Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.9
5.4
Journals
Pharmaceutics
Special Issues
Model-Informed Precision Dosing
share announcement

Model-Informed Precision Dosing

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

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 55358

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Jonás Samuel Pérez-Blanco

E-Mail Website
Guest Editor
1. Department of Pharmaceutical Sciences, University of Salamanca, Pharmacy Faculty, Campus Miguel de Unamuno, 37007 Salamanca, Spain
2. Institute for Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, Hospital Virgen de la Vega, Paseo de San Vicente, 58-182, 37007 Salamanca, Spain
Interests: pharmacometrics (PMX); population pharmacokinetics (PopPK); pharmacokinetics-pharmacodynamics (PKPD); model-informed precision dosing (MIPD); modeling and simulation (M&S)
Prof. Dr. José Martínez Lanao

E-Mail Website
Guest Editor
1. Department of Pharmaceutical Sciences, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain
2. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Interests: drug delivery; cell carriers; nanoparticles; pharmacokinetics; anti-infectives; pharmaceutical development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Model-informed precision dosing (MIPD) is an advanced quantitative approach focusing on individualized treatment optimization. MIPD integrates mathematical models of drugs and disease combined with individual patient characteristics (e.g., genotype, anthropometric factors, organ function). MIPD has been highlighted as a useful tool for drug dosage selection in both drug development process and clinical practice. Despite the potential benefits of this methodology toward personalized medicine, its application is still limited.

This Special Issue is focused on new MIPD strategies and methodologies to optimize drug dosage (dosing algorithms, pharmacokinetic–pharmacodynamic indexes, interactive applications, nomograms, etc.) in specific populations, allowing to evaluate the potential improvement on the clinical efficacy and/or safety of the treatments.

Dr. Jonás Samuel Pérez-Blanco
Prof. Dr. José Martínez Lanao
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • model-informed precision dosing (MIPD)
  • efficacy PKPD indexes
  • pharmacokinetics
  • pharmacodynamics
  • PKPD modeling and simulation
  • dosing algorithms
  • nomograms

Published Papers (21 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

4 pages, 215 KiB  
Editorial
Model-Informed Precision Dosing (MIPD)
by Jonás Samuel Pérez-Blanco and José M. Lanao
Pharmaceutics 2022, 14(12), 2731; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14122731 - 06 Dec 2022
Cited by 7 | Viewed by 2147
Abstract
Model-informed precision dosing (MIPD) is an advanced quantitative approach focusing on individualized dosage optimization, integrating complex mathematical and statistical models of drugs and disease combined with individual demographic and clinical patient characteristics [...] Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)

Research

Jump to: Editorial, Review

13 pages, 1862 KiB  
Article
Systematic Comparison of Hospital-Wide Standard and Model-Based Therapeutic Drug Monitoring of Vancomycin in Adults
by Heleen Gastmans, Erwin Dreesen, Sebastian G. Wicha, Nada Dia, Ellen Spreuwers, Annabel Dompas, Karel Allegaert, Stefanie Desmet, Katrien Lagrou, Willy E. Peetermans, Yves Debaveye, Isabel Spriet and Matthias Gijsen
Pharmaceutics 2022, 14(7), 1459; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071459 - 13 Jul 2022
Cited by 2 | Viewed by 1956
Abstract
We aimed to evaluate the predictive performance and predicted doses of a single-model approach or several multi-model approaches compared with the standard therapeutic drug monitoring (TDM)-based vancomycin dosing. We performed a hospital-wide monocentric retrospective study in adult patients treated with either intermittent or [...] Read more.
We aimed to evaluate the predictive performance and predicted doses of a single-model approach or several multi-model approaches compared with the standard therapeutic drug monitoring (TDM)-based vancomycin dosing. We performed a hospital-wide monocentric retrospective study in adult patients treated with either intermittent or continuous vancomycin infusions. Each patient provided two randomly selected pairs of two consecutive vancomycin concentrations. A web-based precision dosing software, TDMx, was used to evaluate the model-based approaches. In total, 154 patients contributed 308 pairs. With standard TDM-based dosing, only 48.1% (148/308) of all of the second concentrations were within the therapeutic range. Across the model-based approaches we investigated, the mean relative bias and relative root mean square error varied from −5.36% to 3.18% and from 24.8% to 28.1%, respectively. The model averaging approach according to the squared prediction errors showed an acceptable bias and was the most precise. According to this approach, the median (interquartile range) differences between the model-predicted and prescribed doses, expressed as mg every 12 h, were 113 [−69; 427] mg, −70 [−208; 120], mg and 40 [−84; 197] mg in the case of subtherapeutic, supratherapeutic, and therapeutic exposure at the second concentration, respectively. These dose differences, along with poor target attainment, suggest a large window of opportunity for the model-based TDM compared with the standard TDM-based vancomycin dosing. Implementation studies of model-based TDM in routine care are warranted. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Graphical abstract

