The Influence of Different Disease States on Rituximab Pharmacokinetics

2020 ◽  
Vol 21 (12) ◽  
pp. 938-946
Author(s):  
Xiaoxing Wang ◽  
Wenwen Du ◽  
Xianglin Zhang ◽  
Pengmei Li
Keyword(s):  
Clinical Practice ◽  
B Cell ◽  
Drug Exposure ◽  
Kidney Diseases ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
B Cell Malignancies ◽  
Related Factors ◽  
Factors Affecting

Background: The anti-CD20 antibody rituximab, which promotes the selective depletion of CD20 positive B cells, was the first targeted therapy that was approved for the treatment of B-cell malignancies, and it is now widely prescribed in both malignant and non-malignant, immune-related diseases. However, the cause of its various clinical responses in certain diseases, have not been clearly elucidated. The variabilities in inter-individual pharmacokinetic and the emerging evidence of the relationships between pharmacokinetic and pharmacodynamic may provide a better understanding of this drug. Methods: We searched and summarized the latest published articles on rituximab pharmacokinetic profiles and the pharmacokinetic/pharmacodynamic models in different patient populations, including B-cell malignancies, rheumatoid arthritis, ANCA-associated vasculitis, and glomerular kidney diseases. Results: Most pharmacokinetic data are drawn from clinical studies in oncology clinical practice. Body weight, gender, and antigen-related factors are proven to be the key factors affecting rituximab pharmacokinetics. In addition, the positive exposure-response relations were reported, which provide encouraging evidence for individualized therapies. While in immune disorders, especially in the off-labeled indications, pharmacokinetic studies are quite limited. Compared with that in B-cell malignancies, the differences in the pharmacokinetic parameters may be attributed to the different pathogeneses of diseases, mechanisms of action and dosing strategies. However, the correlation between drug exposure and clinical outcomes remains unclear. Conclusion: Here, we provide an overview of the complexities associated with rituximab pharmacokinetics and pharmacodynamics in different diseases. Although many influencing factors need to be verified in future studies, a better understanding of the relationships between pharmacokinetic and pharmacodynamic may assist in optimizing rituximab clinical practice.

The HCK/BTK inhibitor KIN-8194 is active in MYD88 driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance.

Blood ◽  
2021 ◽  
Author(s):  
Guang Yang ◽  
Jinhua Wang ◽  
Li Tan ◽  
Manit Munshi ◽  
Xia Liu ◽  
...  
Keyword(s):  
B Cell ◽  
Malignant Cell ◽  
Pharmacokinetic Parameters ◽  
B Cell Malignancies ◽  
Lymphoma Cells ◽  
Dual Inhibitor ◽  
Growth And Survival ◽  
Activating Mutations ◽  
Ibrutinib Resistance

Activating mutations in MYD88 promote malignant cell growth and survival through HCK mediated BTK activation. Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481 particularly BTKCys481Ser are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88 mutated lymphoma cells, including ibrutinib resistant BTKCys481Ser expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained HCK and BTK inhibition for 24 hours following single oral administration of KIN-8194 in MYD88 mutated TMD-8 ABC DLBCL xenografted mice with either wild-type BTK (BTKWT) or BTKCys481Ser expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT and BTKCys481Ser expressing TMD-8 DLBCL xenografted mice, including sustained complete responses >12 weeks off treatment in mice with BTKWT expressing TMD-8 tumors. The Bcl-2 inhibitor venetoclax enhanced the anti-tumor activity of KIN-8194 in BTKWT and BTKCys481Ser expressing MYD88 mutated lymphoma cells, and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.

scholarly journals Pharmacokinetic relationships in psychotropic drugs effects

2021 ◽  
pp. 3-8
Author(s):  
G. B. Kolyvanov ◽  
A. A. Litvin ◽  
R. V. Shevchenko ◽  
S. Yu. Raskin ◽  
P. O. Bochkov ◽  
...  
Keyword(s):  
Complex System ◽  
Clinical Practice ◽  
Medical Practice ◽  
Psychotropic Drugs ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Preclinical Studies ◽  
Therapeutic Approaches

The review discusses relationships between pharmacokinetic parameters and effects of psychotropic drugs, both in preclinical studies and clinical practice. The identification of such correlations can serve as a basis for understanding the complex system of relationships between pharmacokinetic and pharmacodynamic mechanisms in the manifestation of the action of this group of drugs and allows us to use the data of pharmacokinetic studies to optimize therapeutic approaches in medical practice.

