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Pharmaceutics
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Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and...
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Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics

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

Deadline for manuscript submissions: closed (20 May 2025) | Viewed by 10312

Special Issue Editor

Dr. Raj Badhan

E-Mail Website
Guest Editor
Aston Pharmacy School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
Interests: pharmacokinetics; PBPK; drug metabolism; drug-drug interactions; modelling and simulation; clinical pharmacy; medicines optimization

Special Issue Information

Dear Colleagues,

I am delighted to announce a Special Issue in Pharmaceutics, titled "Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics". As the Guest Editor, I invite academics specialising in pharmacokinetics to contribute their cutting-edge research to this pivotal edition.

Precision dosing has emerged as a cornerstone in optimising therapeutic outcomes and minimising adverse effects. This Special Issue provides a dedicated platform to showcase advancements in the application of pharmacokinetics and pharmacometrics, unravelling the intricacies of drug disposition and clinical response.

We welcome submissions that explore novel methodologies, technological innovations, and integrative approaches in precision dosing. Whether it be population pharmacokinetics, model-informed precision dosing, or the utilisation of real-world data, we encourage contributions that push the boundaries of knowledge in this critical field.

The goal of this Special Issue is to showcase strong examples of successfully applied pharmacokinetic modelling approaches that support precision dosing and highlight the present status quo and future perspectives of this technology in the field of pharmacometrics.

We look forward to receiving your contributions.

Dr. Raj Badhan
Guest Editor

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

  • pharmacokinetics
  • pharmacometrics
  • PBPK
  • drug–drug interactions
  • pediatrics
  • pregnancy
  • oral bioavailability
  • modelling and simulation
  • population pharmacokinetics

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Published Papers (6 papers)

