scholarly journals Population-based meta-analysis of chloroquine: informing chloroquine pharmacokinetics in COVID-19 patients

2020 ◽  
Author(s):  
Xueting Yao ◽  
Xiaoyu Yan ◽  
Xiaohan Wang ◽  
Ting Cai ◽  
Shun Zhang ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Safety Margin ◽  
Volume Of Distribution ◽  
Population Based ◽  
Ethical Review ◽  
Peripheral Compartment ◽  
Dosing Regimen ◽  
First Order ◽  
Population Pk ◽  
Dosing Regimens

Abstract Aims Chloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure–efficacy/safety relationship and provide a basis for a possible dosing regimen optimization. Subject and methods In this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications. Results A two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h−1, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml). Conclusion Model-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics–pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19.

scholarly journals Population Pharmacokinetics Analysis of Amikacin Initial Dosing Regimen in Elderly Patients

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 100
Author(s):  
Hideo Kato ◽  
Suzanne L. Parker ◽  
Jason A. Roberts ◽  
Mao Hagihara ◽  
Nobuhiro Asai ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Compartment Model ◽  
The Elderly ◽  
Volume Of Distribution ◽  
Parameter Estimates ◽  
Limited Data ◽  
Dosing Regimen ◽  
Population Pk ◽  
Dosing Regimens ◽  
Dosing Intervals

There are limited data of amikacin pharmacokinetics (PK) in the elderly population. Hence, we aimed to describe the population PK of amikacin in elderly patients (>70 years old) and to establish optimized initial dosing regimens. We simulated individual maximum concentrations in plasma (Cmax) and minimal concentrations (Cmin) for several dosing regimens (200–2000 mg every 24, 48, and 72 h) for patients with creatinine clearance (CCr) of 10–90 mL/min and analyzed efficacy (Cmax/minimal inhibitory concentration (MIC) ≥ 8) for MICs of 4, 8, and 16 mg/L and safety (Cmin < 4 mg/L). A one-compartment model best described the data. CCr was the only covariate associated with amikacin clearance. The population PK parameter estimates were 2.25 L/h for clearance and 18.0 L for volume of distribution. Dosing simulations recommended the dosing regimens (1800 mg) with dosing intervals ranging 48–72 h for patients with CCr of 40–90 mL/min based on achievement of both efficacy for the MIC of 8 mg/L and safety. None of the dosing regimens achieved the targets for an MIC of 16 mg/L. We recommend the initial dosing regimen using a nomogram based on CCr for an MIC of ≤8 mg/L in elderly patients with CCr of 40–90 mL/min.

scholarly journals Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Katharine E. Stott ◽  
Justin Beardsley ◽  
Sarah Whalley ◽  
Freddie Mukasa Kibengo ◽  
Nguyen Thi Hoang Mai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Rate Constant ◽  
Cryptococcal Meningitis ◽  
Drug Exposure ◽  
Meta Analysis ◽  
Central Compartment ◽  
Order Rate Constant ◽  
Peripheral Compartment ◽  
First Order ◽  
Amphotericin B Deoxycholate

ABSTRACT There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h−1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h−1. The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144–168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

scholarly journals Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Saeed A. Alqahtani ◽  
Abdullah S. Alsultan ◽  
Hussain M. Alqattan ◽  
Ahmed Eldemerdash ◽  
Turki B. Albacker
Keyword(s):  
Heart Surgery ◽  
Open Heart Surgery ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Albumin Concentration ◽  
Open Heart ◽  
Blood Samples ◽  
Dosing Regimens

ABSTRACTThe purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analyzed using an Architect i4000SR immunoassay analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 168 blood samples were analyzed from 28 patients. The pharmacokinetics of vancomycin are best described by a two-compartment model with between-subject variability in clearance (CL), the volume of distribution of the central compartment (V1), and volume of distribution of the peripheral compartment (V2). The CL and theV1of vancomycin were related to creatinine CL (CLCR), body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC0–24/MIC > 400 for an MIC of 1 mg/liter, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, the administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15- and 20-mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 and 30 mg/kg) of vancomycin.