19 pages, 1150 KiB  
Article
Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study
by Vanesa Escudero-Ortiz, Vanessa Domínguez-Leñero, Ana Catalán-Latorre, Joseba Rebollo-Liceaga and Manuel Sureda
Pharmaceutics 2022, 14(6), 1216; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14061216 - 08 Jun 2022
Cited by 6 | Viewed by 2062
Abstract
Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to [...] Read more.
Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. Objective: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. Materials and methods: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. Results: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure–efficacy analysis. Conclusions: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

12 pages, 1029 KiB  
Article
Population Pharmacokinetics of Valproic Acid in Pediatric and Adult Caucasian Patients
by Paulo Teixeira-da-Silva, Jonás Samuel Pérez-Blanco, Dolores Santos-Buelga, María José Otero and María José García
Pharmaceutics 2022, 14(4), 811; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040811 - 07 Apr 2022
Cited by 3 | Viewed by 2454
Abstract
(1) Background: The aim of this study was to explore the valproic acid (VPA) pharmacokinetic characteristics in a large population of pediatric and adult Caucasian patients and to establish a robust population pharmacokinetic (PopPK) model. (2) Methods: A total of 2527 serum VPA [...] Read more.
(1) Background: The aim of this study was to explore the valproic acid (VPA) pharmacokinetic characteristics in a large population of pediatric and adult Caucasian patients and to establish a robust population pharmacokinetic (PopPK) model. (2) Methods: A total of 2527 serum VPA samples collected from 1204 patients included in a therapeutic drug monitoring program were retrospectively analyzed. Patients were randomly assigned to either a model development group or an external evaluation group. PopPK analysis was performed on 1751 samples from 776 patients with NONMEM using a nonlinear mixed-effect modelling approach. The influence of demographic, anthropometric, treatment and comedication variables on the apparent clearance (CL/F) of VPA was studied. The bootstrap method was used to evaluate the final model internally. External evaluation was carried out using 776 VPA serum samples from 368 patients. (3) Results: A one-compartment model with first-order absorption and elimination successfully described the data. The final model included total body weight, age and comedication with phenytoin, phenobarbital and carbamazepine with a significant impact on VPA elimination. Internal and external evaluations demonstrated the good predictability of the model. (4) Conclusions: A PopPK model of VPA in Caucasian patients was successfully established, which will be helpful for model-informed precision dosing approaches in clinical patient care. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

