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Clinical Pharmacokinetics Jun 2023Daratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of... (Review)
Review
Daratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory and newly diagnosed multiple myeloma or newly diagnosed light-chain amyloidosis. CD38 is heavily expressed on malignant myeloma cells, and daratumumab exerts anti-myeloma activity via immune-mediated mechanisms, direct induction of apoptosis, and immunomodulation. Daratumumab is used as monotherapy or in combination with standard-of-care myeloma therapies, including proteasome inhibitors, immunomodulatory agents, DNA-alkylating agents, and corticosteroids. Following an intravenous infusion, daratumumab exhibits nonlinear pharmacokinetics (PK), as clearance decreases with higher doses and over time because of target-mediated effects. Dosing schedules vary depending on indications and co-administered drugs, but generally daratumumab is administered weekly for 6-9 weeks followed by a less frequent dosing regimen, once every 2-4 weeks. Daratumumab exposure is strongly correlated with efficacy, and the exposure-efficacy relationship follows a maximal effect model, whereas exposure is not correlated with safety endpoints. The approved dose of 16 mg/kg of daratumumab results in the saturation of 99% of the target at the end of weekly dosing in most patients, and high target saturation is maintained over time during the less frequent dosing schedule. Infusion-related reactions are frequently observed in patients given daratumumab, particularly with the first infusion, thus prompting long durations of infusion (~ 7 h) and splitting of the first dose across 2 days. This led to the development of a subcutaneous delivery formulation for daratumumab (Dara-SC). Dara-SC provides a similar efficacy and safety profile to intravenous daratumumab (Dara-IV) but has a much lower rate of infusion-related reactions and a shorter infusion time. Exposure-response relationships for efficacy and safety endpoints were similar between Dara-SC and Dara-IV, and co-administered drugs with either Dara-IV or Dara-SC do not significantly affect daratumumab PK. Except for baseline myeloma type and albumin level, none of the other investigated disease and patient characteristics (renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group performance status) was identified to have clinically relevant effects on exposure to daratumumab monotherapy or combination therapy regimens. Dara-IV exposure was significantly lower in patients with immunoglobulin G myeloma compared with patients with non-immunoglobulin G myeloma (p < 0.0001) and in patients with a lower albumin level, whereas the overall response rate was similar regardless of the myeloma type and albumin level. Daratumumab dose adjustment is not currently recommended based on disease and patient characteristics.
Topics: Humans; Antineoplastic Agents; Antibodies, Monoclonal; Multiple Myeloma; Albumins; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37129750
DOI: 10.1007/s40262-023-01240-8 -
Seminars in Dialysis Sep 2019Dialyzer clearance of urea multiplied by dialysis time and normalized for urea distribution volume (Kt/V or simply Kt/V) has been used as an index of dialysis adequacy... (Review)
Review
Dialyzer clearance of urea multiplied by dialysis time and normalized for urea distribution volume (Kt/V or simply Kt/V) has been used as an index of dialysis adequacy since more than 30 years. This article reviews the flaws of Kt/V, starting with a lack of proof of concept in three randomized controlled hard outcome trials (RCTs), and continuing with a long list of conditions where the concept of Kt/V was shown to be flawed. This information leaves little room for any conclusion other than that Kt/V, as an indicator of dialysis adequacy, is obsolete. The dialysis patient might benefit more if, instead, the nephrology community concentrates in the future on pursuing the optimal dialysis dose that conforms with adequate quality of life and on factors that are likely to affect outcomes more than Kt/V. These include residual renal function, volume status, dialysis length, ultrafiltration rate, the number of intra-dialytic hypotensive episodes, interdialytic blood pressure, serum potassium and phosphate, serum albumin, and C reactive protein.
Topics: Blood Urea Nitrogen; C-Reactive Protein; Humans; Kidney Failure, Chronic; Phosphates; Potassium; Quality of Life; Renal Dialysis; Serum Albumin; Ultrafiltration; Urea
PubMed: 31025455
DOI: 10.1111/sdi.12811 -
Expert Opinion on Drug Metabolism &... Sep 2020A poor pharmacokinetic profile due to inadequate distribution and rapid renal clearance limits site-specific target engagement and drug efficacy. The inherent properties... (Review)
Review
INTRODUCTION
A poor pharmacokinetic profile due to inadequate distribution and rapid renal clearance limits site-specific target engagement and drug efficacy. The inherent properties of human serum albumin for broad tissue distribution, prolonged circulation, and ligand transport have been engineered into albumin-based drug designs to modulate the pharmacokinetics to increase efficacy and reduce the frequency of dose.
AREAS COVERED
This review highlights albumin structural features, ligand binding, and molecular interactions key to albumin-drug designs and an overview of the repertoire of albumin-drugs and approaches, with focus on pharmacokinetics of marketed products and clinical trials.
