1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

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Population Pharmacokinetics and Dosing Simulation of Vancomycin Administered by Continuous Injection in Critically Ill Patient

Antibiotics ◽

10.3390/antibiotics10101228 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1228

Author(s):

Romain Garreau ◽

Benoît Falquet ◽

Lisa Mioux ◽

Laurent Bourguignon ◽

Tristan Ferry ◽

...

Keyword(s):

Critically Ill ◽

External Validation ◽

Ideal Body Weight ◽

Intermittent Infusion ◽

Compartment Model ◽

Critically Ill Patient ◽

Population Pharmacokinetic ◽

Measured Concentration ◽

Icu Patients ◽

Final Model

Background: Vancomycin is widely used for empirical antimicrobial therapy in critically ill patients with sepsis. Continuous infusion (CI) may provide more stable exposure than intermittent infusion, but optimal dosing remains challenging. The aims of this study were to perform population pharmacokinetic (PK) analysis of vancomycin administered by CI in intensive care unit (ICU) patients to identify optimal dosages. Methods: Patients who received vancomycin by CI with at least one measured concentration in our center over 16 months were included, including those under continuous renal replacement therapy (CRRT). Population PK was conducted and external validation of the final model was performed in a dataset from another center. Simulations were conducted with the final model to identify the optimal loading and maintenance doses for various stages of estimated creatinine clearance (CRCL) and in patients on CRRT. Target exposure was defined as daily AUC of 400–600 mg·h/L on the second day of therapy (AUC24–48 h). Results: A two-compartment model best described the data. Central volume of distribution was allometrically scaled to ideal body weight (IBW), whereas vancomycin clearance was influenced by CRRT and CRCL. Simulations performed with the final model suggested a loading dose of 27.5 mg/kg of IBW. The maintenance dose ranged from 17.5 to 30 mg/kg of IBW, depending on renal function. Overall, simulation showed that 55.8% (95% CI; 47–64%) of patients would achieve the target AUC with suggested dosages. Discussion: A PK model has been validated for vancomycin administered by CI in ICU patients, including patients under CRRT. Our model-informed precision dosing approach may help for early optimization of vancomycin exposure in such patients.

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Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00570-06 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1822-1826 ◽

Cited By ~ 16

Author(s):

Olanrewaju Okusanya ◽

Alan Forrest ◽

Robin DiFrancesco ◽

Sanela Bilic ◽

Susan Rosenkranz ◽

...

Keyword(s):

Plasma Concentrations ◽

Compartment Model ◽

Central Compartment ◽

Volume Of Distribution ◽

Information Criteria ◽

Secondary Peak ◽

Pharmacokinetic Analysis ◽

Therapeutic Drug ◽

Healthy Human ◽

Two Compartment Model

ABSTRACT Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

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Population Pharmacokinetics of Vancomycin in Adult Patients with Long Bones’ Fractures

Serbian Journal of Experimental and Clinical Research ◽

10.2478/sjecr-2019-0025 ◽

2019 ◽

Vol 0 (0) ◽

Author(s):

Jasmina Milovanovic ◽

Radica Živković Zaric ◽

Nikola Rosic ◽

Dejana Ruzić Zecevic ◽

Dragan Milovanovic ◽

...

Keyword(s):

