Evaluating the clinical impact of a shortened infusion duration for ramucirumab: A population pharmacokinetic model-based approach.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 191-191
Author(s):  
Paolo Abada ◽  
Yiu-Keung Lau ◽  
Ran Wei ◽  
Lisa O’Brien ◽  
Amanda Long ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Study Data ◽  
Population Pharmacokinetic ◽  
Time Profiles ◽  
Concentration Time ◽  
Increased Risk ◽  
Grade 3 ◽  
Infusion Duration

191 Background: Ramucirumab is a human recombinant immunoglobin G1 monoclonal antibody (mAb) antagonist of vascular endothelial growth factor receptor-2. Ramucirumab dosed at 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks, either as monotherapy or in combination with chemotherapy, was initially studied with as an intravenous infusion over 60 minutes following premedication with a histamine-1 receptor antagonist. Lengthy intravenous infusions are inconvenient for patients and increase the workloads of nursing and administrative staff. Shortening the infusion duration of ramucirumab could therefore benefit both patients and healthcare professionals. The current analysis determined the impact such a change could have on the pharmacokinetic (PK) profile of ramucirumab. Additionally, the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration), common adverse events associated with mAb infusions, was assessed. Methods: A population pharmacokinetic model was established using concentration–time data collected from 2522 patients who received one of five different ramucirumab regimens involving an intravenous infusion over ~60 minutes in 17 clinical studies. The final PK model was used to simulate concentration–time profiles and exposure parameters following ramucirumab infusion durations of 30 vs 60 min. Phase II/III clinical study data from patients receiving ramucirumab were pooled to assess the association between ramucirumab infusion rate and incidence of immediate IRRs using multivariate logistic regression analysis. Results: Ramucirumab infusions of 30- and 60-min durations resulted in equivalent concentration–time profiles and, hence, equivalent systemic exposure to ramucirumab. Among 3216 patients receiving ramucirumab in phase II/III studies, 254 (7.9%) had at least one immediate any-grade IRR; 17 (0.5%) experienced grade ≥3 immediate IRRs. The incidence of immediate IRRs (any grade or grade ≥3) was similar across infusion rate quartiles. Under multivariate logistic analysis, infusion rate was not significantly associated with an increased risk of an immediate IRR (odds ratio per 1 mg/min increase 1.014, 95% confidence interval 0.999, 1.030; p=0.071). Conclusions: Administering ramucirumab using different infusion durations (30 vs 60 min) did not affect ramucirumab exposure. Analysis of clinical study data showed a faster infusion rate was not associated with an increased risk of immediate IRRs. It is considered unlikely that shortening the infusion duration of ramucirumab will impact its clinical efficacy or overall safety profile, and is now an option for administration in the U.S.

scholarly journals Daptomycin Pharmacokinetics in Adolescents Undergoing Hemodialysis and Peritoneal Dialysis: A Case Series With Pharmacokinetic Modeling

2021 ◽  
Vol 26 (2) ◽  
pp. 123-132
Author(s):  
Sin Yin Lim ◽  
Teresa Lewis ◽  
Sukyung Woo ◽  
Martin Turman ◽  
David W. A. Bourne ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Pharmacokinetic Model ◽  
Obese Subject ◽  
Case Series ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Old Patients ◽  
Concentration Time ◽  
Increased Risk ◽  
Dosing Regimens

BACKGROUND Children who undergo hemodialysis (HD) and peritoneal dialysis are at increased risk of infection. Daptomcyin is used to treat resistant infections; however, the pharmacokinetics of daptomycin in pediatric and adolescent dialysis patients remain unknown. METHODS We report the safety and pharmacokinetics of a single intravenous 5 mg/kg dose of daptomycin for 6 individuals age 12 to 17 years old who underwent HD or continuous cycling peritoneal dialysis (CCPD). Daptomycin concentrations from all samples were determined by high-performance liquid chromatography. A non-compartmental analysis was performed to compare the pharmacokinetic parameters among HD and CCPD patients. A population pharmacokinetic model was developed to describe the concentration-time profiles of daptomycin in plasma, urine, and dialysis effluent. Monte Carlo simulations were performed to assess the pharmacodynamic outcomes. RESULTS All subjects tolerated the single dose of daptomycin. During HD, significant drug removal was observed, compared with CCPD (26% vs 5% of total dose). A low daptomycin renal clearance (<12% of total clearance) with moderate variability (40.5%) was observed among subjects with residual renal function. An anuric and obese subject who received CCPD treatment appeared to have >80% higher daptomycin area under the plasma concentration-time curve than the other CCPD subjects. Dosing regimens that achieved predefined pharmacodynamic targets were reported. CONCLUSIONS Daptomycin clearance was faster in 12- to 17-year-old patients receiving HD than CCPD. Administration of daptomycin immediately after HD reduces drug loss. The CCPD treatment, anuria, and obesity may increase the risk for drug accumulation. Our pharmacokinetic model can be further used to optimize dosing regimens of daptomycin in this population.