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13 pages, 900 KiB  
Article
Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study
by Verena Gotta, Chantal Csajka, Antonia Glauser, Christoph Berger, Marc Pfister and Paolo Paioni
Pharmaceutics 2025, 17(5), 544; https://doi.org/10.3390/pharmaceutics17050544 - 22 Apr 2025
Viewed by 215
Abstract
Background: Optimal dosing of cefepime in infants 1–2 months remains undefined. Objectives: We aimed to quantify the risk of potentially neurotoxic exposure with high-dose cefepime (50 mg/kg/8 h) in infants 1–2 months of age, as compared to adjacent age groups (neonates, infants [...] Read more.
Background: Optimal dosing of cefepime in infants 1–2 months remains undefined. Objectives: We aimed to quantify the risk of potentially neurotoxic exposure with high-dose cefepime (50 mg/kg/8 h) in infants 1–2 months of age, as compared to adjacent age groups (neonates, infants 2–12 months) and lower dose treatment (50 mg/kg/12 h). Methods: Pharmacometric simulations were performed using two published population pharmacokinetic models combined with demographic data, including serum creatinine, for neonates and infants ≤ 12 months. Adult-derived safety thresholds for potential neurotoxicity were defined as steady-state trough concentration (Ctrough) > 20 or > 35 mg/L, respectively. The corresponding probability of target attainment (PTA) was calculated as free concentration, 50% of the time during the dosing interval above the minimal inhibitory concentration (MIC) breakpoint of 8 mg/L (Pseudomonas spp.) (50% fT>MIC8mg/L). Results: The predicted risk of Ctrough > 20 (>35) mg/L under high-dose cefepime was 40–54% (12–22%) in infants 1–2 months while providing high PTA (100%). It was predicted to be 1.3–1.7 fold higher in neonates (model 1), and reduced 1.8–2.4 fold in infants 2–12 months (model 1), or to be similar (model 2), respectively. Both models predicted approximately 2–4 fold reduced risk using lower dose treatments while maintaining high PTA (≥97%). Conclusions: The risk of potential neurotoxic concentrations in infants > 1 month treated with cefepime 50 mg/kg/8 h is high if defined by adult safety thresholds. Lower dose cefepime in infants 1–2 months could be a safe option without compromising PTA, if defined as 50% fT>MIC8mg/L. Achievement of 100% fT>MIC8mg/L may require prolonged infusion time even under high-dose treatment. Future research is required to evaluate potentially age-dependent safety thresholds. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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17 pages, 3329 KiB  
Article
Integration of Ontogeny-Based Changes for Predicting the Exposure of Diphenhydramine in the Pediatric Population: A PBPK Modeling Approach
by Ammara Zamir, Muhammad Fawad Rasool, Faleh Alqahtani, Hussain Alqhtani and Tanveer Ahmad
Pharmaceutics 2024, 16(12), 1553; https://doi.org/10.3390/pharmaceutics16121553 - 4 Dec 2024
Viewed by 1502
Abstract
Background: Diphenhydramine is an anti-tussive used periodically to treat seasonal colds, contact dermatitis, and anaphylactic reactions. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of diphenhydramine in predicting its systemic exposure among healthy pediatrics (children and adolescents) by leveraging data [...] Read more.
Background: Diphenhydramine is an anti-tussive used periodically to treat seasonal colds, contact dermatitis, and anaphylactic reactions. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of diphenhydramine in predicting its systemic exposure among healthy pediatrics (children and adolescents) by leveraging data files from adults (young and elderly). Methods: The data profiles comprising serum/plasma concentration over time and parameters related to diphenhydramine were scrutinized via exhaustive literature analysis and consolidated in the PK-Sim software version 11.1. This modeling methodology commences with developing an adult model and then translating it to the pediatrics which compares the predicted concentration–time datasets with the reported values. Results: The accuracy of model anticipations was then assessed for each pharmacokinetics (PK) variable, i.e., the area under the curve from 0 to infinity (AUC0-∞), maximal serum/plasma concentration (Cmax), and clearance of the diphenhydramine in plasma (CL) by employing the predicted/observed ratios (Rpre/obs), and average fold error (AFE), which fell within the pre-defined benchmark of 2-fold. The predicted and observed Cmax values for pediatrics were 3-fold greater in comparison to the young adults following a 25 mg dose depicting a need to monitor dosage schedules among children closely. Conclusions: These model-based anticipations confirmed the authenticity of the developed pediatric model and enhanced the comprehension of developmental variations on PK of diphenhydramine. This may assist healthcare professionals in ensuring the significance of lifespan applicability in personalized dose regimens, promoting therapeutic efficacy and minimizing side effects in chronic conditions among children. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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20 pages, 3562 KiB  
Article
Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment
by Mohammed S. Alasmari, Faleh Alqahtani, Fawaz Alasmari and Abdullah Alsultan
Pharmaceutics 2024, 16(12), 1540; https://doi.org/10.3390/pharmaceutics16121540 - 1 Dec 2024
Viewed by 1270
Abstract
Background/Objectives: Etrasimod is a newly FDA-approved Sphingosine-1-Phosphate modulator indicated for moderate and severe ulcerative colitis. It is extensively metabolized in the liver via the cytochrome P450 system and may accumulate markedly in patients with hepatic dysfunction, exposing them to toxicity. The aim of [...] Read more.