Bone Fractures ◽

Laboratory Data ◽

Compartment Model ◽

Adult Patients ◽

Population Pharmacokinetic ◽

Final Model ◽

Two Compartment Model ◽

Daily Dose ◽

Study Population ◽

The Mean

Abstract Vancomycin is a tricyclic glycopeptide antibiotic, mostly used in the treatment of severe staphylococcal and enterococcal infections, especially in orthopedic surgery. The purpose of this analysis was to develop a population pharmacokinetic (PPK) model of vancomycine in hospitalized patients with bone fractures and identify important factors which influence its clearance (CL). A total of ninety-nine measurements of vancomycin serum concentrations were used in our population modeling. A two-compartment model was applied to describe the pharmacokinetics of vancomycin using subroutines ADVAN3 and TRANS4. The study population included patients of both sexes, with the mean age of 62.12±14.69 years and body weight of 80.32±12.44kg. Vancomycin was administered as intravenous infusion with average daily dose of 1772.73±521.34mg. Out of twenty different factors evaluated in the study (including demographic, clinical and laboratory data), only daily dose of vancomycin (DD) and co-medication with piperacillin/tazobactam (PT) showed significant effect on clearance of vancomycin. The final model was described by the following equation: CL (l/h) = 0.03 + 0.000468 x DD + 0.675 x PT. Bootstrapping was used for validation of the final model. In conclusion, the main causes of variability in the clearance of vancomycin among adult patients with bone fractures are daily dose of vancomycin and co-medication with piperacillin/tazobactam.

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Cefepime precision dosing tool: From Standard to Precise Dose Using Nonparametric Population Pharmacokinetics

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02046-21 ◽

2021 ◽

Author(s):

Mohammad H. Alshaer ◽

Sylvain Goutelle ◽

Barbara Santevecchi ◽

Bethany Shoulders ◽

Veena Venugopalan ◽

...

Keyword(s):

Compartment Model ◽

Volume Of Distribution ◽

Target Range ◽

Population Pharmacokinetic ◽

Support Points ◽

Two Compartment Model ◽

Central Volume ◽

Model Support ◽

Median Rate ◽

Concentration Prediction

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate cefepime population pharmacokinetic (PK) model and integrate into precision dosing tool for implementation. Two datasets (680 patients) were used to build cefepime PK model in Pmetrics, and three datasets (34 patients) were used for the validation. A separate application dataset (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 hr −1 (adults) and 0.96 hr −1 (pediatrics), central volume of distribution 13.85 L, and rate of transfer from the central to the peripheral compartments 1.22 hr −1 and from the peripheral to the central compartments 1.38 hr −1 . After integration in BestDose, the observed vs. predicted cefepime concentration fit using the application dataset was excellent (R 2 >0.98) and the median difference between observed and what BestDose predicted in a second occasion was 4%. For OID, cefepime 0.5-1g 4-hour infusion q8-24hr with CrCl<70 mL/min was needed to achieve a target range of free trough:MIC 1-4 at MIC 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation and the median concentration prediction bias was 4%. OID algorithm was provided.

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Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients

Thrombosis and Haemostasis ◽

10.1160/th17-06-0390 ◽

2018 ◽

Vol 47 (04) ◽

pp. 621-629 ◽

Cited By ~ 6

Author(s):

Lisette Schütte ◽

Reinier van Hest ◽

Sara Stoof ◽

Frank Leebeek ◽

Marjon Cnossen ◽

...

Keyword(s):

Compartment Model ◽

Volume Of Distribution ◽

Time Profile ◽

Small Subset ◽

Population Pharmacokinetic ◽

Haemophilia A ◽

Mixed Effect ◽

Large Variability ◽

Nonlinear Mixed Effect ◽

Two Compartment Model

Background Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict. Objectives Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling. Patients and Methods Retrospective data of 128 nonsevere HA patients (age 7–75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reproducibility of FVIII:C response was defined as less than 25% difference in peak FVIII:C between administrations. Results A total of 623 FVIII:C measurements from 142 desmopressin administrations were available; 14 patients had received two administrations at different occasions. The FVIII:C time profile was best described by a two-compartment model with first-order absorption and elimination. Interindividual variability of the estimated baseline FVIII:C, central volume of distribution and clearance were 37, 43 and 50%, respectively. The most recently measured FVIII:C (FVIII-recent) was significantly associated with FVIII:C response to desmopressin (p < 0.001). Desmopressin administration resulted in an absolute FVIII:C increase of 0.47 IU/mL (median, interquartile range: 0.32–0.65 IU/mL, n = 142). FVIII:C response was reproducible in 6 out of 14 patients receiving two desmopressin administrations. Conclusion FVIII:C response to desmopressin in nonsevere HA patients was adequately described by a population PK model. Large variability in FVIII:C response was observed, which could only partially be explained by FVIII-recent. FVIII:C response was not reproducible in a small subset of patients. Therefore, monitoring FVIII:C around surgeries or bleeding might be considered. Research is needed to study this further.