scholarly journals The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19

2020 ◽  
Author(s):  
Virginia D. Schmith ◽  
Jie (Jessie) Zhou ◽  
Lauren RL Lohmer
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Maximum Plasma ◽  
Time Profiles ◽  
Concentration Time ◽  
Single Oral Administration ◽  
The Ideal

AbstractIntroductionCaly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5μM. The concentration resulting in 50% inhibition (IC50, 2 µM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted.MethodSimulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose.ResultsPlasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0857 µM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 µM).ConclusionsThe likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.

scholarly journals Evaluating clinical impact of a shortened infusion duration for ramucirumab: a model-based approach

2021 ◽  
Vol 87 (5) ◽  
pp. 635-645
Author(s):  
Ling Gao ◽  
Yiu-Keung Lau ◽  
Ran Wei ◽  
Lisa O’Brien ◽  
Amanda Long ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Time Course ◽  
Pharmacokinetic Profile ◽  
Sensitivity Analyses ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Concentration Profiles ◽  
Increased Risk ◽  
The Impact ◽  
Infusion Duration

Abstract Purpose We investigated the impact of infusion duration (30 and 60 min) on the pharmacokinetic profile of ramucirumab using a population pharmacokinetic (PopPK) modeling approach. We also assessed the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration) using ramucirumab phase II/III study data. Methods The impact of different infusion durations (30 vs. 60 min) on the time-course of ramucirumab concentration profiles were evaluated using a PopPK model, established using ramucirumab pharmacokinetic data from 2522 patients. Logistic regression was used to evaluate the association between ramucirumab infusion rate and incidence of immediate IRRs in clinical trials. Results Ramucirumab time-course concentration profiles were equivalent following a 30- or 60-min infusion. In the pooled clinical study dataset, 254 of 3216 (7.9%) patients receiving ramucirumab experienced at least one immediate IRR (any grade). When grouped according to infusion rate quartile, the incidence of immediate IRRs (any grade or grade ≥ 3) was similar across quartiles; findings were confirmed in sensitivity analyses. The risk of immediate IRRs was not found to be associated with infusion rate based on multivariate logistic analysis. Conclusion Shortening the infusion duration of ramucirumab from 60 to 30 min has no impact on ramucirumab exposure. Analysis of trial data found no relationship between an increased risk of immediate IRRs and a faster infusion rate. Such a change in infusion duration is unlikely to affect the clinical efficacy or overall safety profile of ramucirumab.

scholarly journals Population Pharmacokinetic Model for Intravenous ASN100 in Healthy Subjects

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S529-S529
Author(s):  
Scott A Van Wart ◽  
Christopher Stevens ◽  
Zoltan Magyarics ◽  
Steven A Luperchio ◽  
Paul G Ambrose
Keyword(s):  
Healthy Subjects ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic

scholarly journals Pharmacokinetics and Pharmacogenetics of Cyclophosphamide in a Neonate and Infant Childhood Cancer Patient Population

2021 ◽  
Vol 14 (3) ◽  
pp. 272
Author(s):  
Shelby Barnett ◽  
Julie Errington ◽  
Julieann Sludden ◽  
David Jamieson ◽  
Vianney Poinsignon ◽  
...  
Keyword(s):  
Cancer Patient ◽  
Childhood Cancer ◽  
Patient Population ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Clearance ◽  
Current Data ◽  
Population Pharmacokinetic ◽  
Older Children ◽  
Patient Groups

Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients administered cyclophosphamide at doses ranging from 100–1500 mg/m2 (5–75 mg/kg), with various infusion times as determined by the standard treatment regimen that each patient was receiving. Polymorphisms in genes including CYP2B6 and CYP2C19 were investigated. Data generated for cyclophosphamide were analysed using a previously published population pharmacokinetic model. Cyclophosphamide pharmacokinetics was assessed in 111 samples obtained from 25 patients ranging from 4–23 months of age. The average cyclophosphamide clearance for the patients was 46.6 mL/min/m2 (ranging from 9.4–153 mL/min/m2), with marked inter-patient variability observed (CV 41%). No significant differences in cyclophosphamide clearance or exposure (AUC) were observed between patient groups as separated by age or body weight. However, marked differences in drug clearance and metabolism were noted between the current data in children <2 years of age and recently published results from a comparable study conducted by our group in older children, which reported significantly lower cyclophosphamide clearance values and metabolite exposures using the same population pharmacokinetic model for analysis. Whilst this study demonstrates no significant differences in cyclophosphamide clearance in patients <2 years, it highlights large differences in dosing protocols across tumour types. Furthermore, the study suggests marked differences in cyclophosphamide clearance in children less than two years of age as compared to older patients.

scholarly journals Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 54 ◽  
Author(s):  
Amaia Soraluce ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Jose Ángel Sánchez-Izquierdo ◽  
Javier Maynar ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Standard Dose ◽  
Compartment Model ◽  
Antimicrobial Treatment ◽  
Population Pharmacokinetic ◽  
Renal Replacement Therapies ◽  
Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

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