Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2545-2545
Author(s):  
H. Wu ◽  
R. K. Ramanathan ◽  
S. Srychor ◽  
B. A. Zamboni ◽  
S. Ramalingam ◽  
...  
Keyword(s):  
Body Weight ◽  
Solid Tumors ◽  
Topoisomerase I ◽  
Plasma Concentrations ◽  
Ideal Body Weight ◽  
Compartment Model ◽  
Individual Variability ◽  
Synthetic Analogue ◽  
Population Pk ◽  
Linear And Nonlinear

2545 Background: CKD-602, a semi-synthetic analogue of campothecin, is a potent topoisomerase I inhibitor. S-CKD602, a PEGylated long-circulating liposomal formulation of CKD-602, was developed to achieve a longer intra-tumoral exposure of CKD602 and a higher therapeutic index. Age and body composition were reported to affect the pharmacokinetics (PK) of S- CKD602 (Zamboni, ASCO'07). A population PK model for encapsulated and released CKD-602 following administration of S- CKD602 was developed to assess factors that may influence S-CKD602 PK. Methods: Plasma samples from 45 patients (pts) with solid tumors were collected in a phase I study. S-CKD602 was administered as a 1 h IV infusion with doses ranging from 0.1 to 2.5 mg/m2. Plasma concentrations of encapsulated (n=292) and released (n=268) CKD-602 were measured by LC-MS/MS, and population PK modeling was performed using NONMEM. Results: Pts were classified as linear and nonlinear pts according to the clearance (CL) of encapsulated CKD-602 using a classic two stage PK modeling approach. Mean ± SD ratio of total body weight to ideal body weight of pts with linear and nonlinear CL of encapsulated CKD-602 was 1.13 ± 0.16 and 1.53 ± 0.29, respectively (P = 0.003). PK of encapsulated CKD-602 was described by 1-compartment model with nonlinear CL (Michaelis-Menten kinetics). PK of released CKD-602 was described by a 2- compartment model with linear CL for all pts. The presence of primary or metastatic tumor(s) located in the liver decreased the inter- individual variability (IIV) in the CL of encapsulated CKD-602 by 13%. Typical values of Vmax of encapsulated CKD-602 in pts with and without hepatic tumor(s) were 156 and 103 μg/h, respectively (P < 0.001). The inclusion of age decreased IIV in the release of CKD-602 from S-CKD602 by 22%. Typical values of release of CKD-602 from S-CKD602 in pts < 60 years old (yo) and pts ≥ 60 yo were 0.21 and 0.10 L/h, respectively (P < 0.001). Conclusions: These data suggest that older patients (pts ≥ 60 yo) have a reduced release of CKD-602 from S-CKD602. In addition, pts with tumors in the liver may have an increased clearance of S-CKD602. These observations have potential implications in the optimal dosing of liposomal agents. [Table: see text]

Population pharmacokinetic (PK) analysis of ABT-869 in solid tumors and acute myelogenous leukemia (AML) patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3567-3567
Author(s):  
N. Gupta ◽  
P. M. Diderichsen ◽  
J. Steinberg ◽  
J. L. Ricker ◽  
R. Humerickhouse ◽  
...  
Keyword(s):  
Body Weight ◽  
Growth Factor ◽  
Solid Tumors ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Disease State ◽  
Myelogenous Leukemia ◽  
Population Pharmacokinetic ◽  
First Order ◽  
Population Pk

3567 Background: ABT-869 is an orally bioavailable, potent and specific inhibitor of all vascular endothelial growth factor and platelet derived growth factor family receptor tyrosine kinases. The objectives of this analysis were to understand the population pharmacokinetics of ABT-869 and explore the effect of several demographic/disease state covariates influencing ABT-869 disposition. Methods: A population PK analysis of 181 patients (pts) enrolled in two phase 1 (multiple types of solid tumors and AML) and three phase 2 monotherapy studies (non-small cell lung cancer, hepatocellular carcinoma [HCC] and renal cell carcinoma) was conducted. Approximately 90% of pts received ABT-869 based on body-weight dosing while the remaining pts had flat dosing. Available plasma concentrations obtained after intensive and sparse pre-dose PK sampling were analyzed by population PK using the non linear mixed effects modeling (NONMEM) approach. Potential covariates including body weight, body surface area (BSA), age, sex, creatinine clearance (CrCL) and disease state (HCC vs. non-HCC pts) were tested. Results: The mean body weight of enrolled pts was 71 kg and 57% were Asian, 36% Caucasian and 7% other races. The ABT-869 plasma concentration time profile was well described by a one-compartment model with first order absorption and elimination process. Oral clearance (CL/F) was not affected by body weight (range 35–177 kg); however, apparent volume of distribution (V/F) increased by 6L per 0.1 mg/m2 increase in BSA. CrCL (39.9–290.3 ml/min) was not a significant covariate on V/F and CL/F suggesting renally impaired pts do not require a different dose/dosing regimen. HCC pts had ∼40% lower CL/F values than pts with other malignancies suggesting a lower dose would be appropriate for HCC (Child Pugh A and B) pts. Conclusions: Population PK analysis showed that ABT-869 PK can be well described by a one-compartment model with first order absorption and elimination. Race and impaired renal function does not appear to alter PK. HCC pts had lower CL/F value therefore a lower dose may be recommended in these patients. Implications of increased V/F with increasing body size and appropriate dosing strategy are undergoing further analysis. [Table: see text]

