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Pharmaceutics
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Population Pharmacokinetics and Its Clinical Applications
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Population Pharmacokinetics and Its Clinical Applications

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: 28 February 2026 | Viewed by 16767

Special Issue Editors

Prof. Dr. Katarina Vučićević

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Guest Editor
Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
Interests: clinical pharmacokinetics; population PKPD models; pharmacometrics; TDM; model-informed dosing optimization; NONMEM
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Branislava Miljković

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Guest Editor
Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
Interests: clinical pharmacokinetics; variability in pharmacokinetics; drug-drug interactions; TDM

Special Issue Information

Dear Colleagues,

Population pharmacokinetics, a field within pharmacokinetics, investigates the variability of drug concentrations between individuals in a selected population. It has gained considerable interest in recent years due to its potential to optimize drug dosing, improve therapeutic outcomes, and minimize adverse effects. This Special Issue focuses on the recent advances in population pharmacokinetics, with an emphasis on the clinical applications for personalized dosing in various therapeutic areas and special populations.

I am pleased to invite you to contribute original research articles, reviews, and methodological papers to this Special Issue entitled Population Pharmacokinetics and Its Clinical Applications. This issue aims to address the increasing demand for personalized medicine and optimized drug therapies. Population pharmacokinetics, a field within pharmacokinetics, investigates the variability in drug concentration among individuals in a selected population. It has gained significant interest in recent years due to its potential to support drug dosing optimization while enhancing therapeutic outcomes and minimizing adverse effects.

This Special Issue focuses on the recent advances in population pharmacokinetics, with an emphasis on the clinical applications for personalized dosing in various therapeutic areas and special populations. The scope of this Special Issue covers a broad range of topics related to population pharmacokinetics, including but not limited to the following: methodological advances in population modeling algorithms and simulation techniques; disease-specific applications of population pharmacokinetics in various therapeutic areas such as infectious diseases, inflammatory bowel diseases, and psychiatric disorders to predict individual patient responses and personalize treatment strategies; pharmacokinetic considerations for special populations such as pediatric, elderly, and patients with comorbidities; the integration of pharmacogenetic data into population pharmacokinetic models; and the potential for genotype-guided dosing strategies. The articles compiled in this Special Issue highlight the evolving landscape of population pharmacokinetics and its role in drug development and clinical practice.

I would like to extend my gratitude to all the authors who have chosen this Special Issue as a platform to publish their research findings. I look forward to receiving your contributions.

Prof. Dr. Katarina Vučićević
Prof. Dr. Branislava Miljković
Guest Editors

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Keywords

  • model-informed precision dosing (MIPD)
  • therapeutic drug monitoring (TDM)
  • dosing adjustments
  • special populations
  • nonlinear mixed-effects modeling (NONMEM)
  • PK/PD models

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Published Papers (13 papers)