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Rapidly maturing fentanyl clearance in preterm neonates

Archives of Disease in Childhood - Fetal and Neonatal Edition ◽

10.1136/archdischild-2018-315920 ◽

2019 ◽

Vol 104 (6) ◽

pp. F598-F603 ◽

Cited By ~ 5

Author(s):

Swantje Völler ◽

Robert B Flint ◽

Peter Andriessen ◽

Karel Allegaert ◽

Luc J I Zimmermann ◽

...

Keyword(s):

Gestational Age ◽

Compartment Model ◽

Volume Of Distribution ◽

Preterm Neonates ◽

Population Pharmacokinetic ◽

Additional Information ◽

Two Compartment Model ◽

Require Dose ◽

Preterm Newborns ◽

Pharmacodynamic Data

BackgroundFentanyl is frequently used off-label in preterm newborns. Due to very limited pharmacokinetic and pharmacodynamic data, fentanyl dosing is mostly based on bodyweight. This study describes the maturation of the pharmacokinetics in preterm neonates born before 32 weeks of gestation.Methods442 plasma samples from 98 preterm neonates (median gestational age: 26.9 (range 23.9–31.9) weeks, postnatal age: 3 (range 0–68) days, bodyweight 1.00 (range 0.39–2.37) kg) were collected in an opportunistic trial and fentanyl plasma levels were determined. NONMEM V.7.3 was used to develop a population pharmacokinetic model and to perform simulations.ResultsFentanyl pharmacokinetics was best described by a two-compartment model. A pronounced non-linear influence of postnatal and gestational age on clearance was identified. Clearance (L/hour/kg) increased threefold, 1.3-fold and 1.01-fold in the first, second and third weeks of life, respectively. In addition, clearance (L/hour/kg) was 1.4-fold and 1.7-fold higher in case of a gestational age of 28 and 31 weeks, respectively, compared with 25 weeks. Volume of distribution changed linearly with bodyweight and was 8.7 L/kg. To achieve similar exposure across the entire population, a continuous infusion (µg/kg/hour) dose should be reduced by 50% and 25% in preterm neonates with a postnatal age of 0–4 days and 5–9 days in comparison to 10 days and older.ConclusionBecause of low clearance, bodyweight-based dosages may result in fentanyl accumulation in neonates with the lowest postnatal and gestational ages which may require dose reduction. Together with additional information on the pharmacodynamics, the results of this study can be used to guide dosing.

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1321. Population Pharmacokinetic (PK) and Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Analyses for Dalbavancin in Pediatric Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1503 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S671-S672

Author(s):

Timothy J Carrothers ◽

H Maxime Lagraauw ◽

Lars Lindbom ◽

Todd Riccobene

Keyword(s):

Renal Function ◽

Single Dose ◽

Allometric Scaling ◽

Pediatric Patients ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Target Attainment ◽

Phase 3 ◽

Final Model ◽

Age Range

Abstract Background Dalbavancin is a lipoglycopeptide approved for treating adults with acute bacterial skin and skin structure infections (ABSSSI). It has a terminal half-life of >14 days, which allows for administration as a single-dose regimen. Pediatric studies for dalbavancin include three phase 1 studies and a phase 3 study in patients from birth to 17 years with ABSSSI or neonatal sepsis. Methods A population PK model was developed using 1124 concentrations from 211 pediatric patients. Allometric scaling of clearance, and volume parameters was included with exponents fixed at 0.75 and 1, respectively. Based on exploratory analysis and prior knowledge, serum albumin was included as a covariate on all PK parameters, and creatinine clearance or estimated glomerular filtration rate (eGFR) was included as a covariate on clearance. eGFR for patients < 2 years accounted for renal maturation. Additional covariates were assessed by stepwise covariate modeling (SCM). The final model was qualified by visual predictive checks (VPCs) and bootstrapping and was used to simulate 1000 PK profiles for various pediatric age groups, ranging from preterm neonates to adolescents. PK/PD target attainment (PTA) was calculated for targets associated with stasis, 1-log kill, and 2-log kill of Staphylococcus aureus in the murine thigh infection model. Results Dalbavancin PK was well-characterized by a 3-compartment model. SCM did not find any significant covariates besides albumin, weight, and renal function. VPCs demonstrated that the final model has good predictive performance across the full age range. Simulations showed that single-dose regimens of 22.5 mg/kg for patients < 6 years and 18 mg/kg for patients 6 to < 18 years resulted in PTA ≥94% for MICs up to 2 mg/L for the stasis target and up to 0.5 mg/L for the 2-log kill target. PTA for pediatric patients was similar to adults, and exposures (AUCs) were contained within the range for adults administered 1500 mg. Conclusion Dalbavancin PK in pediatric patients was well-characterized by a 3-compartment model with allometric scaling of clearance and volume and with albumin and renal function included as covariates. Simulations with the final model demonstrate adequate PTA across the entire age range for the regimens used in the phase 3 pediatric study. Disclosures Timothy J. Carrothers, ScD, AbbVie (Employee) H. Maxime Lagraauw, PhD, qPharmetra (Employee) Lars Lindbom, PhD, qPharmetra (Employee) Todd Riccobene, PhD, AbbVie (Employee)