EXPERT OPINION
Comparison, and advantages as well as disadvantages of the endogenous albumin-binding versus recombinant albumin construct approach, and half-life extension and intracellular drug delivery applications. The section addresses current challenges and solutions to the different drug designs, and considerations needed to progress the field such as conjugation chemistries, drug loading, and animal models. The section highlights the need for a paradigm shift in the field from 'utilizing' to 'controlling' albumin transport with recombinant human albumin variants engineered for tuned affinity to albumin cellular receptors.
Topics: Animals; Drug Delivery Systems; Drug Design; Humans; Pharmaceutical Preparations; Pharmacokinetics; Serum Albumin, Human; Tissue Distribution
PubMed: 32729729
DOI: 10.1080/17425255.2020.1801633 -
Gastroenterology Oct 2023Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have...
BACKGROUND & AIMS
Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition.
METHODS
Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry.
RESULTS
Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid.
CONCLUSIONS
Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.
Topics: Humans; Acute Disease; Pancreatitis; Fatty Acids, Nonesterified; Oleic Acid; Inflammation; Albumins; Phosphatidylcholines
PubMed: 37263302
DOI: 10.1053/j.gastro.2023.05.034 -
Journal of Clinical Medicine Nov 2023Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response,... (Review)
Review
Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response, and up to 50% of the patients can experience a loss of response to anti-tumor necrosis factor therapy. These undesirable outcomes can be attributed to either a mechanistic failure or pharmacokinetic (PK) issues characterized by an inadequate drug exposure and a high drug clearance. There are several factors associated with accelerated clearance of biologics including increased body weight, low serum albumin and immunogenicity. Drug clearance has gained a lot of attention recently as cumulative data suggest that there is an association between drug clearance and therapeutic outcomes in patients with IBD. Moreover, clearance is used by model informed precision dosing (MIDP) tools, or PK dashboards, to adjust the dosing for reaching a target drug concentration threshold towards a more personalized application of TDM. However, the role of drug clearance in clinical practice is yet to be determined. This comprehensive review aims to present data regarding the variables affecting the clearance of specific biologics, the association of clearance with therapeutic outcomes and the role of clearance monitoring and MIPD in patients with IBD.
PubMed: 38002743
DOI: 10.3390/jcm12227132 -
American Journal of Kidney Diseases :... May 2022Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of...
RATIONALE & OBJECTIVE
Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy.
STUDY DESIGN
Cross-sectional.
SETTINGS & PARTICIPANTS
The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications.
EXPOSURES
Semiquantitative score of IFTA reported by 2 trained pathologists.
OUTCOMES
We measured plasma and urine concentrations of 9 endogenous secretory solutes using a targeted liquid chromatography/mass spectrometry assay. We used linear regression to test associations of urine-to-plasma ratios (UPRs) of these solutes with IFTA score after controlling for estimated glomerular filtration rate (eGFR) and albuminuria.
RESULTS
Among 418 participants, mean age was 53 years, 51% were women, 64% were White, and 18% were Black. Mean eGFR was 50mL/min/1.73m, and median urinary albumin-creatinine ratio was 819mg/g. Compared with individuals with≤25% IFTA, those with>50% IFTA had 12%-37% lower UPRs for all 9 secretory solutes. Adjusting for age, sex, race, eGFR, and urine albumin and creatinine levels attenuated the associations, yet a trend of lower secretion across groups remained statistically significant (P<0.05 for trend) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (P<0.05 for trend).
LIMITATIONS
Single time point and spot measures of secretory solutes.
CONCLUSIONS
Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.
Topics: Albumins; Albuminuria; Creatinine; Cross-Sectional Studies; Female; Fibrosis; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Kidney Tubules; Male; Middle Aged
PubMed: 34571064
DOI: 10.1053/j.ajkd.2021.08.015 -
Clinical Pharmacology and Therapeutics Aug 2021Treatment failure of antibiotic therapy due to insufficient efficacy or occurrence of toxicity is a major clinical challenge, and is expected to become even more urgent... (Review)
Review
Treatment failure of antibiotic therapy due to insufficient efficacy or occurrence of toxicity is a major clinical challenge, and is expected to become even more urgent with the global rise of antibiotic resistance. Strategies to optimize treatment in individual patients are therefore of crucial importance. Currently, therapeutic drug monitoring plays an important role in optimizing antibiotic exposure to reduce treatment failure and toxicity. Biomarker-based strategies may be a powerful tool to further quantify and monitor antibiotic treatment response, and reduce variation in treatment response between patients. Host response biomarkers, such as CRP, procalcitonin, IL-6, and presepsin, could potentially carry significant information to be utilized for treatment individualization. To achieve this, the complex interactions among immune system, pathogen, drug, and biomarker need to be better understood and characterized. The purpose of this tutorial is to discuss the use and evidence of currently available biomarker-based approaches to inform antibiotic treatment. To this end, we also included a discussion on how treatment response biomarker data from preclinical, healthy volunteer, and patient-based studies can be further characterized using pharmacometric and system pharmacology based modeling approaches. As an illustrative example of how such modeling strategies can be used, we describe a case study in which we quantitatively characterize procalcitonin dynamics in relation to antibiotic treatments in patients with sepsis.