scholarly journals FRI0465 TOFACITINIB POPULATION PHARMACOKINETICS IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS: A POOLED ANALYSIS OF DATA FROM THREE CLINICAL STUDIES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 830.2-830
Author(s):  
C. Vong ◽  
X. Wang ◽  
A. Hazra ◽  
A. Mukherjee ◽  
T. Nicholas ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Absorption Rate ◽  
Lag Time ◽  
Pooled Analysis ◽  
Oral Solution ◽  
Dosing Regimen ◽  
First Order ◽  
Link Type ◽  
Population Pk ◽  
Modelling Approach

Background:Tofacitinib is an oral JAK inhibitor that is being investigated for juvenile idiopathic arthritis (JIA).Objectives:To describe tofacitinib pharmacokinetics (PK) in patients with JIA, identify potential covariates accounting for variability in exposure, assess the formulation effect of oral solution vs tablet and propose a simplified dosing regimen.Methods:This was a pooled analysis of data from 3 tofacitinib clinical studies in patients with JIA aged 2−<18 years: a Phase 1, open-label (OL), non-randomised study (NCT01513902); a Phase 3, randomised, double-blind, placebo-controlled, withdrawal study (NCT02592434); and an OL long-term extension study (NCT01500551). Tofacitinib was dosed at 5 mg twice daily (BID) in patients ≥40 kg or at body weight (BW)-based lower doses BID in patients <40 kg, to achieve average concentrations (Cavg) comparable with those in patients receiving 5 mg BID. A sparse PK sampling scheme was applied, and the plasma samples were assayed using a validated, sensitive and specific high-performance liquid chromatography tandem mass spectrometric method (lower limit of quantification = 0.100 ng/mL). A nonlinear mixed-effects modelling approach was used for the population PK model, and population parameter variability was assumed to be log-normally distributed. Covariates relating to patient demographics, disease characteristics, concomitant medications and formulation (oral solution vs tablet) were selected using a stepwise covariate modelling approach, and parameter-covariate relationships were evaluated using stepwise forward-inclusion (p<0.05) backward-deletion (p<0.001) procedures. The effect of time-varying BW on oral clearance (CL/F) and apparent volume of distribution (V/F) was characterised using an allometric model. Final model quality was assessed by Visual Predictive Checks (VPCs).Results:Of 246 patients in the analysis, 74.0% were female; 87.8% were white, 2% were black, 10.2% were ‘other’ races and no patients were Asian. Median (range) BW was 46.3 (11.1−121.8) kg. Initially, 100 patients received oral solution and 146 patients received tablets; 11 patients switched formulations during the studies. A one compartment disposition model with first-order absorption and a lag time sufficiently described the data. Final estimates for CL/F, V/F and the first-order absorption rate constant (ka) for tablets were 26.1 L/hr, 89.2 L and 2.78 hr-1, respectively. The only statistically significant covariate was a formulation effect on ka. All parameters were estimated adequately. Estimated allometric exponents were 0.310 for CL/F and 0.537 for V/F. Absorption was described with an estimated lag time of 0.186 hr, and the oral solution had a 1.64-fold faster absorption rate vs the tablet. VPCs sufficiently described the observed data over time, across BWs and ages. Given the PK characterisation and variability in patients with JIA, a simplified dosing scheme was proposed, targeting Cavgvalues equivalent to those in patients receiving 5 mg BID: 3.2 mg BID solution in patients 10−<20 kg; 4 mg BID solution in patients 20−<40 kg; and 5 mg BID tablet or solution in patients ≥40 kg.Conclusion:Tofacitinib population PK in patients with JIA were adequately described by a one compartment model parameterised in terms of CL/F, V/F and first-order absorption with a lag time. Drug absorption from the oral solution was faster than from the tablet. Tofacitinib does not require dose modification or restrictions for any covariates, except BW, to account for differences in Cavg. Based on the results of this analysis, a simplified BW-based dosing regimen was proposed.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Camille Vong Shareholder of: Pfizer Inc, at time of analysis, Employee of: Pfizer Inc, at time of analysis, Xiaoxing Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Anasuya Hazra Shareholder of: Pfizer Inc, at time of analysis, Employee of: Pfizer Inc, at time of analysis, Arnab Mukherjee Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Timothy Nicholas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cheng Chang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

scholarly journals Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

2016 ◽  
Vol 60 (5) ◽  
pp. 2888-2894 ◽  
Author(s):  
Daniel Gonzalez ◽  
Paula Delmore ◽  
Barry T. Bloom ◽  
C. Michael Cotten ◽  
Brenda B. Poindexter ◽  
...  
Keyword(s):  
Volume Of Distribution ◽  
Safety Study ◽  
Term Infants ◽  
Content Type ◽  
Acid Glycoprotein ◽  
Optimal Dosing ◽  
Population Pk ◽  
Postmenstrual Age ◽  
Dosing Regimens ◽  
State Concentration