15 pages, 1653 KiB  
Article
Model-Informed Precision Dosing of Linezolid in Patients with Drug-Resistant Tuberculosis
by Laurynas Mockeliunas, Lina Keutzer, Marieke G. G. Sturkenboom, Mathieu S. Bolhuis, Lotte M. G. Hulskotte, Onno W. Akkerman and Ulrika S. H. Simonsson
Pharmaceutics 2022, 14(4), 753; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040753 - 30 Mar 2022
Cited by 8 | Viewed by 2567
Abstract
Linezolid is an efficacious medication for the treatment of drug-resistant tuberculosis but has been associated with serious safety issues that can result in treatment interruption. The objectives of this study were thus to build a population pharmacokinetic model and to use the developed [...] Read more.
Linezolid is an efficacious medication for the treatment of drug-resistant tuberculosis but has been associated with serious safety issues that can result in treatment interruption. The objectives of this study were thus to build a population pharmacokinetic model and to use the developed model to establish a model-informed precision dosing (MIPD) algorithm enabling safe and efficacious dosing in patients with multidrug- and extensively drug-resistant tuberculosis. Routine hospital therapeutic drug monitoring data, collected from 70 tuberculosis patients receiving linezolid, was used for model development. Efficacy and safety targets for MIPD were the ratio of unbound area under the concentration versus time curve between 0 and 24 h over minimal inhibitory concentration (fAUC0–24h/MIC) above 119 and unbound plasma trough concentration (fCmin) below 1.38 mg/L, respectively. Model building was performed in NONMEM 7.4.3. The final population pharmacokinetic model consisted of a one-compartment model with transit absorption and concentration- and time-dependent auto-inhibition of elimination. A flat dose of 600 mg once daily was appropriate in 67.2% of the simulated patients from an efficacy and safety perspective. Using the here developed MIPD algorithm, the proportion of patients reaching the efficacy and safety target increased to 81.5% and 88.2% using information from two and three pharmacokinetic sampling occasions, respectively. This work proposes an MIPD approach for linezolid and suggests using three sampling occasions to derive an individualized dose that results in adequate efficacy and fewer safety concerns compared to flat dosing. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

13 pages, 2201 KiB  
Article
Free and Open-Source Posologyr Software for Bayesian Dose Individualization: An Extensive Validation on Simulated Data
by Cyril Leven, Anne Coste and Camille Mané
Pharmaceutics 2022, 14(2), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020442 - 18 Feb 2022
Cited by 5 | Viewed by 2285
Abstract
Model-informed precision dosing is being increasingly used to improve therapeutic drug monitoring. To meet this need, several tools have been developed, but open-source software remains uncommon. Posologyr is a free and open-source R package developed to enable Bayesian individual parameter estimation and dose [...] Read more.
Model-informed precision dosing is being increasingly used to improve therapeutic drug monitoring. To meet this need, several tools have been developed, but open-source software remains uncommon. Posologyr is a free and open-source R package developed to enable Bayesian individual parameter estimation and dose individualization. Before using it for clinical practice, performance validation is mandatory. The estimation functions implemented in posologyr were benchmarked against reference software products on a wide variety of models and pharmacokinetic profiles: 35 population pharmacokinetic models, with 4.000 simulated subjects by model. Maximum A Posteriori (MAP) estimates were compared to NONMEM post hoc estimates, and full posterior distributions were compared to Monolix conditional distribution estimates. The performance of MAP estimation was excellent in 98.7% of the cases. Considering the full posterior distributions of individual parameters, the bias on dosage adjustment proposals was acceptable in 97% of cases with a median bias of 0.65%. These results confirmed the ability of posologyr to serve as a basis for the development of future Bayesian dose individualization tools. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Graphical abstract

10 pages, 1394 KiB  
Article
Model-Based Equivalent Dose Optimization to Develop New Donepezil Patch Formulation
by Woojin Jung, Heeyoon Jung, Ngoc-Anh Thi Vu, Gwan-Young Kim, Gyoung-Won Kim, Jung-woo Chae, Taeheon Kim and Hwi-yeol Yun
Pharmaceutics 2022, 14(2), 244; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020244 - 20 Jan 2022
Cited by 4 | Viewed by 2173
Abstract
Donepezil patch was developed to replace the original oral formulation. To accurately describe the pharmacokinetics of donepezil and investigate compatible doses between two formulations, a population pharmacokinetic model for oral and transdermal patches was built based on a clinical study. Plasma donepezil levels [...] Read more.
Donepezil patch was developed to replace the original oral formulation. To accurately describe the pharmacokinetics of donepezil and investigate compatible doses between two formulations, a population pharmacokinetic model for oral and transdermal patches was built based on a clinical study. Plasma donepezil levels were analyzed via liquid chromatography/tandem mass spectrometry. Non-compartmental analyses were performed to derive the initial parameters for compartmental analyses. Compartmental analysis (CA) was performed with NLME software NONMEM assisted by Perl-speaks-NONMEM, and R. Model evaluation was proceeded via visual predictive checks (VPC), goodness-of-fit (GOF) plotting, and bootstrap method. The bioequivalence test was based on a 2 × 2 crossover design, and parameters of AUC and Cmax were considered. We found that a two-compartment model featuring two transit compartments accurately describes the pharmacokinetics of nine subjects administered in oral, as well as of the patch-dosed subjects. Through evaluation, the model was proven to be sufficiently accurate and suitable for further bioequivalence tests. Based on the bioequivalence test, 114 mg/101.3 cm2–146 mg/129.8 cm2 of donepezil patch per week was equivalent to 10 mg PO donepezil per day. In conclusion, the pharmacokinetic model was successfully developed, and acceptable parameters were estimated. However, the size calculated by an equivalent dose of donepezil patch could be rather large. Further optimization in formulation needs to be performed to find appropriate usability in clinical situations. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