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Research

16 pages, 10030 KiB  
Article
Population Pharmacokinetic Modeling of Total and Unbound Pamiparib in Glioblastoma Patients: Insights into Drug Disposition and Dosing Optimization
by Charuka Wickramasinghe, Seongho Kim, Yuanyuan Jiang, Xun Bao, Yang Yue, Jun Jiang, Amy Hong, Nader Sanai and Jing Li
Pharmaceutics 2025, 17(4), 524; https://doi.org/10.3390/pharmaceutics17040524 - 16 Apr 2025
Viewed by 333
Abstract
Background: This study aimed to develop a population pharmacokinetic (PK) model that characterized the plasma concentration–time profiles of the total and unbound pamiparib, a PARP inhibitor, in glioblastoma patients and identified patient factors influencing the PK. Methods: The total and unbound pamiparib plasma [...] Read more.
Background: This study aimed to develop a population pharmacokinetic (PK) model that characterized the plasma concentration–time profiles of the total and unbound pamiparib, a PARP inhibitor, in glioblastoma patients and identified patient factors influencing the PK. Methods: The total and unbound pamiparib plasma concentration data were obtained from 41 glioblastoma patients receiving 60 mg of pamiparib twice daily. Nonlinear mixed-effects modeling was performed using Monolix (2024R1) to simultaneously fit the total and unbound drug plasma concentration data. The covariate model was developed by covariate screening using generalized additive modeling followed by stepwise covariate modeling. Model simulations were performed following oral doses of 10–60 mg BID. Results: The total and unbound pamiparib plasma concentration–time profiles were best described by a one-compartment model with first-order absorption and elimination. Creatinine clearance and age were the significant covariates on the apparent volume of distribution (V/F) and apparent clearance (CL/F), respectively, explaining ~22% and ~5% of IIV of V/F and CL/F. Population estimates of the absorption rate constant (Ka), V/F, CL/F, and unbound fraction for the total drug were 1.58 h−1, 44 L, 2.59 L/h, and 0.041. Model simulations suggested that doses as low as 20 mg BID may be adequate for therapeutic effects in a general patient population, assuming that a target engagement ratio (i.e., unbound Css,min/IC50) of 5 or above is sufficient for full target engagement. Conclusions: The total and unbound pamiparib plasma PK are well characterized by a linear one-compartment model, with creatinine clearance as the significant covariate on V/F. Model simulations support further clinical investigation into dose reduction to optimize the benefit-to-risk ratio of pamiparib, particularly in combination therapies. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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16 pages, 513 KiB  
Article
Measurement of Anti-TNF Biologics in Serum Samples of Pediatric Patients: Comparison of Enzyme-Linked Immunosorbent Assay (ELISA) with a Rapid and Automated Fluorescence-Based Lateral Flow Immunoassay
by Chiara Rossi, Raffaele Simeoli, Giulia Angelino, Sara Cairoli, Fiammetta Bracci, Daniela Knafelz, Erminia Francesca Romeo, Simona Faraci, Giusyda Tarantino, Alessandro Mancini, Alessia Vitale, Carlo Dionisi Vici, Silvia Magni Manzoni, Paola De Angelis and Bianca Maria Goffredo
Pharmaceutics 2025, 17(4), 421; https://doi.org/10.3390/pharmaceutics17040421 - 26 Mar 2025
Viewed by 287
Abstract
Background: Therapeutic drug monitoring (TDM) of infliximab (IFX) and adalimumab (ADL) mainly relies on the use of enzyme-linked immunosorbent assays (ELISA). More recently, rapid assays have been developed and validated to reduce turnaround time (TAT). Here, we compared IFX and ADL concentrations [...] Read more.
Background: Therapeutic drug monitoring (TDM) of infliximab (IFX) and adalimumab (ADL) mainly relies on the use of enzyme-linked immunosorbent assays (ELISA). More recently, rapid assays have been developed and validated to reduce turnaround time (TAT). Here, we compared IFX and ADL concentrations measured with both ELISA and a new fluorescence-based lateral flow immunoassay (AFIAS). Methods: In serum samples from pediatric patients, IFX and ADL drug levels, and total anti-IFX antibodies were measured using clinically validated ELISA kits (Immundiagnostik AG). Samples were further analyzed using a new rapid assay (AFIAS, Boditech Med Inc.) to measure drug levels and total anti-IFX antibodies. Results: Spearman’s correlation coefficients (rho) were 0.98 [95% confidence interval (CI) 0.97 to 0.99] for IFX (p < 0.001) and 0.83 (95% CI 0.72 to 0.90) for ADL (p < 0.001). Calculated % bias was −14.09 (95% Limits of agreement, LoA, −52.83 to 24.66) for IFX and 15.79 (LoA −37.14 to 68.73) for ADL. For the evaluation of total anti-IFX antibodies, we did not collect sufficient data to establish a statistically significant correlation between AFIAS and ELISA. The inter-rater agreement showed a “substantial” and a “moderate” agreement for IFX and ADL, respectively. Conclusions: Our results show that the AFIAS assay has an accuracy and analytical performance comparable to that of the ELISA method used for TDM of IFX and ADL. Therefore, the introduction of this device into routine clinical practice could provide results more quickly and with similar accuracy as ELISA, allowing clinicians to rapidly formulate clinical decisions. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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16 pages, 1017 KiB  
