring that necessary laboratory work, clinical disease activity scoring, or radiographic imaging were completed prior to submission of the consult results for insurer approval. Conclusion National rates of HBV screening and TB screening for patients prescribed BRMs continue to be suboptimal. The pharmacist-managed virtual consult service is a novel practice model to increase the screening rate to 100% to ensure the safety and appropriate monitoring of patients who are starting or continued on these complex medications.

Monitoring plasma concentrations of psychotropic drugs

1974 ◽  
Vol 12 (2) ◽  
pp. 6-8
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Tissue Concentration ◽  
Plasma Concentrations ◽  
Water Concentration ◽  
Plasma Samples ◽  
Active Metabolites ◽  
The Relationship ◽  
The Brain ◽  
Reliable Methods

Techniques are now available for estimating the plasma concentration of several drugs used in psychiatry. These techniques are clearly important for research but they can hardly be expected to improve the clinical management of patients unless the estimation is sensitive, reliable and reasonably quick; the method should be specific for the particular drug but should also specifically estimate any active metabolites. Even when reliable figures have been obtained, much more information is needed before they can be interpreted. The relationship between plasma (or plasma water) concentration and relevant tissue concentration (e. g. in the brain) must be known. Plasma samples should be taken at appropriate times, e. g. after the attainment of ‘steady-state’ conditions: plasma and tissue levels will then be in equilibrium. Diagnoses must be soundly based if inferences are to be drawn. Reliable methods of assessing clinical response must be available. These requirements pose difficult problems in psychiatry.

scholarly journals Anti-tumor necrosis factor therapy in patients with inflammatory bowel disease; comorbidity, not patient age, is a predictor of severe adverse events

2020 ◽  
Vol 35 (12) ◽  
pp. 2331-2338
Author(s):  
Vera E. R. Asscher ◽  
◽  
Quirine van der Vliet ◽  
Karen van der Aalst ◽  
Anniek van der Aalst ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Adverse Events ◽  
Older Patients ◽  
Tumor Necrosis ◽  
Patient Age ◽  
Younger Patients ◽  
Patient Âgé ◽  
Serious Infections ◽  
Severe Adverse Events ◽  
Necrosis Factor

Abstract Purpose To assess safety and effectiveness of anti-tumor necrosis factor (anti-TNF) therapy in IBD patients ≥ 60 years. Methods Ninety IBD patients ≥ 60 years at initiation of anti-TNF therapy, 145 IBD patients ≥ 60 years without anti-TNF therapy and 257 IBD patients < 60 years at initiation of anti-TNF therapy were retrospectively included in this multicentre study. Primary outcome was the occurrence of severe adverse events (SAEs), serious infections and malignancies. Secondary outcome was effectiveness of therapy. Cox regression analyses were used to assess differences in safety and effectiveness. In safety analyses, first older patients with and without anti-TNF therapy and then older and younger patients with anti-TNF therapy were assessed. Results In older IBD patients, the use of anti-TNF therapy was associated with serious infections (aHR 3.920, 95% CI 1.185–12.973, p = .025). In anti-TNF-exposed patients, cardiovascular disease associated with serious infections (aHR 3.279, 95% CI 1.098–9.790, p = .033) and the presence of multiple comorbidities (aHR 9.138 (1.248–66.935), p = .029) with malignancies, while patient age did not associate with safety outcomes. Effectiveness of therapy was not affected by age or comorbidity. Conclusion Older patients receiving anti-TNF therapy have a higher risk of serious infections compared with older IBD patients without anti-TNF therapy, but not compared with younger patients receiving anti-TNF therapy. However, in anti-TNF-exposed patients, comorbidity was found to be an indicator with regards to SAEs. Effectiveness was comparable between older and younger patients.

scholarly journals The Role of Pharmacokinetics in Anaesthesia: Application to Intravenous Infusions

1987 ◽  
Vol 15 (1) ◽  
pp. 7-14 ◽  
Author(s):  
D. R. Stanski
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Drug Dose ◽  
Metabolic Clearance ◽  
Drug Infusion ◽  
Fixed Rate ◽  
Elimination Half

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.

scholarly journals Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine.

1997 ◽  
Vol 41 (8) ◽  
pp. 1765-1769 ◽  
Author(s):  
S C Chien ◽  
A T Chow ◽  
M C Rogge ◽  
R R Williams ◽  
C W Hendrix
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Plasma Concentration ◽  
The Body ◽  
Maximum Plasma Concentration ◽  
Maximum Plasma ◽  
Cell Counts ◽  
Pharmacokinetic Profiles ◽  
Study Results ◽  
Immunodeficiency Virus

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.

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