16 pages, 1175 KiB  
Article
Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients
by Femke de Velde, Brenda C. M. de Winter, Michael N. Neely, Jan Strojil, Walter M. Yamada, Stephan Harbarth, Angela Huttner, Teun van Gelder, Birgit C. P. Koch, Anouk E. Muller and on behalf of the COMBACTE-NET Consortium
Pharmaceutics 2021, 13(12), 2170; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122170 - 16 Dec 2021
Cited by 2 | Viewed by 2233
Abstract
Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients [...] Read more.
Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

13 pages, 2023 KiB  
Article
Development of a Model-Informed Dosing Tool to Optimise Initial Antibiotic Dosing—A Translational Example for Intensive Care Units
by Ferdinand Anton Weinelt, Miriam Songa Stegemann, Anja Theloe, Frieder Pfäfflin, Stephan Achterberg, Lisa Schmitt, Wilhelm Huisinga, Robin Michelet, Stefanie Hennig and Charlotte Kloft
Pharmaceutics 2021, 13(12), 2128; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122128 - 10 Dec 2021
Cited by 3 | Viewed by 2630
Abstract
The prevalence and mortality rates of severe infections are high in intensive care units (ICUs). At the same time, the high pharmacokinetic variability observed in ICU patients increases the risk of inadequate antibiotic drug exposure. Therefore, dosing tailored to specific patient characteristics has [...] Read more.
The prevalence and mortality rates of severe infections are high in intensive care units (ICUs). At the same time, the high pharmacokinetic variability observed in ICU patients increases the risk of inadequate antibiotic drug exposure. Therefore, dosing tailored to specific patient characteristics has a high potential to improve outcomes in this vulnerable patient population. This study aimed to develop a tabular dosing decision tool for initial therapy of meropenem integrating hospital-specific, thus far unexploited pathogen susceptibility information. An appropriate meropenem pharmacokinetic model was selected from the literature and evaluated using clinical data. Probability of target attainment (PTA) analysis was conducted for clinically interesting dosing regimens. To inform dosing prior to pathogen identification, the local pathogen-independent mean fraction of response (LPIFR) was calculated based on the observed minimum inhibitory concentrations distribution in the hospital. A simple, tabular, model-informed dosing decision tool was developed for initial meropenem therapy. Dosing recommendations achieving PTA > 90% or LPIFR > 90% for patients with different creatinine clearances were integrated. Based on the experiences during the development process, a generalised workflow for the development of tabular dosing decision tools was derived. The proposed workflow can support the development of model-informed dosing tools for initial therapy of various drugs and hospital-specific conditions. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

