scholarly journals 1115. Evaluation of Gepotidacin (GSK2140944) Pharmacokinetics and Food Effect in Japanese Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S650-S651
Author(s):  
Mohammad Hossain ◽  
Courtney Tiffany ◽  
Aline Barth ◽  
Aparna Raychaudhuri ◽  
Etienne F Dumont
Keyword(s):  
Tolerability Profile ◽  
Time Curve ◽  
Fed State ◽  
Fasted State ◽  
Drug Concentrations ◽  
Tract Infections ◽  
Oral Doses ◽  
Japanese Subjects

Abstract Background Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial replication and has in vitro and in vivo activity against key pathogens, including drug-resistant strains, associated with a range of infections. Gepotidacin is currently in Phase 3 clinical studies for the treatment of uncomplicated urinary tract infections and gonorrhea. This study (NCT02853435) was designed to assess gepotidacin pharmacokinetics (PK) in Japanese subjects (fasted and fed). Methods A tablet formulation of 750 mg gepotidacin free base was used in the study, which was conducted in two parts: Part 1, gepotidacin PK was assessed following 1500 and 3000 mg single oral doses in the fasted state; and Part 2, gepotidacin PK was assessed following 1500, 2250, and 3000 mg single oral doses in the fed state. Serial blood and urine samples were collected in both study parts. Results Part 1: The area under the plasma drug concentration-time curve from time 0 to infinity (AUC[0–∞]) and maximum observed concentration (Cmax) were slightly higher in Japanese subjects than in Caucasian subjects at the same dose levels and with the same formulation. Following gepotidacin dosing in the fasted state, the 1500 mg dose was tolerated, while the 3000 mg dose was poorly tolerated with mild or moderate gastro-intestinal adverse effects (GI AEs) reported by most subjects shortly after being dosed. Part 2: PK was linear with doses in the range of 1500–3000 mg. Administration of gepotidacin 3000 mg tablets in the fed state slightly reduced Cmax and slightly increased AUC at the 3000 mg dose level. The 1500 and 2250 mg doses were tolerated while the 3000 mg dose was better tolerated compared to the fasted state with fewer and short-lived GI AEs, mostly mild in intensity. After oral administration of 1500–3000 mg, high urine drug concentrations were achieved, remaining above the minimum inhibitory concentration of 4 μg/mL for up to 24 hours. Conclusion The PK of gepotidacin following administration of a single oral dose to Japanese subjects was linear from 1500–3000 mg and food decreased Cmax without impact on exposure (AUC). Administration of gepotidacin with food resulted in an improved GI tolerability profile at the higher dose tested in Japanese subjects. Disclosures Mohammad Hossain, PhD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Courtney Tiffany, BSc, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Aline Barth, MSC;PHD, GlaxoSmithKline plc. (Employee, Shareholder, Employee of and shareholder in GlaxoSmithKline plc.) Aparna Raychaudhuri, Ph.D., GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Etienne F. Dumont, MD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and shareholder in GlaxoSmithKline plc.)

scholarly journals Pharmacokinetics of EDP-420 after Multiple Oral Doses in Healthy Adult Volunteers and in a Bioequivalence Study

2009 ◽  
Vol 53 (8) ◽  
pp. 3218-3225 ◽  
Author(s):  
Li-Juan Jiang ◽  
Yat Sun Or
Keyword(s):  
Systemic Exposure ◽  
Bioequivalence Study ◽  
Respiratory Pathogens ◽  
Capsule Formulation ◽  
Dose Study ◽  
Effect Of Food ◽  
Tract Infections ◽  
Oral Doses

ABSTRACT EDP-420 (also known as EP-013420, or S-013420) is a first-in-class bridged bicyclolide currently in clinical development for the treatment of respiratory tract infections (RTI) and has previously shown favorable pharmacokinetic (PK) and safety profiles after the administration of single oral doses of a suspension to healthy volunteers. Here we report its PK profile after the administration of multiple oral doses of a suspension to healthy adults. Bioequivalence between suspension and capsule formulations, as well as the effect of food, is also reported. The most important PK features of EDP-420 observed in these clinical studies are its long half-life of 17 to 18 h and its high systemic exposure, which support once-daily dosing and treatment durations potentially shorter than those of most other macrolide antibiotics. EDP-420 is readily absorbed following oral administration in both suspension and capsule formulations. In the multiple-oral-dose study, steady state was achieved on day 1 by using a loading dose of 400 mg/day, followed by 2 days of 200 mg/day. A high-fat meal had no effect on the bioavailability of EDP-420 administered in a capsule formulation. EDP-420 was well tolerated, with no serious or severe adverse events reported, and no subject was discontinued from the study due to an adverse event. Based on its human PK and safety profiles, together with its in vitro/in vivo activities against common respiratory pathogens, EDP-420 warrants further development, including trials for clinical efficacy in the treatment of RTI.