ABSTRACTClindamycin may be active against methicillin-resistantStaphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC forS. aureusof 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)

scholarly journals Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Elizabeth A. Lakota ◽  
Scott A. Van Wart ◽  
Michael Trang ◽  
Evan Tzanis ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Phase 1 ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Uncomplicated Urinary Tract Infection ◽  
Phase 3 ◽  
Data Set ◽  
First Order ◽  
Final Population ◽  
Population Pk

ABSTRACT Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a subcompartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females than males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external phase 3 ABSSSI data set. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

scholarly journals Adherence to Artemisinin-Based Combination Therapy for the Treatment of Uncomplicated Malaria: A Systematic Review and Meta-Analysis

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Ahmad M. Yakasai ◽  
Muhammad Hamza ◽  
Mahmood M. Dalhat ◽  
Musa Bello ◽  
Muktar A. Gadanya ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Meta Analysis ◽  
Retail Sector ◽  
Inclusion Criteria ◽  
Dosing Regimen ◽  
The Public ◽  
Prevalence Estimates ◽  
Fatty Food ◽  
Dosing Regimens ◽  
Predictors Of Adherence

Adherence to artemisinin-based combination therapy (ACT) is not clearly defined. This meta-analysis determines the prevalence and predictors of adherence to ACT. Twenty-five studies and six substudies met the inclusion criteria. The prevalence of ACT adherence in the public sector was significantly higher compared to retail sector (76% and 45%, resp.,P<0.0001). However, ACT adherence was similar across different ACT dosing regimens and formulations. In metaregression analysis prevalence estimates of adherence significantly decrease with increasing year of study publicationP=0.046. Factors found to be significant predictors of ACT adherence were years of education ≥ 7{odds ratio (OR) (95% CI) = 1.63 (1.05–2.53)}, higher income{2.0 (1.35–2.98)}, fatty food{4.6 (2.49–8.50)}, exact number of pills dispensed{4.09 (1.60–10.7)}, and belief in traditional medication for malaria{0.09 (0.01–0.78)}. The accuracy of pooled estimates could be limited by publication bias, and differing methods and thresholds of assessing adherence. To improve ACT adherence, educational programs to increase awareness and understanding of ACT dosing regimen are interventions urgently needed. Patients and caregivers should be provided with an adequate explanation at the time of prescribing and/or dispensing ACT.

scholarly journals Pharmacokinetics and Pharmacodynamics of Cefepime in Patients with Various Degrees of Renal Function

2003 ◽  
Vol 47 (6) ◽  
pp. 1853-1861 ◽  
Author(s):  
Vincent H. Tam ◽  
Peggy S. McKinnon ◽  
Ronda L. Akins ◽  
George L. Drusano ◽  
Michael J. Rybak
Keyword(s):  
Renal Function ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Minimum Concentration ◽  
Median Volume ◽  
Dosing Regimens ◽  
Rapid Clearance ◽  
Highly Correlated ◽  
Median Rate

ABSTRACT This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CLCR) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C min). C min in this group was found to be 3.3 ± 3.6 mg/liter (mean and standard deviation), compared to 19.5 ± 21.5 mg/liter in patients with a CLCR of between 60 and 100 ml/min (P = 0.025) and 14.0 ± 11.5 mg/liter in patients with a CLCR of <60 ml/min (P = 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CLCR were highly correlated (P = 0.00033) according to the equation CL= 0.324 liters/h + (0.0551 × CLCR). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h−1, respectively. The time-concentration profiles for 1,000 patients (CLCRs, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C min that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs ≤2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are ≥4 mg/liter), particularly when CLCR exceeds 120 ml/min.