18 pages, 977 KiB  
Article
Pseudomonas aeruginosa Susceptibility in Spain: Antimicrobial Activity and Resistance Suppression Evaluation by PK/PD Analysis
by Ana Valero, Alicia Rodríguez-Gascón, Arantxa Isla, Helena Barrasa, Ester del Barrio-Tofiño, Antonio Oliver, Andrés Canut and María Ángeles Solinís
Pharmaceutics 2021, 13(11), 1899; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111899 - 08 Nov 2021
Cited by 8 | Viewed by 2472
Abstract
Pseudomonas aeruginosa remains one of the major causes of healthcare-associated infection in Europe; in 2019, 12.5% of invasive isolates of P. aeruginosa in Spain presented combined resistance to ≥3 antimicrobial groups. The Spanish nationwide survey on P. aeruginosa antimicrobial resistance mechanisms and molecular [...] Read more.
Pseudomonas aeruginosa remains one of the major causes of healthcare-associated infection in Europe; in 2019, 12.5% of invasive isolates of P. aeruginosa in Spain presented combined resistance to ≥3 antimicrobial groups. The Spanish nationwide survey on P. aeruginosa antimicrobial resistance mechanisms and molecular epidemiology was published in 2019. Based on the information from this survey, the objective of this work was to analyze the overall antimicrobial activity of the antipseudomonal antibiotics considering pharmacokinetic/pharmacodynamic (PK/PD) analysis. The role of PK/PD to prevent or minimize resistance emergence was also evaluated. A 10,000-subject Monte Carlo simulation was executed to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) considering the minimum inhibitory concentration (MIC) distribution of bacteria isolated in ICU or medical wards, and distinguishing between sample types (respiratory and non-respiratory). Ceftazidime/avibactam followed by ceftolozane/tazobactam and colistin, categorized as the Reserve by the Access, Watch, Reserve (AWaRe) classification of the World Health Organization, were the most active antimicrobials, with differences depending on the admission service, sample type, and dose regimen. Discrepancies between EUCAST-susceptibility breakpoints for P. aeruginosa and those estimated by PK/PD analysis were detected. Only standard doses of ceftazidime/avibactam and ceftolozane/tazobactam provided drug concentrations associated with resistance suppression. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

16 pages, 2812 KiB  
Article
Population Pharmacokinetics of Meropenem in Critically Ill Korean Patients and Effects of Extracorporeal Membrane Oxygenation
by Dong-Hwan Lee, Hyoung-Soo Kim, Sunghoon Park, Hwan-il Kim, Sun-Hee Lee and Yong-Kyun Kim
Pharmaceutics 2021, 13(11), 1861; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111861 - 04 Nov 2021
Cited by 5 | Viewed by 1752
Abstract
Limited studies have investigated population pharmacokinetic (PK) models and optimal dosage regimens of meropenem for critically ill adult patients using the probability of target attainment, including patients receiving extracorporeal membrane oxygenation (ECMO). A population PK analysis was conducted using non-linear mixed-effect modeling. Monte [...] Read more.
Limited studies have investigated population pharmacokinetic (PK) models and optimal dosage regimens of meropenem for critically ill adult patients using the probability of target attainment, including patients receiving extracorporeal membrane oxygenation (ECMO). A population PK analysis was conducted using non-linear mixed-effect modeling. Monte Carlo simulation was used to determine for how long the free drug concentration was above the minimum inhibitory concentration (MIC) at steady state conditions in patients with various degrees of renal function. Meropenem PK in critically ill patients was described using a two-compartment model, in which glomerular filtration rate was identified as a covariate for clearance. ECMO did not affect meropenem PK. The simulation results showed that the current meropenem dosing regimen would be sufficient for attaining 40%fT>MIC for Pseudomonas aeruginosa at MIC ≤ 4 mg/L. Prolonged infusion over 3 h or a high-dosage regimen of 2 g/8 h was needed for MIC > 2 mg/L or in patients with augmented renal clearance, for a target of 100%fT>MIC or 100%fT>4XMIC. Our study suggests that clinicians should consider prolonged infusion or a high-dosage regimen of meropenem, particularly when treating critically ill patients with augmented renal clearance or those infected with pathogens with decreased in vitro susceptibility, regardless of ECMO support. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