scholarly journals Distribution and Antimicrobial Activity of Fosfomycin in the Interstitial Fluid of Human Soft Tissues

2000 ◽  
Vol 44 (10) ◽  
pp. 2728-2732 ◽  
Author(s):  
Martin Frossard ◽  
Christian Joukhadar ◽  
Boban M. Erovic ◽  
Peter Dittrich ◽  
Paulus E. Mrass ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissues ◽  
Pharmacokinetic Profile ◽  
Interstitial Space ◽  
Soft Tissue Infections ◽  
Time Curve ◽  
Tract Infections ◽  
High Degree

ABSTRACT Fosfomycin is a broad-spectrum antibiotic which is established as therapy for uncomplicated lower urinary tract infections. In addition, preliminary data indicate that fosfomycin has a potential role in the treatment of soft tissue infections. However, the use of fosfomycin has not been established for this condition, and it is unclear whether the level of fosfomycin penetration into human soft tissues is high enough to eradicate relevant pathogens. To better characterize the antibiotic potential of fosfomycin, we applied a combined in vivo pharmacokinetic-in vitro pharmacodynamic model to human volunteers. For this purpose fosfomycin concentrations in vivo in the fluid of the interstitial space of human soft tissues were measured by microdialysis following intravenous infusion of 4 or 8 g of fosfomycin (n = 6). Subsequently, bacterial isolates with relevance for soft tissue infections were exposed to concentrations according to the in vivo pharmacokinetic profile in the interstitial space fluid obtained by microdialysis. Our experiments indicated a high degree of soft tissue penetration for fosfomycin, with ratios of the area under the concentration-time curve from 0 to 8 h for muscle (AUC0–8muscle )/AUC0–8serum of 0.48 ± 0.08 and 0.53 ± 0.04 and ratios of AUC0–8adipose tissue /AUC0–8serum of 0.74 ± 0.12 and 0.71 ± 0.11 following administration of 4 and 8 g, respectively. In corresponding in vitro simulation experiments with selected isolates of Staphylococcus aureus,Enterobacter cloacae, and Serratia marcescensfor which MICs were 16 μg/ml, organisms were undetectable after a single dosing interval. Fosfomycin exhibits a strong ability to penetrate into the fluid of the interstitial space of soft tissues and reaches levels sufficient to substantially inhibit the growth of relevant bacteria at the target site. We therefore conclude that fosfomycin might qualify as an alternative candidate for the therapy of soft tissue infections.

scholarly journals In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

2020 ◽  
Vol 21 (7) ◽  
Author(s):  
J. Martir ◽  
T. Flanagan ◽  
J. Mann ◽  
N. Fotaki
Keyword(s):  
Drug Product ◽  
Drug Dissolution ◽  
Simulated Gastric Fluid ◽  
Dissolution Testing ◽  
Fed State ◽  
Fasted State ◽  
Direct Administration ◽  
The Impact

Abstract In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.

scholarly journals Mutant Selection Window in Levofloxacin and Moxifloxacin Treatments of Experimental Pneumococcal Pneumonia in a Rabbit Model of Human Therapy

2004 ◽  
Vol 48 (5) ◽  
pp. 1699-1707 ◽  
Author(s):  
Delphine Croisier ◽  
Manuel Etienne ◽  
Emilie Bergoin ◽  
Pierre-Emmanuel Charles ◽  
Catherine Lequeu ◽  
...  
Keyword(s):  
Rabbit Model ◽  
Wild Type ◽  
Bacterial Reduction ◽  
Time Curve ◽  
Mutant Selection ◽  
Drug Concentrations ◽  
Selection Window ◽  
Human Therapy

ABSTRACT For some pneumococci the fluoroquinolone MICs are low but the mutant prevention concentrations (MPCs) are high; this difference defines in vitro the mutant selection window (MSW). We investigated in vivo the bacterial reduction and the occurrence of resistant mutants with moxifloxacin (MFX; 400 mg once daily) or levofloxacin (LVX; 500 mg twice daily) in treatments similar to those in humans with experimental pneumonia due to pneumococci (expPP) exhibiting various MICs and MPCs. The MIC/MPC for MFX and LVX and genotypes were as follows: strain 16089, 0.125/0.125 and 0.5/0.5 (wild type); strain MS1A, 0.25/0.25 and 1/2 (efflux); strain MS2A, 0.25/4 and 1.75/28 (parC79); strain MR3B4, 0.25/4 and 2/32 (parC79); strain M16, 0.5/2 and 8/32 (parC83); strain Gyr-1207, 1.5/3 and 8/16 (gyrA); and strain MQ3A, 4/4 and 16/64 (parC and gyrA). Both drugs were efficient with wild type-expPP, but only MFX was efficient with efflux-expPP. No bacterial reduction was observed for parC-expPPs due to mutants observed in 18 to 100% of animals, depending on the strain and the drug tested. These mutants showed unbound area under the concentration-time curve and MICs of from 50 to 164 for MFX. The in vivo pharmacodynamic boundaries of the MSW were different for MFX and LVX. We conclude that, after LVX or MFX treatment, mutants occur in vivo if there is a preexisting parC mutation, since the drug concentrations fall below the MPCs of these strains. Since the MPC determination cannot be routinely determined, these phenotypes or genotypes should be detected by simple tests to guide the therapeutic options.