Phase II Study of Phenylacetate in Patients With Recurrent Malignant Glioma: A North American Brain Tumor Consortium Report

1999 ◽  
Vol 17 (3) ◽  
pp. 984-984 ◽  
Author(s):  
Susan M. Chang ◽  
John G. Kuhn ◽  
H. Ian Robins ◽  
S. Clifford Schold ◽  
Alexander M. Spence ◽  
...  
Keyword(s):  
Body Weight ◽  
Treatment Failure ◽  
Malignant Glioma ◽  
Plasma Concentrations ◽  
Ideal Body Weight ◽  
Dose Schedule ◽  
Recurrent Malignant Glioma ◽  
Time To Treatment ◽  
Time To Treatment Failure ◽  
Ideal Body

PURPOSE: To determine the response rate, time to treatment failure, and toxicity of phenylacetate in patients with recurrent malignant glioma and to identify plasma concentrations achieved during repeated continuous infusion of this agent. PATIENTS AND METHODS: Adult patients with recurrent malignant glioma were treated with phenylacetate. The schedule consisted of a 2-week continuous, intravenous infusion followed by a 2-week rest period (14 days on, 14 days off). A starting dose of 400 mg/kg total body weight per day of phenylacetate was initially used and subsequently changed to 400 mg/kg/d based on ideal body weight. Intrapatient dose escalations were allowed to a maximum of 450 mg/kg ideal body weight/d. Tumor response was assessed every 8 weeks. The National Cancer Institute common toxicity criteria were used to assess toxicity. Plasma concentrations achieved during the patients' first two 14-day infusions were assessed. RESULTS: Forty-three patients were enrolled between December 1994 and December 1996. Of these, 40 patients were assessable for toxicity and response to therapy. Reversible symptoms of fatigue and somnolence were the primary toxicities, with only mild hematologic toxicity. Thirty (75%) of the 40 patients failed treatment within 2 months, seven (17.5%) had stable disease, and three (7.5%) had a response defined as more than 50% reduction in the tumor. Median time to treatment failure was 2 months. Thirty-five patients have died, with a median survival of 8 months. Pharmacokinetic data for this dose schedule showed no difference in the mean plasma concentrations of phenylacetate between weeks 1 and 2 or between weeks 5 and 6. CONCLUSION: Phenylacetate has little activity at this dose schedule in patients with recurrent malignant glioma. Further studies with this drug would necessitate an evaluation of a different dose schedule.

Population Pharmacokinetic Model of ADVATE in Pediatric and Adult Patients with Hemophilia A.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3492-3492
Author(s):  
Myungshin Oh ◽  
Sven Björkman ◽  
Phillip Schroth ◽  
Sandor Fritsch ◽  
Peter Collins ◽  
...  
Keyword(s):  
Body Weight ◽  
Hemophilia A ◽  
Individual Variability ◽  
Patient Specific ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Data Sets ◽  
Residual Variability ◽  
Population Pk ◽  
Variability Model

