Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice

Roganović, Maša; Homšek, Ana; Jovanović, Marija; Topić-Vučenović, Valentina; Ćulafić, Milica; Miljković, Branislava; Vučićević, Katarina

doi:10.5937/arhfarm71-32901

Cited by 4 publications

(5 citation statements)

References 83 publications

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“…Similarly to our finding, most of previous studies failed to demonstrate the influence of co-therapy [7,11,38]. Although our previous multiple regression analysis showed increase in MTX concentrations with drugs in focus [8], the results of population analysis may be more reliable due to methodological advantages [10], and covariates were treated as time-varying during the analysis. Nevertheless, a few models explained some of the variability in pharmacokinetics by including concomitant medications [4], such as dexamethasone and/or vancomycin [13,15].…”

Section: Discussionsupporting

confidence: 82%

“…Population pharmacokinetic modeling is a valuable tool for evaluating covariates with significant influence on pharmacokinetic parameters and the extent of their influence. Moreover, it can account for both between-and within-subject variability, enabling individual tailoring of therapy [9,10]. Several categories of covariates have been described in previous MTX models, but the results are not fully consistent [4].…”

Section: Introductionmentioning

confidence: 99%

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Understanding hemoglobin contribution to high-dose methotrexate disposition—population pharmacokinetics in pediatric patients with hematological malignancies

Škorić,

Jovanović,

Kuzmanović

et al. 2024

Eur J Clin Pharmacol

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Aim was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) and to describe the sources of variability. The study included 50 patients (1-18 years) who received 3 or 5 g/m 2 of HDMTX. Nonlinear mixed effects modeling approach was applied for data analysis. Parameter estimation was performed by FOCEI, whereas stepwise covariate modeling was used to assess variability factors. The final two-compartment model incorporates the effect of body weight using allometric scaling and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical 70 kg subject were: 11 L/h for clearance (CL), 46.5 L and 16.4 L for volume of central (V1) and peripheral compartment (V2), respectively, and 0.168 L/h for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 30% in MTX CL was observed among patients' hemoglobin values reported in the study. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to HDMTX disposition.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Understanding hemoglobin contribution to high-dose methotrexate disposition—population pharmacokinetics in pediatric patients with hematological malignancies

Škorić,

Jovanović,

Kuzmanović

et al. 2024

Eur J Clin Pharmacol

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“…A visual predictive check (VPC) was performed with the Pearl-speaks-NONMEM module (PsN, version 5.2.6) based on 1000 simulations. Bootstrap 95% confidence intervals for the estimated parameters were evaluated [ 32 ]. For each patient, the individual AUC 24 was calculated based on the dosing regimen and estimated individual CL.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation—A Step toward Correct Dosing

Milaković,

Kovačević,

Kovačević

et al. 2024

Pharmaceutics

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During veno-venous extracorporeal membrane oxygenation (vv ECMO) therapy, antimicrobial drugs are frequently used, and appropriate dosing is challenging due to there being limited data to support the dosage. Linezolid is effective against multidrug-resistant Gram-positive pathogens frequently isolated in ECMO patients. In total, 53 steady-state linezolid levels were obtained following 600 mg intravenous (IV) injections every 8 h, and these were used to develop a population pharmacokinetic (PopPK) model in patients with COVID-19-associated acute respiratory distress syndrome (CARDS) on vv ECMO. The data were analyzed using a nonlinear mixed-effects modelling approach. Monte Carlo simulation generated 5000 patients’ individual PK parameters and corresponding concentration–time profiles using the PopPK model, following the administration of 600 mg/8 h (a higher-than-standard dosing) and 600 mg/12 h (standard). The probabilities of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) and the cumulative fraction of responses (CFR) for three pathogens were calculated and compared between the two dosing scenarios. Linezolid 600 mg/8 h was predicted to achieve greater than or equal to 85%Tf>MIC in at least 90% of the patients with CARDS on vv ECMO compared to only approximately two thirds of the patients after dosing every 12 h at a minimal inhibitory concentration (MIC) of 2 mg/L. In addition, for the same MIC, fAUC24/MIC ≥ 80 was achieved in almost three times the number of patients following an 8-h versus a 12-h interval. PopPK simulation predicted that a significantly higher proportion of the patients with CARDS on vv ECMO would achieve the PK/PD targets following the 8-h dosing interval compared to standard linezolid dosing. Nevertheless, the safety concern, in particular, for thrombocytopenia, with higher-than-standard linezolid dosage is reasonable, and consequently, monitoring is essential.

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“…Regulatory bodies (EMA and FDA) strongly recommend the implementation of pharmacometric analysis in drug development. 51 Hence, the role of modelling and simulation trials in supporting fixed dosing of SC mAb formulation was essential. In addition, characterization of PK and exposure-response relationship including variability in mAb behaviour was in depth performed by utilizing non-linear-mixed effects modelling approach.…”

Section: Overview Of Currently Registered Sc Mabsmentioning

confidence: 99%

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

Homšek

Spasić

Nikolić

et al. 2022

J Oncol Pharm Pract

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Objective Therapeutic monoclonal antibodies in oncology are slowly becoming the dominant treatment option for many different cancer types. The main route of administration, infusion, requires extensive product preparations, patient hospitalization and close monitoring. Patient comfort improvement, staff workload reduction and cost savings dictated the development of subcutaneous formulations. The aim of this review is to present pharmacokinetic characteristics of subcutaneous products, discuss the differences between intravenous and subcutaneous routes and to point out the advantages as well as challenges of administration route shift from the formulation development and pharmacometric angle. Data sources Food and Drug administration's Purple book database and electronic medicines compendium were used to identify monoclonal antibodies in oncology approved as subcutaneous forms. Using keywords subcutaneous, monoclonal antibodies, pharmacokinetics, model, as well as specific drugs previously identified, both PubMed and ScienceDirect databases were researched. Data summary There are currently six approved subcutaneous onco-monoclonal antibodies on the market. For each of them, exposure to the drug was similar in relation to infusion, treatment effectiveness was the same, administration was well tolerated by the patients and costs of the medical service were reduced. Conclusion Development of subcutaneous forms for existing and emerging new monoclonal antibodies for cancer treatment as well as shifting from administration via infusion should be encouraged due to patient preference, lower costs and overall lack of substantial differences in efficacy and safety between the two routes.

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Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice

Cited by 4 publications

References 83 publications

Understanding hemoglobin contribution to high-dose methotrexate disposition—population pharmacokinetics in pediatric patients with hematological malignancies

Understanding hemoglobin contribution to high-dose methotrexate disposition—population pharmacokinetics in pediatric patients with hematological malignancies

Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation—A Step toward Correct Dosing

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

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