Article
Vedolizumab Clearance as a Surrogate Marker for Remission in Inflammatory Bowel Disease Patients: Insights from Real-World Pharmacokinetics
by Srđan Marković, Đorđe Kralj, Petar Svorcan, Tamara Knežević Ivanovski, Olga Odanović, Sanja Obradović, Ana Homšek, Marija Jovanović, Rada Savić and Katarina M. Vučićević
Pharmaceutics 2024, 16(12), 1629; https://doi.org/10.3390/pharmaceutics16121629 - 23 Dec 2024
Viewed by 949
Abstract
Background/Objectives: Vedolizumab (VDZ) is approved in the treatment of patients with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD). VDZ exhibits considerable variability in its pharmacokinetic (PK) profile, and its exposure-response relationship is not yet fully understood. The aim was to [...] Read more.
Background/Objectives: Vedolizumab (VDZ) is approved in the treatment of patients with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD). VDZ exhibits considerable variability in its pharmacokinetic (PK) profile, and its exposure-response relationship is not yet fully understood. The aim was to investigate the variability in VDZ trough levels and PK parameters, to assess the relationship between VDZ PK and biochemical response, as well as clinical and endoscopic outcomes. Methods: We included 61 UC and 45 CD patients. Patients’ data and trough VDZ concentrations were retrospectively obtained. Population PK analysis was performed using non-linear mixed-effects modelling with NONMEM (version 7.5). Graphs and statistical analyses were performed using R (version 4.1.3). Results: In total, 116 trough VDZ concentrations from 106 patients were described by a two-compartment model. For a typical patient, clearance (CL) was estimated at 0.159 L/day, while in patients previously treated with anti-TNFα agents, VDZ CL increased by 26.4% on average. In univariate binary logistic regression, VDZ trough concentration was not statistically significant predictor of remission, whereas CL was. Moreover, combined CL and faecal calprotectin (FCP) were a statistically significant predictors of remission. The hazard ratio (HR) for CL above 0.1886 L/day was 0.35 (p = 0.05) and for FCP below 250 µg/g was 2.66 (p = 0.02) in a time-to-event analysis. Conclusions: Our population PK model incorporates the effect of prior anti-TNFα agents on CL, suggesting its association with more severe forms of IBD. VDZ CL emerged as a more robust and clinically relevant predictor of remission in IBD patients than trough concentration. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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16 pages, 1581 KiB  
Article
Personalized Secukinumab Treatment in Patients with Plaque Psoriasis Using Model-Informed Precision Dosing
by Karine Rodriguez-Fernandez, Javier Zarzoso-Foj, Marina Saez-Bello, Almudena Mateu-Puchades, Antonio Martorell-Calatayud, Matilde Merino-Sanjuan, Elena Gras-Colomer, Monica Climente-Marti and Victor Mangas-Sanjuan
Pharmaceutics 2024, 16(12), 1576; https://doi.org/10.3390/pharmaceutics16121576 - 10 Dec 2024
Viewed by 1172
Abstract
Background/Objectives: Patient care and control of inflammatory disorders, such as psoriasis, can be improved by model-informed precision dosing (MIPD) techniques based on population pharmacokinetic/pharmacodynamic (PK/PD) models. Clinical dose selection decisions based on MIPD strategies need to take account of the uncertainty associated with [...] Read more.
Background/Objectives: Patient care and control of inflammatory disorders, such as psoriasis, can be improved by model-informed precision dosing (MIPD) techniques based on population pharmacokinetic/pharmacodynamic (PK/PD) models. Clinical dose selection decisions based on MIPD strategies need to take account of the uncertainty associated with the individual PK/PD model parameters, which is determined by the quantity of individual observational data collected in clinical practice. Methods: The aim of this study was to propose an approach for personalized dosage regimens of secukinumab (SCK) in 22 Spanish patients with plaque psoriasis, whose severity level was considered moderate to severe, taking into account the uncertainty associated with individual parameters in a population-based PK/PD model. Results: The link between SCK serum concentrations and Psoriasis Area and Severity Index (PASI) scores was explained using an indirect response model. A maximum inhibition (Imax) drug effect model was applied to limit the progression of psoriatic skin lesions within the turnover PD mechanism, which explains the changes in PASI scores during treatment. A first-order remission rate constant for psoriatic lesions (kout = 0.11 day−1) was estimated. Conclusions: According to the MIPD strategy, 50% of patients would require an optimized regimen and 14% would require an intensified dosage regimen in comparison to current clinical treatment. This research has shown its usefulness as a tool for choosing individualized SCK dosage regimens in patients with long-lasting plaque psoriasis to improve the probability of achieving satisfactory response levels. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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18 pages, 3471 KiB  