Abstract Abstract 3492 Poster Board III-429 Introduction The objective of this analysis was to characterize the population pharmacokinetic (PK) model of ADVATE® (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method) in hemophilia A patients. This included estimation of typical population pharmacokinetic parameters and inter-individual and residual variability and identification of covariates that are significant predictors of variability in a pooled population of children and adults. Patients and Methods Plasma FVIII activity PK data were collected for 3 ADVATE® clinical trials in previously treated patients: 184 full PK data sets for 100 adults/adolescents, aged 10 to 65 years, and from 52 reduced sample PK data sets for 52 children, aged 1 to 6 years. Population PK analysis was conducted using non-linear mixed effects modeling with the first-order integral approximation method in SAS® software (NLMIXED procedure). A two-compartment model was used as the base model and the influence of age and weight were explored. Results Two-compartment PK models with additive plus proportional residual variability model and exponential inter-individual variability model adequately described the data. Clearance (CL) is significantly correlated with age and body weight and central volume of distribution (V1) is also related with body weight. The estimated population PK parameters were (mean parameter, (inter-individual variability %)): CL (2.92 mL/kg·h, 22%), V1 (0.46 dL/kg, 5.2%), peripheral volume V2 (0.09 dL/kg) and inter-compartmental clearance Q (2.07 mL/ kg·h). Conclusions A population PK model that describes the combined PK data from adults and pediatric studies has been constructed. A significant portion of inter-individual variability in both volume and clearance can be explained by subject weight. An additional smaller effect of age on clearance but not volume was observed. A population PK model for Factor VIII could provide the clinician with advantages in designing a patient specific treatment regimen. It could provide more relevant guidance in individual patient pharmacokinetics than just incremental recovery without the burden of a full PK assessment of the patient. Disclosures: Oh: Baxter: Employment. Off Label Use: Prophylaxis is not indicated in the US. Björkman:Baxter: Consultancy; Octapharma: Consultancy. Schroth:Baxter: Employment. Fritsch:Baxter: Employment. Collins:Bayer: Consultancy; Novo Nordisk: Consultancy; Baxter: Consultancy. Fischer:Bayer: Consultancy; Wyeth: Consultancy; Baxter: Consultancy. Blanchette:Bayer: Consultancy; Baxter: Consultancy. Casey:Baxter: Employment. Spotts:Baxter: Employment. Ewenstein:Baxter: Employment.

Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors.

1994 ◽  
Vol 12 (3) ◽  
pp. 532-538 ◽  
Author(s):  
D S Sonnichsen ◽  
C A Hurwitz ◽  
C B Pratt ◽  
J J Shuster ◽  
M V Relling
Keyword(s):  
Solid Tumors ◽  
High Performance ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Data Sets ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Time Curve ◽  
Elimination Clearance

PURPOSE Our aim was to evaluate the pharmacokinetics and pharmacodynamics of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) in children, and to determine whether paclitaxel exhibited saturable pharmacokinetics. PATIENTS AND METHODS We evaluated the pharmacokinetics and pharmacodynamics of paclitaxel (200 to 420 mg/m2) administered as a 24-hour intravenous (i.v.) infusion in a phase 1 study of 30 pediatric patients (age, 2.3 to 22.8 years) with refractory solid tumors. Fourteen serial blood samples were obtained during and up to 48 hours after the infusion, and paclitaxel concentrations were measured by a high-performance liquid chromatography-UV (HPLC-UV) method. Four pharmacokinetic models were compared for their ability to describe the patients' data. RESULTS Paclitaxel disposition was not consistent with a first-order, two-compartment pharmacokinetic model. Rather, the majority of data sets were best described by a two-compartment model that incorporated both saturable tissue distribution and saturable elimination; a smaller number of patient data sets were best described by models that incorporated either saturable distribution or saturable elimination. Clearance was dose-dependent, with a median clearance at the lower dosages (< 400 mg/m2) of 161 mL/min/m2, and at the highest dosages (> 400 mg/m2) of 123 mL/min/m2 (P = .044). The duration that paclitaxel plasma concentrations exceeded 0.1 mumol/L was highly variable (range, 26 to 71 hours). There was a trend toward higher median area under the concentration-versus-time curve (AUC) in those children with musculoskeletal (72 mumol/L.h; P = .054) or neurologic toxicity (54 mumol/L.h; P = .062) versus those without toxicity (30 mumol/L.h). Toxicity was not significantly correlated with dosage. CONCLUSION We conclude that paclitaxel distribution and elimination are saturable, and that estimates of paclitaxel systemic exposure correlate better with toxicity than does dosage.

scholarly journals 1574. Predictive Ability and Bias of Vancomycin Population PK Models in an Obese Adult Population

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S575-S575
Author(s):  
Paul E Sabourenkov ◽  
Robert C McLeay
Keyword(s):  
Body Weight ◽  
Predictive Ability ◽  
Ideal Body Weight ◽  
Total Body Weight ◽  
Specific Model ◽  
Obesity Class ◽  
Predictive Error ◽  
Population Pk ◽  
Obese Population ◽  
Total Body