scholarly journals PHARMACOKINETIC STUDY OF BEDAQUILINE AMONG INDIAN MDR-TB PATIENTS IN CLINICAL SETTINGS

2021 ◽  
Author(s):  
Vamshikrishna Gone ◽  
Shalini Thakur ◽  
Nithya Valupadasu ◽  
Yashaswini Akoju ◽  
Bhuvana Chandra Pasupuleti ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Routine Clinical Practice ◽  
Multi Drug Resistance ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Clinical Settings ◽  
Diseased Person ◽  
Mdr Tb ◽  
Us Fda

Bedaquiline, a novel drug was approved for the treatment of multi-drug resistance tuberculosis (MDR-TB) by the US FDA in 2012. It is majorly caused because of the transmission of multi-resistant strain from a diseased person to a healthy individual and by genetic factors. Safety, efficacy, and bactericidal activity of Bedaquiline were reported in various studies, but the pharmacokinetic analysis of Bedaquiline in clinical settings was unclear. This study serves as evidence for the physicians regarding the pharmacokinetic data and managing drug therapy and for better patient outcome in routine clinical practice. This study is conducted in a total of 58 patients with newly diagnosed, smear-positive, MDR-TB patients who received Bedaquiline as per RNTCP guidelines. Plasma samples were collected after the Bedaquiline administration. The patient samples were analyzed. The pharmacokinetic data were drawn by using software kinetic-2000, version 5.03.The observed Cmax was 2523.08 ng/mL, Tmax was reached at 4 hrs, AUC(0-24) was 21727.1 ng *hr/mL, AUMC (0-24) was 222953.8 ng *hr2/mL. Whereas the half-life of the drug was found at 7 .02 hrs and mean residence time (MRT) was found to be 10.25 hrs respectively. The data was even on the 14th day of therapy. The Cmax is shown to be 5937.1ng/mL reaching the Cmax at about 5 hours. While the AUC(0-24) was found to be 65780 ng *hr/mL. Conclusively, pharmacokinetic parameters were evaluated and found to be within the desired limits with minimal changes. This method can be further used for the quantification of Bedaquiline in routine clinical practice.

Abbreviated, Dose Dense Fludarabine and Rituximab for Elderly Patients with Indolent B Cell Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4796-4796
Author(s):  
Gabriela Ballester ◽  
Lisa Frazer ◽  
Maria Tirona ◽  
Oscar F Ballester
Keyword(s):  
B Cell ◽  
Drug Exposure ◽  
Conflicts Of Interest ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Number Of Patients ◽  
Histological Transformation ◽  
Dose Dense

Abstract Abstract 4796 Introduction Therapy for indolent B cell malignancies is primarily palliative. Therefore limiting toxicities by reducing drug exposure is desirable, particularly in elderly individuals. The combination of fludarabine and rituximab has been extensively used in patients with these disorders. We sought to decrease the number of fludarabine cycles, attempting to maintain the high response rates of this combination by increasing the doses of rituximab and the dose density. Patients and Methods We designed an abbreviated, but dose dense regimen (addFR) consisting of fludarabine 25 mg/m2/d for 5 days on weeks 1, 6 and 11 plus rituximab at 375mg/m2 on weeks 2-5 and 7-10. Maintenance was offered to responding patients with rituximab for 4 weekly doses every 6 months (for 2 years). This schema represents a 50% decrease in the dosage on fludarabine with a 33% increase in the dosage of rituximab compared to the standard regimen. Twelve patients with a median age of 70 years, (range 43 to 85, 9 of the 12 patient are older than 65 years of age) have been treated. Nine patients had chronic lymphocytic leukemia (CLL, n= 5) or small lymphocytic lymphoma (SLL, n= 4). Three patients had marginal zone lymphoma (MZL). Three patients had received prior therapy. Responses were assessed by standard criteria 4 weeks after completion of the planned 11 weeks of therapy. Results Two patients are still completing their 11 weeks of therapy. Ten patients have completed the 11 weeks of addFR. They are evaluable for toxicity and responses. Hematological toxicities included neutropenia Grade >III in 2 patients with a single episode of neutropenic fevers requiring hospitalization. One patient with refractory disease was shown to have histological transformation from SLL to a diffuse large B cell lymphoma. All of the remaining 9 patients achieved a complete clinical remission, including 8 patients with CLL/SLL and 1 patient with MZL. With a median follow up of 13 months (range 10 to 23 months); these 9 patients have remained free of disease progression. Conclusions addFR seems to be well tolerated and effective even in patients older than 65 years of age. Experience with a larger number of patients and longer follow up is needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Assessment of Confirmed Clinical Hypersensitivity to Rituximab in Patients Affected with B-Cell Neoplasia