Flat-Dosing Versus BSA-Based Dosing for MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) Analysis of Pooled Data From 4 Phase-1 Studies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1433-1433 ◽  
Author(s):  
Neeraj Gupta ◽  
Mohammad Saleh ◽  
Karthik Venkatakrishnan
Keyword(s):  
Body Weight ◽  
Phase 1 ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Oral Dosing ◽  
First Order ◽  
Investigational Agent ◽  
Concentration Time ◽  
Population Pk

Abstract Abstract 1433 Background: Investigational agent MLN9708 is a potent, reversible and specific 20S proteasome inhibitor. Both intravenous (IV) and oral administration are being studied on a twice-weekly (Days 1, 4, 8, and 11; 21-day cycles) and weekly (Days 1, 8, and 15; 28-day cycles) schedule. The twice-weekly doses studied are 0.125–2.34 mg/m2 for IV and 0.24–2.23 mg/m2 for oral dosing. Weekly doses tested are 0.125–1.4 mg/m2 for IV and 0.24–3.95 mg/m2 for oral dosing. MLN9708 completely hydrolyzes to the pharmacologically active MLN2238 in aqueous solutions. Here we report a population PK analysis of pts with solid tumors, lymphoma or multiple myeloma (MM) enrolled in 4 ongoing phase 1 studies of IV and oral dosing on a twice-weekly (Days 1, 4, 8, 11; 21-day cycle) and weekly (Days 1, 8, 15; 28-day cycle) schedule. Methods: MLN9708 dose was based on body surface area (BSA) for both twice-weekly and weekly dosing schedules in solid tumor, lymphoma and MM patients (N=85). MLN2238 concentration-time data were analyzed using a non-linear mixed effects modeling approach (NONMEM® VII), with Intel® Visual Fortran Compiler, and the output was processed with SPLUS v8.1. Compartmental PK models were coded using the ADVAN 12 subroutine of NONMEM. A log-transform both sides approach was used. Estimation was by the First Order Conditional Estimation (FOCE) method with eta-epsilon interaction. Covariates tested included body weight, BSA, age, sex, dose and albumin on both clearance (CL) and volume, while creatinine clearance (CrCl), bilirubin, AST and ALT were only tested on CL parameters. Model validation and robustness were assessed using bootstrap simulations (N=1000) and visual predictive checks (N=100). Results: Mean age of 85 pts was 60.7 years, mean body weight was 80.0 kg, 87% of pts were Caucasian, and 58% were male. MLN9708 population PK was described by a three-compartment model with first order elimination. All model parameters were estimated with adequate precision when IV and oral data were fitted together. Of all the covariates tested, only body size descriptors (body weight and BSA) were found to be a significant covariate only on peripheral volume of distribution, V3 (p<0.01). Since BSA was more significant than body weight it was kept in the final model. Mean [%CV] CL (1.86 [7.0] L/h) and central volume of distribution (V2, 11.7 [13.1] L) were not affected by body weight or BSA. Inter-individual variability (IIV) was approximately 45% for CL, 82% for V2 and 30% for peripheral volume of distribution, with 17% of IIV in V3 explained by BSA. Absolute bioavailability (F) was estimated to be 62% based on this analysis. Based on simulations using the final population PK model, there was no difference in concentration-time profile or exposures (AUC or Cmax) between the BSA-based and the flat doses. Conclusions: Population PK analysis showed that the plasma concentration-time profile of MLN2238 can be well described by a three-compartment model with first order elimination process. Body size did not significantly impact AUC or Cmax, supporting a switch from BSA-based dosing to flat dosing in all ongoing and planned clinical studies. Ability to use a flat dosing paradigm may be a benefit for oral administration of MLN9708 due to its potential to simplify clinical management. Disclosures: Gupta: Millennium Pharmaceuticals, Inc.: Employment. Off Label Use: Investigational agent in clinical development for the treatment of solid tumors, lymphoma and MM. Saleh:Millennium Pharmaceuticals, Inc.: Student internship. Venkatakrishnan:Millennium Pharmaceuticals, Inc.: Employment.

scholarly journals Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Céline Thibault ◽  
Jean Lavigne ◽  
Catherine Litalien ◽  
Nastya Kassir ◽  
Yves Théorêt ◽  
...  
Keyword(s):  
Adverse Event ◽  
Standard Of Care ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Content Type ◽  
Final Population ◽  
Optimal Dosing ◽  
Population Pk ◽  
Dosing Regimens

ABSTRACT Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

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