Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs

2002 ◽  
Vol 20 (24) ◽  
pp. 4713-4721 ◽  
Author(s):  
Lena E. Friberg ◽  
Anja Henningsson ◽  
Hugo Maas ◽  
Laurent Nguyen ◽  
Mats O. Karlsson
Keyword(s):  
Mean Transit Time ◽  
Pharmacodynamic Model ◽  
Parameter Estimates ◽  
Chemotherapeutic Drugs ◽  
Similar System ◽  
Feedback Parameter ◽  
Time Profiles ◽  
Concentration Time ◽  
Fixed System ◽  
Transit Compartments

PURPOSE: To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs. PATIENTS AND METHODS: Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2′-deoxy-2′-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory Emax model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software. RESULTS: For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs. CONCLUSION: This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.

scholarly journals Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model

2016 ◽  
Vol 60 (5) ◽  
pp. 3178-3182 ◽  
Author(s):  
Megan K. Luther ◽  
Louis B. Rice ◽  
Kerry L. LaPlante
Keyword(s):  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Pharmacodynamic Model ◽  
Infection Model ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Time Profiles ◽  
Concentration Time ◽  
Vancomycin Resistant

ABSTRACTAmpicillin-ceftriaxone combination therapy has become a predominant treatment for seriousEnterococcus faecalisinfections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluatedE. faecalisin anin vitropharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin-ceftriaxone againstE. faecalis.

Nitrate and chloride formation in chloramination

1994 ◽  
Vol 30 (9) ◽  
pp. 101-110
Author(s):  
V. Diyamandoglu
Keyword(s):  
Kinetic Model ◽  
Analytical Method ◽  
Kinetic Data ◽  
Experimental Results ◽  
Mass Balances ◽  
Time Profiles ◽  
Slow Decay ◽  
Concentration Time ◽  
End Products ◽  
Chlorine Residuals

The formation of nitrate and chloride as end-products of chloramination (combined chlorination) was investigated at pH ranging between 6.9 and 9.6 at 25°C. The experimental results comprised concentration-time profiles of combined chlorine residuals along with nitrate and chloride. Nitrite, if present, was always below the detectibility limit of the analytical method used (25 ppb). Mass balances on chlorine species depicted that chloride formed during the slow decay of combined chlorine residuals does not account for all the chlorine lost. This substantiates the formation of other reaction end-products which are yet to be identified. A kinetic model for chloramination is proposed based on the kinetic data obtained in this study.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

Impulse-response function of splanchnic circulation with model-independent constraints: theory and experimental validation

2003 ◽  
Vol 285 (4) ◽  
pp. G671-G680 ◽  
Author(s):  
Ole L. Munk ◽  
Susanne Keiding ◽  
Ludvik Bass
Keyword(s):  
Portal Vein ◽  
Impulse Response ◽  
Response Function ◽  
Mean Transit Time ◽  
Impulse Response Function ◽  
Parameter Estimates ◽  
Time Activity ◽  
Time Activity Curve ◽  
Transit Times ◽  
Activity Curve

Modeling physiological processes using tracer kinetic methods requires knowledge of the time course of the tracer concentration in blood supplying the organ. For liver studies, however, inaccessibility of the portal vein makes direct measurement of the hepatic dual-input function impossible in humans. We want to develop a method to predict the portal venous time-activity curve from measurements of an arterial time-activity curve. An impulse-response function based on a continuous distribution of washout constants is developed and validated for the gut. Experiments with simultaneous blood sampling in aorta and portal vein were made in 13 anesthetized pigs following inhalation of intravascular [15O]CO or injections of diffusible 3- O-[11C]methylglucose (MG). The parameters of the impulse-response function have a physiological interpretation in terms of the distribution of washout constants and are mathematically equivalent to the mean transit time ( T̄) and standard deviation of transit times. The results include estimates of mean transit times from the aorta to the portal vein in pigs: T̄ = 0.35 ± 0.05 min for CO and 1.7 ± 0.1 min for MG. The prediction of the portal venous time-activity curve benefits from constraining the regression fits by parameters estimated independently. This is strong evidence for the physiological relevance of the impulse-response function, which includes asymptotically, and thereby justifies kinetically, a useful and simple power law. Similarity between our parameter estimates in pigs and parameter estimates in normal humans suggests that the proposed model can be adapted for use in humans.

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 Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

Antibiotics ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 113 ◽  
Author(s):  
Noriyuki Ishihara ◽  
Nobuhiro Nishimura ◽  
Kazuro Ikawa ◽  
Fumi Karino ◽  
Kiyotaka Miura ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Elderly Patients ◽  
Distribution Volume ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Target Attainment ◽  
Old Patients ◽  
Final Model ◽  
Concentration Time ◽  
Population Pk

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen–minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration–time curve over 24 h ≥ 96 μg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75–101) years, were investigated. The plasma-concentration–time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 μg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50–60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

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