scholarly journals Comparative survival of commercial probiotic formulations: tests in biorelevant gastric fluids and real-time measurements using microcalorimetry

2015 ◽  
Vol 6 (1) ◽  
pp. 141-151 ◽  
Author(s):  
M. Fredua-Agyeman ◽  
S. Gaisford
Keyword(s):  
Real Time ◽  
Gastric Fluid ◽  
Simulated Gastric Fluid ◽  
Fed State ◽  
Fasted State ◽  
Nutritional Advice ◽  
Freeze Dried ◽  
Viable Bacteria

The large number of probiotic products now available makes the decision about which product to choose difficult both for the consumer and for the specialist providing dietary/nutritional advice. Data on the viability of the bacteria in these products, in an in vivo situation, are therefore important. This study was designed to explore the comparative health and survival of probiotic species in various commercial formulations, using more realistic test systems. This might allow further understanding of factors that must be controlled to optimise the delivery of live healthy bacteria to the lower gut. A total of eight commercially available probiotic preparations were selected for enumeration tests and in vitro gastric tolerance tests. Tolerance assays were conducted in porcine gastric fluid (PGF) fed and fasted state (pH 3.4±0.04), simulated gastric fluid (SGF, pH adjusted to 1.2 and 3.4) and fasted state simulated gastric fluid (FaSSGF, pH adjusted to 1.6 and 3.4). Isothermal microcalorimetry was also used to measure real-time growth of probiotics after exposure to simulated gastric fluid. Results from the enumeration tests indicated that recovery of viable organisms per dose is the same as or better than the stated label claims for liquid-based formulations, but lower than the stated claim for freeze-dried products. Results from the in vitro tolerance tests overall suggest that the PGF provided a harsher environment than the simulated systems at similar pH. In general, liquid-based products tested tended to give superior results in terms of survival compared with the freeze-dried products tested. Results from tests in the fed state in PGF suggested that food greatly affects viability. Microcalorimetric data showed that for some products probiotic species were able to grow following exposure to gastric fluid, suggesting that viable bacteria reach the gut in vivo.

scholarly journals In Vitro and In Vivo Antibacterial Activities of L-084, a Novel Oral Carbapenem, against Causative Organisms of Respiratory Tract Infections

2001 ◽  
Vol 45 (1) ◽  
pp. 203-207 ◽  
Author(s):  
Shuichi Miyazaki ◽  
Takayuki Hosoyama ◽  
Nobuhiko Furuya ◽  
Yoshikazu Ishii ◽  
Tetsuya Matsumoto ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Respiratory Tract Infections ◽  
Antibacterial Activities ◽  
Time Curve ◽  
Infection Models ◽  
Underlying Mechanisms ◽  
Tract Infections ◽  
Better Than

ABSTRACT L-084 (a prodrug of LJC 11,036 [L-036]) is a new oral carbapenem. Here we compared the in vitro and in vivo antibacterial activities of L-036 with those of imipenem, faropenem, ceditoren-pivoxil, cefdinir, amoxicillin, and levofloxacin. The MICs at which 90% of the isolates were inhibited of L-036 against methicillin-susceptible staphylococci,Streptococcus pneumoniae including penicillin-resistant organisms, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae including ampicillin-resistant organisms, Legionella pneumophila, andMoraxella catarrhalis were equal to or less than 1 μg/ml. In pharmacokinetics studies of L-084 in lungs of mice, the maximum concentration in serum, half-life, and area under the concentration-time curve of this drug were 9.09 μg/g of tissue, 6.18 h, and 31.0 μg · h/ml, respectively. In murine respiratory infection models of penicillin-susceptible and -resistantS. pneumoniae and H. influenzae, the efficacies of L-084 were better than those of reference drugs. Our results indicate that the in vitro high potency and good distribution in the lungs might be the underlying mechanisms of its efficacy in the murine model of pneumonia.

scholarly journals Cefoxitin as an Alternative to Carbapenems in a Murine Model of Urinary Tract Infection Due to Escherichia coli Harboring CTX-M-15-Type Extended-Spectrum β-Lactamase