Abstract Background Accurate dosing of vancomycin is difficult due to high inter-individual variability of vancomycin pharmacokinetics (PK), and is particularly challenging in obese patients. Vancomycin is hydrophilic, yet total body weight (TBW) has traditionally been used for dosing in the general population, and also into the obese population. The aim of this study was to evaluate the performance of published vancomycin PK models in a large set of routine clinical data obtained from an obese population. Methods De-identified data were available from 1717 courses of vancomycin administered to obese adults (BMI ≥ 30) from hospitals across the United States, EU, and Australia. Three population PK models, Buelga et al. (2005), Goti et al. (2018), and an obese-specific model, Adane et al. (2015), were used to predict plasma concentrations at the time of each recorded vancomycin assay, and their accuracy and bias were compared. Goodness of fit at both the population and individual level was assessed, and elastic net regression was used to identify any sources of predictive error in the obese-specific model. Model parameters for each model were then re-estimated, and a variety of body size metrics were evaluated. Results The Buelga et al. one-compartment model had the best predictive ability (Table 1). In all models, bias (calculated as MME; mean per-patient mean predictive error) by obesity class was observed at both the population and individual levels, and unexpectedly was largest in the obese-specific model. In the obese-specific model, predictive error correlated with the use of TBW as a model covariate. A set of models derived from Adane et al. model were then developed to correct for weight. Using ideal body weight (IBW) on Vd and no correction for weight on CL provided the best fit. The derived model accounted for 81% of variance in plasma concentration and exhibited negligible bias by obesity class (population MME = -0.75 (i), -0.06 (ii), and -0.50 (iii) mg/L; individual MME = −0.20 (i), −0.02 (ii), and −0.02 (iii) mg/L). Conclusion Existing vancomycin population PK models for use in the obese population are biased in higher obesity classes due to the use of total body weight. A novel population PK model developed using ideal body weight exhibits negligible bias across obesity classes as well as improved predictive ability. Disclosures All authors: No reported disclosures.

scholarly journals Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

2016 ◽  
Vol 60 (3) ◽  
pp. 1830-1833 ◽  
Author(s):  
R. Brigg Turner ◽  
Aaron Cumpston ◽  
Michael Sweet ◽  
Frank Briggs ◽  
Douglas Slain ◽  
...  
Keyword(s):  
Body Weight ◽  
Single Dose ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Ideal Body Weight ◽  
Normal Weight ◽  
Controlled Study ◽  
Pharmacokinetic Analysis ◽  
Obese Patients ◽  
Time Curve

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m2, respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h;P= 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter;P= 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter;P= 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.)

Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice

2010 ◽  
Vol 104 (08) ◽  
pp. 252-260 ◽  
Author(s):  
Paul Zufferey ◽  
Denis Baylot ◽  
Philippe Nguyen ◽  
Jeanne-Yvonne Borg ◽  
Michaela Fontenay ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Compartment Model ◽  
Individual Variability ◽  
Everyday Practice ◽  
Population Pharmacokinetic ◽  
Antithrombotic Agent ◽  
Orthopaedic Patients

SummaryFondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.

Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 496-496
Author(s):  
Lene Alifrangis ◽  
Rik Schoemacker ◽  
Niels Jorgen Ostergaard Skartved ◽  
Rikke Hald ◽  
Maria Düring ◽  
...  
Keyword(s):  
Body Weight ◽  
Compartment Model ◽  
Hepatic Function ◽  
Individual Variability ◽  
Tumor Type ◽  
Phase 3 ◽  
Extrinsic Factors ◽  
Poppk Model ◽  
Non Linear ◽  
Intrinsic And Extrinsic Factors