Background/Objectives: Etrasimod is a newly FDA-approved Sphingosine-1-Phosphate modulator indicated for moderate and severe ulcerative colitis. It is extensively metabolized in the liver via the cytochrome P450 system and may accumulate markedly in patients with hepatic dysfunction, exposing them to toxicity. The aim of the current study is to utilize a physiologically-based pharmacokinetic modeling approach to evaluate the impact of hepatic impairment on the pharmacokinetic behavior of etrasimod and to appropriately select dosage regimens for patients with chronic liver disease; Methods: PK-Sim was used to develop the etrasimod PBPK model, which was verified using clinical data from healthy subjects and subsequently adapted to reflect the physiological changes associated with varying degrees of hepatic dysfunction; Results: Simulations indicated that hepatic clearance of etrasimod is clearly reduced in patients with Child–Pugh B and C liver impairment. Based on these findings, dosing adjustments were proposed to achieve therapeutic exposures equivalent to those in individuals with normal liver function. In the Child–Pugh B and C population groups, 75% and 62.5%, respectively, of the standard dose were enough to have comparable exposure to the healthy population. These adjusted dosages aim to mitigate the risk of drug toxicity while maintaining efficacy; Conclusions: The PBPK model provides a robust framework for individualizing drug therapy in patients with hepatic impairment, ensuring safer and more effective treatment outcomes. Further clinical studies are warranted to verify these dosing recommendations and to refine the model for broader clinical applications. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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16 pages, 3464 KiB  
Article
Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation
by Yong-Kyun Kim, Kyeong-Min Jo, Jae-Ha Lee, Ji-Hoon Jang, Eun-Jun Choe, Gaeun Kang, Dae-Young Zang and Dong-Hwan Lee
Pharmaceutics 2024, 16(4), 499; https://doi.org/10.3390/pharmaceutics16040499 - 5 Apr 2024
Cited by 1 | Viewed by 1818
Abstract
In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK [...] Read more.
In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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30 pages, 6228 KiB  
Article
The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine
by Khairulanwar Burhanuddin, Afzal Mohammed and Raj K. S. Badhan
Pharmaceutics 2024, 16(4), 489; https://doi.org/10.3390/pharmaceutics16040489 - 2 Apr 2024
Cited by 1 | Viewed by 2152
Abstract
The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity [...] Read more.
The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity on amlodipine pharmacokinetics and the need for dose adjustment has not been studied previously. This study applied the physiologically based pharmacokinetic modelling and established a paediatric obesity population to assess the impact of obesity on amlodipine pharmacokinetics in children and explore the possible dose adjustments required to reach the same plasma concentration as non-obese paediatrics. The difference in predicted maximum concentration (Cmax) and area under the curve (AUC) were significant between children with and without obesity across the age group 2 to 18 years old when a fixed-dose regimen was used. On the contrary, a weight-based dose regimen showed no difference in Cmax between obese and non-obese from 2 to 9 years old. Thus, when a fixed-dose regimen is to be administered, a 1.25- to 1.5-fold increase in dose is required in obese children to achieve the same Cmax concentration as non-obese children, specifically for children aged 5 years and above. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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37 pages, 2140 KiB  
Systematic Review
Clinical Pharmacokinetics of Fexofenadine: A Systematic Review
by Maryam Batool, Ammara Zamir, Faleh Alqahtani, Tanveer Ahmad, Hamid Saeed and Muhammad Fawad Rasool
Pharmaceutics 2024, 16(12), 1619; https://doi.org/10.3390/pharmaceutics16121619 - 20 Dec 2024
Cited by 1 | Viewed by 2547
Abstract
Background/Objectives: Fexofenadine hydrochloride is a widely prescribed drug for treating histamine-mediated allergic reactions. This review systematically collates existing research on the clinical pharmacokinetics (PK) of fexofenadine, with a copious emphasis on examining the impact of stereoisomerism, disease states, and drug interactions. Methods: The [...] Read more.
Background/Objectives: Fexofenadine hydrochloride is a widely prescribed drug for treating histamine-mediated allergic reactions. This review systematically collates existing research on the clinical pharmacokinetics (PK) of fexofenadine, with a copious emphasis on examining the impact of stereoisomerism, disease states, and drug interactions. Methods: The search engines PubMed, Science Direct, Google Scholar, and Cochrane were scanned systematically for articles concerning the clinical PK of fexofenadine in humans. The extensive literature search yielded 85 articles meeting the inclusion standards. Results: The PK parameters of fexofenadine showed a linear correlation between increasing doses and proportional elevations in PK parameters such as area under the curve from time 0 to infinity (AUC0–∞) and maximum plasma concentration (Cmax). Under fed conditions, its bioavailability was reduced by approximately 50%. Findings from patients with end-stage renal disease (ESRD) displayed a 63% decline in oral clearance (CL/F) of fexofenadine. A drug–food interaction study has displayed that grapefruit juice decreased Cmax (201 ng/mL vs. 128 ng/mL), accompanied by a 30% reduction in the bioavailability of fexofenadine. Furthermore, a drug–herb interaction study with St John’s Wort (SJW) has reported a reduction in CL/F by 10% after a single dose, but long-term administration reversed this effect, resulting in elevated CL/F by 17% of fexofenadine. Conclusions: Since no prior systematic review on the PK of this drug exists, this review amalgamates all pertinent PK parameters in humans by pooling up-to-date data from published studies. This detailed literature review can be advantageous for researchers who want to develop and assess PK models. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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