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Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02808-13 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4718-4726 ◽

Cited By ~ 28

Author(s):

Ping Liu ◽

Diane R. Mould

Keyword(s):

Invasive Aspergillosis ◽

Area Under The Curve ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Institutional Review Boards ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

First Order ◽

Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

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Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00737-21 ◽

2021 ◽

Author(s):

Antonin Praet ◽

Laurent Bourguignon ◽

Florence Vetele ◽

Valentine Breant ◽

Charlotte Genestet ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dose Adjustment ◽

Total Body Weight ◽

Compartment Model ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Population Pharmacokinetic Modeling ◽

Two Compartment Model ◽

Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

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A Modified TNM Classification for Primary Operable Colorectal Cancer

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa093 ◽

2020 ◽

Author(s):

Chundong Zhang ◽

Zubing Mei ◽

Junpeng Pei ◽

Masanobu Abe ◽

Xiantao Zeng ◽

...

Keyword(s):

Colorectal Cancer ◽

Validation Cohort ◽

Tnm Classification ◽

Characteristic Curve ◽

External Validation ◽

Model Fitting ◽

Information Criteria ◽

Stage I ◽

Internal Validation ◽

Clinical Benefits

Abstract Background The American Joint Committee on Cancer (AJCC) 8th tumor/node/metastasis (TNM) classification for colorectal cancer (CRC) has limited ability to predict prognosis. Methods We included 45,379 eligible stage I-III CRC patients from the Surveillance, Epidemiology, and End Results Program. Patients were randomly assigned individually to a training (N =31,772) or an internal validation cohort (N =13,607). External validation was performed in 10,902 additional patients. Patients were divided according to T and N stage permutations. Survival analyses were conducted by a Cox proportional hazard model and Kaplan-Meier analysis, with T1N0 as the reference. Area under receiver operating characteristic curve (AUC) and Akaike information criteria (AIC) were applied for prognostic discrimination and model-fitting, respectively. Clinical benefits were further assessed by decision curve analyses. Results We created a modified TNM (mTNM) classification: stages I (T1-2N0-1a), IIA (T1N1b, T2N1b, T3N0), IIB (T1-2N2a-2b, T3N1a-1b, T4aN0), IIC (T3N2a, T4aN1a-2a, T4bN0), IIIA (T3N2b, T4bN1a), IIIB (T4aN2b, T4bN1b), and IIIC (T4bN2a-2b). In the internal validation cohort, compared to the AJCC 8th TNM classification, the mTNM classification showed superior prognostic discrimination (AUC = 0.675 vs. 0.667, respectively; two-sided P <0.001) and better model-fitting (AIC = 70,937 vs. 71,238, respectively). Similar findings were obtained in the external validation cohort. Decision curve analyses revealed that the mTNM had superior net benefits over the AJCC 8th TNM classification in the internal and external validation cohorts. Conclusions The mTNM classification provides better prognostic discrimination than AJCC 8th TNM classification, with good applicability in various populations and settings, to help better stratify stage I-III CRC patients into prognostic groups.

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