2020 ◽  
Vol 2020 ◽  
pp. 1-5 ◽  
Author(s):  
S. Novelli ◽  
L. Soto ◽  
A. Caballero ◽  
M. E. Moreno ◽  
M. J. Lara ◽  
...  
Keyword(s):  
Clinical Practice ◽  
B Cell ◽  
Drug Exposure ◽  
B Cell Lymphoma ◽  
Infusion Reaction ◽  
Hypersensitivity Reactions ◽  
Drug Interference ◽  
Future Drug ◽  
History Of ◽  
Desensitization Protocol

Rituximab hypersensitivity reactions are rare but are one of the main causes of rituximab elimination from antilymphoma immunochemotherapy treatments. While the clinical picture may be indistinguishable from other infusion-related reactions, hypersensitivity reactions (HSR) do not disappear and instead become more intense with subsequent administrations. Objective. To describe the use of the 12-step protocol for desensitization to intravenous rituximab in clinical practice and the complementary study of a possible IgE-mediated HSR in the context of B-cell lymphoma treatment. Methods. A 12-step rituximab desensitization protocol was performed prospectively within clinical practice in 10 patients with a history of severe infusion reactions or in patients who had a repeated reaction at subsequent doses despite taking more intense preventive measures. Skin prick tests were performed at the time of reaction and at a later time to eliminate false negatives due to possible drug interference. Results. Overall, with the desensitization protocol, 70% of patients were able to complete the scheduled immunochemotherapy. Two patients had to discontinue the therapy due to clinical persistence and the third due to lymphoma progression. Intradermal tests with 0.1% rituximab were positive in only 20% of cases, demonstrating a mechanism of hypersensitivity. Conclusions. The 12-step desensitization protocol is very effective and assumable within healthcare practice. There is a need to determine the mechanism underlying the infusion reaction in a large proportion of cases due to the risk of future drug exposure.

scholarly journals Management of ibrutinib treatment in patients with B-cell malignancies: clinical practice in Portugal and multidisciplinary recommendations

Hematology ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 785-798
Author(s):  
José Pedro Carda ◽  
Lurdes Santos ◽  
José Mário Mariz ◽  
Pedro Monteiro ◽  
Humberto Miguel Gonçalves ◽  
...  
Keyword(s):  
Clinical Practice ◽  
B Cell ◽  
B Cell Malignancies

scholarly journals Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies

2013 ◽  
Vol 31 (1) ◽  
pp. 88-94 ◽  
Author(s):  
Ranjana H. Advani ◽  
Joseph J. Buggy ◽  
Jeff P. Sharman ◽  
Sonali M. Smith ◽  
Thomas E. Boyd ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Dose Escalation ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Data ◽  
Significant Activity ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase

Purpose Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

Cefepime Dosing in Neonates: What is the Evidence?

2019 ◽  
Author(s):  
Danielle McDonald ◽  
Pooja Shah
Keyword(s):  
Clinical Practice ◽  
English Language ◽  
Inhibitory Concentration ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Serum Concentrations ◽  
Dosing Regimen ◽  
Dosing Interval ◽  
Dosing Frequency ◽  
Dosing Strategies

Abstract Objective Recommended cefepime dosing strategies in neonates varies in commonly utilized dosing references with regard to dose and frequency. The objective of this review is to summarize and evaluate the available literature describing cefepime dosing in neonatal patients. Study Design We performed a literature review in MEDLINE using the keyword cefepime. The search was limited to the English language, humans, and patients <2 months of age. We evaluated four pharmacokinetic studies and two studies describing the use of cefepime in clinical practice. Results The available studies assessing cefepime serum concentrations in neonatal patients demonstrated maintenance of adequate pharmacokinetic parameters when utilizing a dosing frequency of every 12 hours, specifically for organisms with a minimum inhibitory concentration (MIC) ≤ 8 mg/L. In studies evaluating clinical outcomes of cefepime use in neonates, the most frequent adverse effects reported included seizures and hypophosphatemia. Microbiologic cure was demonstrated with a dosing regimen of 50 mg/kg per dose every 12 hours. Conclusion Cefepime dosed 30 to 50 mg/kg per dose every 12 hours may be appropriate to achieve a concentration two to four times above an MIC ≤ 8 mg/L for at least 60% of the dosing interval in neonatal patients.