Article
Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors
by John C. Panetta, Nicholas S. Selvo, David Van Mater and Clinton F. Stewart
Pharmaceutics 2024, 16(12), 1528; https://doi.org/10.3390/pharmaceutics16121528 - 28 Nov 2024
Viewed by 1019
Abstract
Background/Objectives: Palbociclib, an oral CDK 4/6 inhibitor, was evaluated in a Pediatric Brain Tumor Consortium (PBTC) phase 1 (NCT02255461; PBTC-042) study to treat children and young adults with recurrent, progressive, or refractory brain tumors. The objectives of this study were to characterize the [...] Read more.
Background/Objectives: Palbociclib, an oral CDK 4/6 inhibitor, was evaluated in a Pediatric Brain Tumor Consortium (PBTC) phase 1 (NCT02255461; PBTC-042) study to treat children and young adults with recurrent, progressive, or refractory brain tumors. The objectives of this study were to characterize the palbociclib population pharmacokinetics in children enrolled on PBTC-042, to conduct a population pharmacodynamic analysis in this patient population, and to perform a simulation study to assess the role of palbociclib exposure on neutropenia and thrombocytopenia. Methods: The palbociclib population pharmacokinetics and pharmacodynamics were characterized in this patient population (n = 34 patients; 4.9–21.6 years old). Population pharmacokinetics were modeled using a one-compartment model with first-order absorption and elimination. Covariate analysis was performed, evaluating demographics, laboratory values, and concomitant medications. A pharmacodynamic model was used to describe the relation between palbociclib plasma exposure and changes in the ANC and platelet counts. Results: The population estimates for the apparent oral volume, apparent oral clearance, and absorption rate constant were 664.5 L/m2, 36.8 L/h/m2, and 0.48 h−1, respectively. The palbociclib apparent oral clearance was decreased in patients with higher AST values (p = 0.0066). The ANC and platelet pharmacodynamic models estimated that the median (5th–95th percentile) time individuals had grade 3 or greater neutropenia was 4 (0, 21) days. Simulations showed that given 75 mg/m2 palbociclib, 49% of the individuals were expected to have grade 3 or greater neutropenia. Conclusions: Palbociclib pharmacokinetics and pharmacodynamics were adequately characterized in this patient population, no unexpected adverse reactions were noted, and the drug was well tolerated. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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11 pages, 1723 KiB  
Article
Development of a Population Pharmacokinetic Gabapentin Model Leveraging Therapeutic Drug Monitoring Concentrations
by Firas Al-Zubaydi, Andrew Wassef, Leonid Kagan and Luigi Brunetti
Pharmaceutics 2024, 16(12), 1514; https://doi.org/10.3390/pharmaceutics16121514 - 25 Nov 2024
Viewed by 1301
Abstract
Background/Objectives: Gabapentin has variable pharmacokinetics (PK), which contributes to difficulty in dosing and increased risk of adverse events. The objective of this study was to leverage gabapentin concentrations from therapeutic drug monitoring (TDM) to develop a population PK (popPK) model and characterize significant [...] Read more.
Background/Objectives: Gabapentin has variable pharmacokinetics (PK), which contributes to difficulty in dosing and increased risk of adverse events. The objective of this study was to leverage gabapentin concentrations from therapeutic drug monitoring (TDM) to develop a population PK (popPK) model and characterize significant covariates that impact gabapentin PK. Methods: Data were retrospectively collected from 82 hospitalized adult patients with TDM gabapentin concentrations. Renal function indicators (i.e., estimated glomerular filtration rate, creatinine clearance, acute kidney injury), body weight parameters (i.e., actual body weight, ideal body weight, adjusted body weight, lean body weight, body mass index, obesity status), fasting plasma glucose levels, and diagnosis of type 2 diabetes were tested as potential covariates. A popPK model was developed in MONOLIX (2020R1, Lixoft, France). Results: A one-compartment model best described gabapentin PK with first-order absorption, dose-dependent bioavailability, first-order elimination, and no lag time. Population parameter estimates for the volume of distribution (Vd), and clearance (Cl) were 44.61 L, and 5.73 L/h, respectively. Serum creatinine was a significant covariate on Cl. Conclusions: The popPK model highlights the importance of renal function in the interindividual variability of gabapentin PK and suggests that diabetes and body weight parameters have no impact on gabapentin PK. Moreover, our study supports the utility of leveraging data obtained from clinical TDM for popPK model development. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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16 pages, 2014 KiB  
Article
Use of Nuclear Factor of Activated T Cell-Regulated Gene Expression for Monitoring Immunosuppression with Extended-Release Tacrolimus after Liver Transplantation—A Proof of Concept