12 pages, 1900 KiB  
Article
In Vitro Pharmacokinetic/Pharmacodynamic Modelling and Simulation of Amphotericin B against Candida auris
by Unai Caballero, Elena Eraso, Javier Pemán, Guillermo Quindós, Valvanera Vozmediano, Stephan Schmidt and Nerea Jauregizar
Pharmaceutics 2021, 13(11), 1767; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111767 - 22 Oct 2021
Cited by 5 | Viewed by 2025
Abstract
The aims of this study were to characterize the antifungal activity of amphotericin B against Candida auris in a static in vitro system and to evaluate different dosing schedules and MIC scenarios by means of semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation. A two-compartment [...] Read more.
The aims of this study were to characterize the antifungal activity of amphotericin B against Candida auris in a static in vitro system and to evaluate different dosing schedules and MIC scenarios by means of semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation. A two-compartment model consisting of a drug-susceptible and a drug-resistant subpopulation successfully characterized the time-kill data and a modified Emax sigmoidal model best described the effect of the drug. The model incorporated growth rate constants for both subpopulations, a death rate constant and a transfer constant between both compartments. Additionally, the model included a parameter to account for the delay in growth in the absence or presence of the drug. Amphotericin B displayed a concentration-dependent fungicidal activity. The developed PK/PD model was able to characterize properly the antifungal activity of amphotericin B against C. auris. Finally, simulation analysis revealed that none of the simulated standard dosing scenarios of 0.6, 1 and 1.5 mg/kg/day over a week treatment showed successful activity against C. auris infection. Simulations also pointed out that an MIC of 1 mg/L would be linked to treatment failure for C. auris invasive infections and therefore, the resistance rate to amphotericin B may be higher than previously reported. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

14 pages, 2169 KiB  
Article
Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients
by Alexandre Le Marouille, Emma Petit, Courèche Kaderbhaï, Isabelle Desmoulins, Audrey Hennequin, Didier Mayeur, Jean-David Fumet, Sylvain Ladoire, Zoé Tharin, Siavoshe Ayati, Silvia Ilie, Bernard Royer and Antonin Schmitt
Pharmaceutics 2021, 13(10), 1708; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101708 - 16 Oct 2021
Cited by 8 | Viewed by 2643
Abstract
Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic [...] Read more.
Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h−1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 µg/L. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

15 pages, 1609 KiB  
Article
Molecular Epidemiology, Antimicrobial Surveillance, and PK/PD Analysis to Guide the Treatment of Neisseria gonorrhoeae Infections
by Rodrigo Alonso, Ainara Rodríguez-Achaerandio, Amaia Aguirre-Quiñonero, Aitor Artetxe, Ilargi Martínez-Ballesteros, Alicia Rodríguez-Gascón, Javier Garaizar and Andrés Canut
Pharmaceutics 2021, 13(10), 1699; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101699 - 15 Oct 2021
Cited by 6 | Viewed by 1921
Abstract
The aim of this study was to apply molecular epidemiology, antimicrobial surveillance, and PK/PD analysis to guide the antimicrobial treatment of gonococci infections in a region of the north of Spain. Antibiotic susceptibility testing was performed on all isolates (2017 to 2019, n [...] Read more.
The aim of this study was to apply molecular epidemiology, antimicrobial surveillance, and PK/PD analysis to guide the antimicrobial treatment of gonococci infections in a region of the north of Spain. Antibiotic susceptibility testing was performed on all isolates (2017 to 2019, n = 202). A subset of 35 isolates intermediate or resistant to at least two antimicrobials were selected to search for resistance genes and genotyping through WGS. By Monte Carlo simulation, we estimated the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the antimicrobials used to treat gonorrhea, both indicative of the probability of treatment success. In total, 2.0%, 6.4%, 5.4%, and 48.2% of the isolates were resistant to ceftriaxone, cefixime, azithromycin, and ciprofloxacin, respectively. Twenty sequence types were identified. Detected mutations were related to antibiotic resistance. PK/PD analysis showed high probability of treatment success of the cephalosporins. In conclusion, multiple populations of N. gonorrhoeae were identified. We can confirm that ceftriaxone (even at the lowest dose: 250 mg) and oral cefixime are good candidates to treat gonorrhea. For patients allergic to cephalosporins, ciprofloxacin should be only used if the MIC is known and ≤0.125 mg/L; this antimicrobial is not recommended for empirical treatment. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

14 pages, 1866 KiB  
Article
Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function
by Idoia Bilbao-Meseguer, Helena Barrasa, Eduardo Asín-Prieto, Ana Alarcia-Lacalle, Alicia Rodríguez-Gascón, Javier Maynar, José Ángel Sánchez-Izquierdo, Goiatz Balziskueta, María Sánchez-Bayton Griffith, Nerea Quilez Trasobares, María Ángeles Solinís and Arantxa Isla
Pharmaceutics 2021, 13(10), 1690; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101690 - 15 Oct 2021
Cited by 11 | Viewed by 2662
Abstract
Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and [...] Read more.
Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