2012 ◽  
Vol 56 (3) ◽  
pp. 1376-1381 ◽  
Author(s):  
Raphaël Lepeule ◽  
Etienne Ruppé ◽  
Patrick Le ◽  
Laurent Massias ◽  
Françoise Chau ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract ◽  
Murine Model ◽  
Content Type ◽  
E Coli ◽  
Extended Spectrum ◽  
Drug Concentrations ◽  
Tract Infections

ABSTRACTWe investigated the efficiency of the cephamycin cefoxitin as an alternative to carbapenems for the treatment of urinary tract infections (UTIs) due toEscherichia coliproducing CTX-M-type extended-spectrum β-lactamases. The susceptible, UTI-inducingE. coliCFT073-RR strain and its transconjugant CFT073-RR Tc (pblaCTX-M-15), harboring ablaCTX-M-15carrying-plasmid, were used for all experiments. MICs of cefoxitin (FOX), ceftriaxone (CRO), imipenem (IMP), and ertapenem (ETP) for CFT073-RR and CFT073-RR Tc (pblaCTX-M-15) were 4 and 4, 0.125 and 512, 0.5 and 0.5, and 0.016 and 0.032 μg/ml, respectively. Bactericidal activity was similarly achievedin vitroagainst the two strains after 3 h of exposure to concentrations of FOX, IMI, and ETP that were 2 times the MIC, whereas CRO was not bactericidal against CFT073-RR Tc (pblaCTX-M-15). The frequencies of spontaneous mutants of the 2 strains were not higher for FOX than for IMP or ETP. In the murine model of UTIs, mice infected for 5 days were treated over 24 h. Therapeutic regimens in mice (200 mg/kg of body weight every 3 h or 4 h for FOX, 70 mg/kg every 6 h for CRO, 100 mg/kg every 2 h for IMP, and 100 mg/kg every 4 h for ETP) were chosen in order to reproduce the percentage of time that free-drug concentrations above the MIC are obtained in humans with standard regimens. All antibiotic regimens produced a significant reduction in bacterial counts (greater than 2 log10CFU) in kidneys and bladders for both strains (P< 0.001) without selecting resistant mutantsin vivo, but the reduction obtained with CRO against CFT073-RR Tc (pblaCTX-M-15) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producingE. coli.

In vitro Lipolysis as a Tool for the Establishment of IVIVC for Lipid-Based Drug Delivery Systems

2019 ◽  
Vol 16 (8) ◽  
pp. 688-697
Author(s):  
Ravinder Verma ◽  
Deepak Kaushik
Keyword(s):  
Drug Delivery ◽  
Ph Value ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Rapid Screening ◽  
Resonance Spectroscopy ◽  
Fed State ◽  
In Vitro Lipolysis ◽  
Ph Stat

: In vitro lipolysis has emerged as a powerful tool in the development of in vitro in vivo correlation for Lipid-based Drug Delivery System (LbDDS). In vitro lipolysis possesses the ability to mimic the assimilation of LbDDS in the human biological system. The digestion medium for in vitro lipolysis commonly contains an aqueous buffer media, bile salts, phospholipids and sodium chloride. The concentrations of these compounds are defined by the physiological conditions prevailing in the fasted or fed state. The pH of the medium is monitored by a pH-sensitive electrode connected to a computercontrolled pH-stat device capable of maintaining a predefined pH value via titration with sodium hydroxide. Copenhagen, Monash and Jerusalem are used as different models for in vitro lipolysis studies. The most common approach used in evaluating the kinetics of lipolysis of emulsion-based encapsulation systems is the pH-stat titration technique. This is widely used in both the nutritional and the pharmacological research fields as a rapid screening tool. Analytical tools for the assessment of in vitro lipolysis include HPLC, GC, HPTLC, SEM, Cryo TEM, Electron paramagnetic resonance spectroscopy, Raman spectroscopy and Nanoparticle Tracking Analysis (NTA) for the characterization of the lipids and colloidal phases after digestion of lipids. Various researches have been carried out for the establishment of IVIVC by using in vitro lipolysis models. The current publication also presents an updated review of various researches in the field of in vitro lipolysis.

Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)

2020 ◽  
Author(s):  
Hacer Kuzu Okur ◽  
Koray Yalcin ◽  
Cihan Tastan ◽  
Sevda Demir ◽  
Bulut Yurtsever ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Mononuclear Cells ◽  
Multiple Organ ◽  
Peripheral Blood Mononuclear ◽  
Dornase Alfa ◽  
Tract Infections ◽  
Adult Peripheral Blood

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

scholarly journals Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors

2021 ◽  
Author(s):  
Venkatesh Pilla Reddy ◽  
Adrian J. Fretland ◽  
Diansong Zhou ◽  
Shringi Sharma ◽  
Buyun Chen ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Kinase Inhibitors ◽  
Pbpk Model ◽  
Model Development ◽  
Limited Information ◽  
Time Curve ◽  
Btk Inhibitor ◽  
Chop Therapy

Abstract Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

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