by Judith Kahn, Eva Maria Matzhold, Peter Schlenke and Peter Schemmer
Pharmaceutics 2024, 16(10), 1317; https://doi.org/10.3390/pharmaceutics16101317 - 11 Oct 2024
Viewed by 1157
Abstract
Background: There is a narrow therapeutic window for immunosuppression using calcineurin inhibitors. Drug trough levels do not reflect immunosuppression and should be replaced by pharmacodynamic monitoring. This prospective cohort study was designed to evaluate the effect of an extended-release formulation of tacrolimus (LCP [...] Read more.
Background: There is a narrow therapeutic window for immunosuppression using calcineurin inhibitors. Drug trough levels do not reflect immunosuppression and should be replaced by pharmacodynamic monitoring. This prospective cohort study was designed to evaluate the effect of an extended-release formulation of tacrolimus (LCP Tac) on the nuclear factor of activated T cell-regulated gene expression (NFAT-RGE). Methods: The expression of interleukin-2, interferon-γ, granulocyte-macrophage colony-stimulating factor, and three reference genes was measured. Samples from 23 patients at defined time points in the first year after liver transplantation were analyzed using a droplet digital polymerase chain reaction. Results: All samples were within the targeted trough levels of LCP Tac, and their LCP Tac peak levels and residual NFAT-RGE showed a strong inverse correlation (r = −0.8). Most importantly, there was an individual immunosuppressive response to the LCP Tac. The mean individual trough effect of LCP Tac on the three target genes when all time points were pooled was 33% (26–56%) in patients without infection and 81% (53–95%) in those with infection (p < 0.011). The mean individual peak effect was 48% (44–64%) in patients without infection and 91% (90–94%) in those with infection (p < 0.001). Conclusions: Thus, tailored immunosuppression based on residual NFAT-RGE could prevent infections associated with over-immunosuppression early after liver transplantation. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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15 pages, 1828 KiB  
Article
Model-Informed Precision Dosing for Personalized Ustekinumab Treatment in Plaque Psoriasis
by Karine Rodríguez-Fernández, Javier Zarzoso-Foj, Marina Saez-Bello, Almudena Mateu-Puchades, Antonio Martorell-Calatayud, Matilde Merino-Sanjuan, Elena Gras-Colomer, Monica Climente-Martí and Victor Mangas-Sanjuan
Pharmaceutics 2024, 16(10), 1295; https://doi.org/10.3390/pharmaceutics16101295 - 4 Oct 2024
Cited by 2 | Viewed by 1455
Abstract
Background/Objectives: Implementing model-informed precision dosing (MIPD) strategies guided by population pharmacokinetic/pharmacodynamic (PK/PD) models could enhance the management of inflammatory diseases such as psoriasis. However, the extent of individual experimental data gathered during MIPD significantly influences the uncertainty in estimating individual PK/PD parameters, affecting [...] Read more.
Background/Objectives: Implementing model-informed precision dosing (MIPD) strategies guided by population pharmacokinetic/pharmacodynamic (PK/PD) models could enhance the management of inflammatory diseases such as psoriasis. However, the extent of individual experimental data gathered during MIPD significantly influences the uncertainty in estimating individual PK/PD parameters, affecting clinical dose selection decisions. Methods: This study proposes a methodology to individualize ustekinumab (UTK) dosing strategies for 23 Spanish patients with moderate to severe chronic plaque psoriasis., considering the uncertainty of individual parameters within a population PK/PD model. Results: An indirect response model from previous research was used to describe the PK/PD relationship between UTK serum concentrations and the Psoriasis Area and Severity Index (PASI) score. A maximum inhibition drug effect (Imax) model was selected, and a first-order remission constant rate of psoriatic skin lesion (kout = 0.016 d−1) was estimated. Conclusions: The MIPD approach predicted that 35% and 26% of the patients would need an optimized and intensified dosage regimen, respectively, compared to the regimen typically used in clinical practice. This analysis demonstrated its utility as a tool for selecting personalized UTK dosing regimens in clinical practice in order to optimize the probability of achieving targeted clinical outcomes in patients with psoriasis. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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14 pages, 2615 KiB  
Article
Effect of Interindividual Variability in Metabolic Clearance and Relative Bioavailability on Rifampicin Exposure in Tuberculosis Patients with and without HIV Co-Infection: Does Formulation Quality Matter?
by Glauco Henrique Balthazar Nardotto, Elin M. Svenson, Valdes Roberto Bollela, Adriana Rocha, Svetoslav Nanev Slavov, João Paulo Bianchi Ximenez, Oscar Della Pasqua and Vera Lucia Lanchote
Pharmaceutics 2024, 16(8), 970; https://doi.org/10.3390/pharmaceutics16080970 - 23 Jul 2024
Viewed by 1354
Abstract
The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetyl-rifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual [...] Read more.