scholarly journals A Systematic Review of the Pharmacokinetics of Antiepileptic Drugs in Neonates With Refractory Seizures

2012 ◽  
Vol 17 (1) ◽  
pp. 31-44
Author(s):  
Joanie K Tulloch ◽  
Roxane R Carr ◽  
Mary H.H Ensom
Keyword(s):  
Antiepileptic Drugs ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Multiple Time ◽  
Serum Concentrations ◽  
Neonatal Seizures ◽  
Level Ii ◽  
Increased Risk ◽  
Refractory Seizures

BACKGROUND Neonatal seizures are associated with neurological sequelae and an increased risk of epilepsy later in life. Phenobarbital and phenytoin remain the antiepileptic drugs (AEDs) most commonly used to treat neonatal seizures, despite their suboptimal effectiveness and safety. As a result, other AEDs, such as levetiracetam and topiramate, are often used in neonates with refractory seizures, despite limited data and off-label use. OBJECTIVES To systematically review published pharmacokinetic data for second-line AEDs used in neonates with seizures and to provide dosing recommendations for these agents in the neonatal population. METHODS A literature search was conducted in PubMed (1949-May 2012), Medline (1950-May 2012), and Embase (1980-May 2012). Each study was ranked according to the quality of evidence it provided, based on the classification system developed by the US Preventive Services Task Force. Information extracted from each study included study design, number of subjects, gestational and postnatal age, AED dosage regimen, pharmacokinetic parameters, pharmacokinetic model, AED serum concentrations, and sampling times. RESULTS Nineteen relevant pharmacokinetic studies involving a total of 8 different drugs were identified. No prospective, randomized, controlled studies (level I evidence) or nonrandomized controlled studies (level II-I evidence) were identified; 2 studies were prospective, nonrandomized, uncontrolled (cohort) studies (level II-2 evidence), 11 studies obtained evidence from multiple time series (level II-3 evidence), and 6 studies were case reports or descriptive studies (level III evidence). CONCLUSIONS There are limited pharmacokinetic data for the use of carbamazepine, levetiracetam, lidocaine, paraldehyde, topiramate, valproic acid, and vigabatrin for neonates with seizures refractory to treatment with first-line antiepileptic agents. Further research is needed to elucidate target AED serum concentrations (if any) required to optimize effectiveness and minimize dose-related adverse effects in neonates.

scholarly journals Nonstationary Pharmacokinetics of Caspofungin in ICU Patients

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Agnieszka Borsuk-De Moor ◽  
Justyna Sysiak-Sławecka ◽  
Elżbieta Rypulak ◽  
Michał Borys ◽  
Paweł Piwowarczyk ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Area Under The Curve ◽  
Population Pharmacokinetic ◽  
Relative Standard Error ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Albumin Concentration ◽  
Relative Standard

ABSTRACT Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic 24-h area under the curve to MIC (AUC0–24/MIC) ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 intensive care unit patients with a suspected invasive fungal infection, with a large proportion of patients requiring extracorporeal therapies, including extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Caspofungin was administered as empirical 70 mg antifungal therapy administered intravenously (i.v.) on the first day and at 50 mg i.v. on the consecutive days once daily, and the concentrations were measured after three subsequent doses. Population pharmacokinetic data were analyzed by nonlinear mixed-effects modeling. The pharmacokinetics of caspofungin was described by two-compartment model. A particular drift of the individual clearance (CL) and the volume of distribution of the central compartment (V1) with time was discovered and described by including three separate typical values of CL and V1 in the final model. The typical CL values at days 1, 2, and 3 were 0.563 liters/h (6.7% relative standard error [6.7%RSE]), 0.737 liters/h (6.1%RSE), and 1.01 liters/h (9.1%RSE), respectively. The change in parameters with time was not explained by any of the recorded covariates. Increasing clearance with subsequent doses was associated with a clinically relevant decrease in caspofungin exposure (>20%). The use of ECMO, CRRT, albumin concentration, and other covariates did not significantly affect caspofungin pharmacokinetics. Additional pharmacokinetic studies are urgently required to assess the possible lack of acquiring steady-state and suboptimal concentrations of the drug in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT03399032.)

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