11 pages, 942 KiB  
Article
Model-Informed Precision Dosing during Infliximab Induction Therapy Reduces Variability in Exposure and Endoscopic Improvement between Patients with Ulcerative Colitis
by Ruben Faelens, Zhigang Wang, Thomas Bouillon, Paul Declerck, Marc Ferrante, Séverine Vermeire and Erwin Dreesen
Pharmaceutics 2021, 13(10), 1623; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101623 - 06 Oct 2021
Cited by 4 | Viewed by 2289
Abstract
Model-informed precision dosing (MIPD) may be a solution to therapeutic failure of infliximab for patients with ulcerative colitis (UC), as underexposure could be avoided, and the probability of endoscopic improvement (pEI; Mayo endoscopic subscore ≤ 1) could be optimized. To investigate in silico [...] Read more.
Model-informed precision dosing (MIPD) may be a solution to therapeutic failure of infliximab for patients with ulcerative colitis (UC), as underexposure could be avoided, and the probability of endoscopic improvement (pEI; Mayo endoscopic subscore ≤ 1) could be optimized. To investigate in silico whether this claim has merit, four induction dosing regimens were simulated: 5 mg/kg (label dosing), 10 mg/kg, covariate-based MIPD (fat-free mass, corticosteroid use, and presence of extensive colitis at baseline), and concentration-based MIPD (based on the trough concentration at day 14). Covariate- and concentration-based MIPD were chosen to target the same median area under the infliximab concentration-time curve up to endoscopy at day 84 (AUCd84), as was predicted from 10 mg/kg dosing. Dosing at 5 mg/kg resulted in a mean ± standard deviation pEI of 55.7 ± 9.0%. Increasing the dose to 10 mg/kg was predicted to improve pEI to 65.1 ± 6.1%. Covariate-based MIPD reduced variability in exposure and pEI (65.1 ± 5.5%). Concentration-based MIPD decreased variability further (66.0 ± 3.9%) but did so at an increased average dose of 2293 mg per patient, as compared to 2168 mg for 10 mg/kg dosing. Mean pEI remained unchanged between 10 mg/kg dosing and MIPD, since the same median AUCd84 was targeted. In conclusion, quantitative simulations predict MIPD will reduce variability in exposure and pEI between patients with UC during infliximab induction therapy. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

16 pages, 1225 KiB  
Article
Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model
by Jurij Aguiar Zdovc, Jurij Hanžel, Tina Kurent, Nejc Sever, Matic Koželj, Nataša Smrekar, Gregor Novak, Borut Štabuc, Erwin Dreesen, Debby Thomas, Tomaž Vovk, Barbara Ostanek, David Drobne and Iztok Grabnar
Pharmaceutics 2021, 13(10), 1587; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101587 - 30 Sep 2021
Cited by 8 | Viewed by 3104
Abstract
Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate [...] Read more.
Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Graphical abstract

21 pages, 963 KiB  
Article
External Model Performance Evaluation of Twelve Infliximab Population Pharmacokinetic Models in Patients with Inflammatory Bowel Disease
by Christina Schräpel, Lukas Kovar, Dominik Selzer, Ute Hofmann, Florian Tran, Walter Reinisch, Matthias Schwab and Thorsten Lehr
Pharmaceutics 2021, 13(9), 1368; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091368 - 31 Aug 2021
Cited by 13 | Viewed by 2918
Abstract
Infliximab is approved for treatment of various chronic inflammatory diseases including inflammatory bowel disease (IBD). However, high variability in infliximab trough levels has been associated with diverse response rates. Model-informed precision dosing (MIPD) with population pharmacokinetic models could help to individualize infliximab dosing [...] Read more.
Infliximab is approved for treatment of various chronic inflammatory diseases including inflammatory bowel disease (IBD). However, high variability in infliximab trough levels has been associated with diverse response rates. Model-informed precision dosing (MIPD) with population pharmacokinetic models could help to individualize infliximab dosing regimens and improve therapy. The aim of this study was to evaluate the predictive performance of published infliximab population pharmacokinetic models for IBD patients with an external data set. The data set consisted of 105 IBD patients with 336 infliximab concentrations. Literature review identified 12 published models eligible for external evaluation. Model performance was evaluated with goodness-of-fit plots, prediction- and variability-corrected visual predictive checks (pvcVPCs) and quantitative measures. For anti-drug antibody (ADA)-negative patients, model accuracy decreased for predictions > 6 months, while bias did not increase. In general, predictions for patients developing ADA were less accurate for all models investigated. Two models with the highest classification accuracy identified necessary dose escalations (for trough concentrations < 5 µg/mL) in 88% of cases. In summary, population pharmacokinetic modeling can be used to individualize infliximab dosing and thereby help to prevent infliximab trough concentrations dropping below the target trough concentration. However, predictions of infliximab concentrations for patients developing ADA remain challenging. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