496 Background: Sym004 consists of two anti-EGFR monoclonal antibodies (futuximab and modotuximab) directed against non-overlapping epitopes in the EGFR domain III. Sym004 induces rapid and efficient removal of the EGFR from the cancer cell surface by triggering EGFR internalization and degradation and has shown promising efficacy in mCRC patients. Based upon a post-hoc analysis of a Phase 2 study, a Phase 3 trial in genomically selected mCRC patients is in preparation. Methods: The aim was to establish a popPK model for Sym004 in order to i) evaluate impact of covariates (intrinsic and extrinsic factors) on Sym004 exposure and ii) provide exposure metrics for a PK/PD analysis. Sym004 serum concentrations were obtained from 330 patients with mCRC (n = 247) or advanced solid tumors (studies Sym004-01, Sym004-02, Sym004-05 and Sym004-06). Sym004 (0.4-18 mg/kg) was dosed by i.v. infusion weekly or every 2nd week, or as a 9 mg/kg loading dose followed by 6 mg/kg weekly (9/6 mg/kg weekly). Non-linear mixed effects modelling was done in NONMEM v7.3.0. Covariates evaluated included body weight, age, sex, race, albumin, renal function, hepatic function, tumor type and size, ECOG and previous anti-EGFR treatments. Results: The base popPK model was a 2-compartment model with linear and non-linear Michaelis-Menten-type elimination and a priori inclusion of body weight on CL, Vmax, V1 and V2. The model captured the non-linear PK well. The final covariate model retained covariates whose point estimates were outside the range of 0.8 to 1.25 and whose 90% confidence intervals did not overlap with the null value and included only body weight and albumin. Inter-individual variability was estimated for CL, Vmax and V1 and was in the range of 18-30%. Simulations were used to assess the clinical relevance of the covariates as judged by the magnitude of the change in exposure of the Phase 3 dose regimen of 9/6 mg/kg weekly. Conclusions: The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses. Clinical trial information: NCT01117428,NCT01417936,NCT02083653,NCT01955473.

scholarly journals Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

2012 ◽  
Vol 57 (3) ◽  
pp. 1144-1149 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Pavlos K. Papasavas ◽  
Darren S. Tishler ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Body Weight ◽  
Ideal Body Weight ◽  
Total Body Weight ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Lean Body Weight ◽  
Morbidly Obese ◽  
Total Body ◽  
Nonobese Patients

ABSTRACTThe pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m2receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (±standard deviation) age, height, and weight were 42.2 ± 12.2 years, 64.8 ± 3.5 in, and 109.5 ± 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ± 1.9 liters/h), which could be inhibited to 85.5% ± 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ± 9.6 liters), and the intercompartment transfer constants (K12andK21) of 8.04 ± 6.22 and 7.99 ± 5.46 h−1, respectively. The areas under the curve for the 12-h dosing interval (AUCτ) were similar between moderately obese and morbidly obese groups: 130.3 ± 60.1 versus 109.2 ± 25.5 μg · h/ml (P= 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r2= 0.524), adjusted body weight (r2= 0.587), lean body weight (r2= 0.495), and ideal body weight (r2= 0.398), but not with BMI (r2= 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUCτ values similar to those seen in nonobese participants.

scholarly journals Optimizing Ceftobiprole Dosage in Pediatric Patients: A Model-Based Approach

2021 ◽  
Author(s):  
Christopher M. Rubino ◽  
Anthony P. Cammarata ◽  
Anne Smits ◽  
Sebastian Schröpf ◽  
Mark Polak ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Generation Cephalosporin ◽  
Population Pharmacokinetic ◽  
Model Based ◽  
Final Population ◽  
Pediatric Study ◽  
Population Pk ◽  
Neonates And Infants

Ceftobiprole is an advanced-generation cephalosporin for intravenous administration with activity against Gram-positive and Gram-negative organisms. A population pharmacokinetic (PK) model characterizing the disposition of ceftobiprole in plasma using data from patients in three pediatric studies was developed. Model-based simulations were subsequently performed to assist in dose optimization for the treatment of pediatric patients with hospital-acquired or community-acquired pneumonia. The population PK dataset comprised 518 ceftobiprole plasma concentrations from 107 patients aged 0 (birth) to 17 years. Ceftobiprole PK was well described by a three-compartment model with linear elimination. Ceftobiprole clearance was modeled as a function of glomerular filtration rate; other PK parameters were scaled to body weight. The final population PK model provided a robust and reliable description of the PK of ceftobiprole in the pediatric study population. Model-based simulations using the final model suggested that a ceftobiprole dose of 15 mg/kg infused over 2 hours and administered every 12 hours in neonates and infants <3 months or every 8 hours in older pediatric patients would result in a ceftobiprole exposure consistent with that in adults and good pharmacokinetic-pharmacodynamic target attainment. The dose should be reduced to 10 mg/kg every 12 hours in neonates and infants <3 months who weigh <4 kg to avoid high exposures. Extended intervals and reduced doses may be required for pediatric patients older than 3 months of age with renal impairment.

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