The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetyl-rifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual variation in the exposure to RIF. Pharmacokinetic, clinical, and demographic data from TB patients with (TB-HIV+ group; n = 18) or without HIV (TB-HIV− group; n = 15) who were receiving RIF as part of a four-drug fixed-dose combination (FDC) regimen (RIF, isoniazid, pyrazinamide, and ethambutol) were analysed, along with the published literature data on the relative bioavailability of different formulations. A population pharmacokinetic model, including the formation of desRIF, was developed and compared to a model based solely on the parent drug. HIV co-infection does not alter the plasma exposure to RIF and the desRIF formation does not contribute to the observed variability in the RIF disposition. The relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard regimen with FDC tablets. Furthermore, participants weighting less than 50 kg do not reach the same RIF plasma exposure as compared to those weighting >50 kg. In conclusion, as no covariate was identified other than body weight on CL/F and Vd/F, low systemic exposure to RIF is likely to be caused by the low bioavailability of the formulation. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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23 pages, 5172 KiB  
Article
Development and Quality Control of a Population Pharmacokinetic Model Library for Caspofungin
by Nuo Xu, Yufei Shi, Yixue Wang, Wenyao Mak, Wenyu Yang, Kar Weng Ng, Yue Wu, Zhijia Tang, Qingfeng He, Gangfeng Yan, Xiaoqiang Xiang and Xiao Zhu
Pharmaceutics 2024, 16(6), 819; https://doi.org/10.3390/pharmaceutics16060819 - 17 Jun 2024
Cited by 1 | Viewed by 1699
Abstract
Background: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of [...] Read more.
Background: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. Objective: This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings. Methods: We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections. Results: A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for C. glabrata, 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level. Conclusion: At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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13 pages, 1872 KiB  
Article
Population Pharmacokinetic Analysis and Simulation of Alternative Dosing Regimens for Biosimilars to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis
by Stephanie F. Ling, Kayode Ogungbenro, Adam S. Darwich, Amirah Binti Mohammad Ariff, Nisha Nair, James Bluett, Ann W. Morgan, John D. Isaacs, Anthony G. Wilson, Kimme L. Hyrich, Anne Barton and Darren Plant
Pharmaceutics 2024, 16(6), 702; https://doi.org/10.3390/pharmaceutics16060702 - 23 May 2024
Cited by 1 | Viewed by 1726
Abstract
Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to [...] Read more.
Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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12 pages, 1602 KiB  
Article
Development of a Web Application for Simulating Plasma Drug Concentrations in Patients with Zolpidem Intoxication
by Hwa Jun Cha, Sungpil Han, Kwan Cheol Pak and Hyungsub Kim
Pharmaceutics 2024, 16(5), 689; https://doi.org/10.3390/pharmaceutics16050689 - 20 May 2024
Viewed by 1543
Abstract
Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) [...] Read more.
Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) model was established using digitized data obtained from twenty-three healthy volunteers after a single oral administration of zolpidem. Based on the final PK model, a web application was developed using open-source R packages such as rxode2, nonmem2rx, and shiny. The final model was a one-compartment model with first-order absorption and elimination with PK parameters, including clearance (CL, 16.9 L/h), absorption rate constant (Ka, 5.41 h−1), volume of distribution (Vd, 61.7 L), and lag time (ALAG, 0.394 h). Using the established population PK model in the current study, we developed a web application that enables users to simulate plasma zolpidem concentrations and visualize their profiles. This user-friendly web application may provide essential clinical information to physicians, ultimately helping in the management of patients with zolpidem intoxication. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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13 pages, 1219 KiB  
Article
Integrating Clopidogrel’s First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite
by Zorica Pejčić, Valentina Topić Vučenović, Branislava Miljković and Katarina M. Vučićević
Pharmaceutics 2024, 16(5), 685; https://doi.org/10.3390/pharmaceutics16050685 - 20 May 2024
Cited by 1 | Viewed by 1664
Abstract
Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85–90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, [...] Read more.
Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85–90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants’ data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study’s generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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