15 pages, 1290 KiB  
Article
Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease
by Silvia Marquez-Megias, Amelia Ramon-Lopez, Patricio Más-Serrano, Marcos Diaz-Gonzalez, Maria Remedios Candela-Boix and Ricardo Nalda-Molina
Pharmaceutics 2021, 13(8), 1244; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13081244 - 12 Aug 2021
Cited by 5 | Viewed by 2378
Abstract
Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to [...] Read more.
Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

14 pages, 1144 KiB  
Article
No Time Dependence of Ciprofloxacin Pharmacokinetics in Critically Ill Adults: Comparison of Individual and Population Analyses
by Martin Šíma, Danica Michaličková, Pavel Ryšánek, Petra Cihlářová, Martin Kuchař, Daniela Lžičařová, Jan Beroušek, Jan Miroslav Hartinger, Tomáš Vymazal and Ondřej Slanař
Pharmaceutics 2021, 13(8), 1156; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13081156 - 27 Jul 2021
Cited by 6 | Viewed by 1959
Abstract
The aim of this prospective PK study was to evaluate the pharmacokinetics of ciprofloxacin dosed within the first 36 h (early phase) and after 3 days of treatment (delayed phase) using individual and population PK analysis. The secondary aim of the study was [...] Read more.
The aim of this prospective PK study was to evaluate the pharmacokinetics of ciprofloxacin dosed within the first 36 h (early phase) and after 3 days of treatment (delayed phase) using individual and population PK analysis. The secondary aim of the study was to evaluate possible dosing implications of the observed PK differences between early and delayed phases to achieve a PK/PD target for ciprofloxacin of AUC24/MIC ≥ 125. Blood concentrations of ciprofloxacin (1 and 4 h after dose and trough) were monitored in critically ill adults in the early and delayed phases of the treatment. Individual and population PK analyses were performed. Complete concentration-time profiles in the early phase, delayed phase, and both phases were obtained from 29, 15, and 14 patients, respectively. No systematic changes in ciprofloxacin PK parameters between the early and delayed phases were observed, although variability was higher at the early phase. Both individual and population analyses provided similar results. Simulations showed that after standard dosing, it is practically impossible to reach the recommended ciprofloxacin PK/PD target (AUC/MIC ≥ 125) for pathogens with MIC ≥ 0.5 mg/L. A dosing nomogram utilizing patients’ creatinine clearance and MIC values was constructed. Both individual and population analyses provided similar results. Therapeutic drug monitoring should be implemented to safeguard the optimal ciprofloxacin exposure. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Figure 1

Review

Jump to: Editorial, Research

19 pages, 404 KiB  
Review
Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics
by Francisco José Toja-Camba, Nerea Gesto-Antelo, Olalla Maroñas, Eduardo Echarri Arrieta, Irene Zarra-Ferro, Miguel González-Barcia, Enrique Bandín-Vilar, Victor Mangas Sanjuan, Fernando Facal, Manuel Arrojo Romero, Angel Carracedo, Cristina Mondelo-García and Anxo Fernández-Ferreiro
Pharmaceutics 2021, 13(7), 935; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13070935 - 23 Jun 2021
Cited by 14 | Viewed by 4976
Abstract
Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due [...] Read more.
Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
►▼ Show Figures

Graphical abstract

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-21
Back to TopTop