Topics: Age Factors; Anti-Bacterial Agents; Bacterial Infections; Biomarkers; C-Reactive Protein; Drug Monitoring; Healthy Volunteers; Humans; Inflammation Mediators; Interleukin-6; Lipopolysaccharide Receptors; Lipopolysaccharides; Metabolic Clearance Rate; Models, Biological; Peptide Fragments; Procalcitonin
PubMed: 33559152
DOI: 10.1002/cpt.2194 -
Clinical Pharmacokinetics Oct 2023Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized...
BACKGROUND AND OBJECTIVE
Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis.
METHODS
Serum pharmacokinetic data in patients receiving mirikizumab 50-1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations.
RESULTS
Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18-64%). The subcutaneous bioavailability of mirikizumab was 48%.
CONCLUSIONS
Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).
Topics: Humans; Colitis, Ulcerative; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Body Weight
PubMed: 37610533
DOI: 10.1007/s40262-023-01281-z -
Frontiers in Immunology 2023Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of...
INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.
METHODS
To investigate whether IV infection impairs alveolar protein clearance, we examined albumin uptake and megalin expression in MLE-12 cells and alveolar epithelial cells (AEC) from murine precision-cut lung slices (PCLS) and in vivo, under IV infection conditions by flow cytometry and western blot. Transcriptional levels from AEC and broncho-alveolar lavage (BAL) cells were analyzed in an in-vivo mouse model by RNAseq.
RESULTS
IV significantly downregulated albumin uptake, independently of activation of the TGF-β1/GSK3β axis that has been previously implicated in the regulation of megalin function. Decreased plasma membrane abundance, total protein levels, and mRNA expression of megalin were associated with this phenotype. In IV-infected mice, we identified a significant upregulation of matrix metalloproteinase (MMP)-14 in BAL fluid cells. Furthermore, the inhibition of this protease partially recovered total megalin levels and albumin uptake.
DISCUSSION
Our results suggest that the previously described MMP-driven shedding mechanisms are potentially involved in downregulation of megalin cell surface abundance and clearance of excess alveolar protein. As lower alveolar edema protein concentrations are associated with better outcomes in respiratory failure, our findings highlight the therapeutic potential of a timely MMP inhibition in the treatment of IV-induced ARDS.
Topics: Animals; Mice; Alveolar Epithelial Cells; Low Density Lipoprotein Receptor-Related Protein-2; Biological Transport; Albumins; Orthomyxoviridae Infections; Orthomyxoviridae
PubMed: 37727782
DOI: 10.3389/fimmu.2023.1260973 -
Kidney Diseases (Basel, Switzerland) Mar 2020Nephropathy problems in the Udhanam region of Andhra Pradesh in India have motivated researchers to investigate the various factors related to chronic kidney disease... (Review)
Review
BACKGROUND
Nephropathy problems in the Udhanam region of Andhra Pradesh in India have motivated researchers to investigate the various factors related to chronic kidney disease (CKD). Initially, studies came across the markers of identification of CKD, i.e., glomerular filtration rate (GFR) and albumin creatinine rate, as global markers of identification. Cystatin C (Cys C) and its reciprocal (1/Cys C) are used to calculate GFR. This is a very easy method compared to the more accurate methods such as radiolabelled tracer clearances, which are invasive, may involve radiation, and require several hours to perform, e.g., 99-diethylene triamine penta-acetic acid (Tc-DTPA) and Cr-EDTA. This article provides the causes (or risk factors), symptoms, and complications of CKD in a clear manner such that even common people can easily understand. Once a patient is detected and proved to be affected by CKD then the patient as well as the caretakers, including doctors, must follow some constraints. Thereby it is possible to prevent CKD progression in the patient. Modern methods are needed to prevent the pathogens which are responsible for CKD.
SUMMARY
With the help of various engineering techniques one can easily design controllers to assess as well as to prevent CKD permanently. The easiest procedure for identifying CKD is to screen people. Current recommendations suggest screening of individuals with diabetes, hypertension, cardiovascular disease, and family history of kidney diseases in the course of routine health check-ups. Much work has been done in medical sciences in the area of CKD, but there is still scope for further research. From the recent studies, advanced tools such as data mining, etc., are considered to be the current trend in the area of CKD.
KEY MESSAGE
From this article, the authors propose that patients who are already affected by urinary tract infection, acute kidney injury, and a family history of CKD should be examined via some basic tests for the presence of CKD.
PubMed: 32309290
DOI: 10.1159/000504622