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Pharmaceuticals
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Population Pharmacokinetics and Pharmacogenetics
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Population Pharmacokinetics and Pharmacogenetics

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 10 December 2025 | Viewed by 11654

Special Issue Editor

Dr. Seung-Hyun Jeong

E-Mail Website
Guest Editor
College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon-si 57922, Jeollanam-do, Republic of Korea
Interests: pharmacokinetics; pharmacodynamics; toxicometrics; risk assessment; physiologically based modeling; lymphatic delivery; nanoformulation and evaluation; bioanalytical method development and validation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The approach to precision medicine that minimizes the side effects of drugs and maximizes their effectiveness has been a scientific challenge that has persisted for a long time. To realize precision medicine, pharmacometric studies have been actively progressing recently, and in particular, various attempts are being made to quantitatively interpret pharmacokinetic variability between individuals. Interpretations of pharmacokinetic variability between individuals can be approached in relation to various physiological, biochemical, and genetic factors, and the new discovery of valid covariates is greatly helping to visualize the possibility of precision medicine.

This Special Issue focuses on mathematical modeling related to the discovery of effective covariates, population pharmacodynamic modeling, and genetic polymorphism in the interpretation of pharmacokinetic variability between individuals. Therefore, pharmacokinetics, pharmacodynamics, in vivo drug quantification, and genetic polymorphism studies (such as enzymes or transporters involved in drug absorption, distribution, metabolism, and excretion) for precision medicine and individualized pharmacotherapy settings will be suitable for the scope of this Special Issue . In addition, studies on predicting drug behavior and efficacy in the body through mathematical modeling, exploring clinical usage based on models, and exploring effective covariates to explain the diversity of pharmacokinetics and pharmacodynamics among individuals will be very welcome. Finally, it is expected that a great deal of useful and interesting research information for the realization of precision medicine will be introduced in this Special Issue.

Dr. Seung-Hyun Jeong
Guest Editor

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Keywords

  • pharmacokinetics
  • pharmacogenetics
  • precision medicine
  • population pharmacometrics model
  • mathematical modeling
  • dosage regimen
  • inter-subject variability

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Published Papers (8 papers)

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33 pages, 8713 KB  
Article
A Systematic Review and Meta-Analysis of Doxazosin Pharmacokinetics in Healthy and Diseased Populations
by Dania Fatima, Mohammed S. Alasmari, Yousef Alshomrani, Ammara Zamir, Faleh Alqahtani, Iltaf Hussain and Muhammad Fawad Rasool
Pharmaceuticals 2025, 18(12), 1825; https://doi.org/10.3390/ph18121825 - 29 Nov 2025
Viewed by 70
Abstract
Background: Doxazosin, an α1-adrenergic antagonist, is commonly used in the management of hypertension and benign prostatic hyperplasia (BPH). Pharmacokinetic (PK) variability across populations may affect drug exposure and clinical response. This systematic review and meta-analysis aimed to summarize PK differences and [...] Read more.
Background: Doxazosin, an α1-adrenergic antagonist, is commonly used in the management of hypertension and benign prostatic hyperplasia (BPH). Pharmacokinetic (PK) variability across populations may affect drug exposure and clinical response. This systematic review and meta-analysis aimed to summarize PK differences and generate pooled estimates of key parameters, including area under the curve (AUC) and maximum plasma concentration (Cmax). Methods: A systematic search of Google Scholar, PubMed, ScienceDirect, and the Cochrane Library identified 25 eligible studies reporting doxazosin PK data. All extracted AUC and Cmax values were dose-normalized prior to synthesis to ensure comparability across different doses and formulations. A random-effects meta-analysis was performed using the metafor package in R to estimate pooled dose-normalized AUC and Cmax while accounting for between-study variability. Heterogeneity was assessed using the I2 statistic. Sensitivity analyses—including leave-one-out diagnostics and Baujat plots—were used to identify influential studies. Publication bias and small-study effects were evaluated through funnel plots, trim-and-fill procedures, and Egger’s regression test. Meta-regression analyses examined the influence of age and body weight on PK parameters. Results: The meta-analysis produced pooled dose-normalized estimates for AUC and Cmax, with high heterogeneity across studies (I2 ≈ 90%). Leave-one-out analyses demonstrated stable pooled estimates; for dose-normalized AUC, exclusion of three influential studies reduced heterogeneity to 82% with only a modest decrease in the pooled mean. Baujat plots identified a small number of studies as key contributors to heterogeneity, while most exerted minimal influence. Funnel plots showed notable asymmetry for both AUC and Cmax, and trim-and-fill analyses suggested possible small-study effects; however, adjusted pooled estimates remained consistent. Egger’s regression confirmed significant asymmetry for dose-normalized AUC (t = 4.41, p = 0.0003) and Cmax (t = 4.35, p = 0.0001). Meta-regression revealed that body weight significantly reduced Cmax, whereas age had no significant effect on either AUC or Cmax. Conclusions: This systematic review and meta-analysis provide a comprehensive evaluation of doxazosin PK across diverse populations. Despite normalization, substantial variability remained in AUC and Cmax, related in part to ethnicity, hepatic impairment, dosage formulation, and body weight. While pooled estimates offer valuable summary reference points, the high heterogeneity and evidence of small-study effects highlight the need for more standardized PK trials and patient-level analyses to better support individualized dosing strategies. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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15 pages, 845 KB  
Article
Population Pharmacokinetics of Radotinib in Healthy Volunteers and Patients with Chronic Myeloid Leukemia
by Minseo Kang, Jiwon Kim, Yerin Lee, Jae Soo Shin, Min Soo Park, Qian Jiang, Eun Kyoung Chung and Jangik I. Lee
Pharmaceuticals 2025, 18(11), 1705; https://doi.org/10.3390/ph18111705 - 10 Nov 2025
Viewed by 438
Abstract
Background/Objectives: Radotinib is a second-generation tyrosine kinase inhibitor (TKI) that has been used for treatment of chronic myeloid leukemia (CML). This study was performed for the first time to characterize the pharmacokinetics of radotinib, identify the factors contributing to pharmacokinetic variabilities and [...] Read more.
Background/Objectives: Radotinib is a second-generation tyrosine kinase inhibitor (TKI) that has been used for treatment of chronic myeloid leukemia (CML). This study was performed for the first time to characterize the pharmacokinetics of radotinib, identify the factors contributing to pharmacokinetic variabilities and explore alternative dosing regimens. Methods: A total of 640 plasma concentration–time datapoints obtained from 47 participants were evaluated using nonlinear mixed-effects modeling to estimate pharmacokinetic parameters and evaluate covariate effects. The study population comprised 23 healthy volunteers (HVs) who received a single, oral dose of 400 mg radotinib and 24 CML patients who repeatedly received 300 mg twice daily. Based on the final population pharmacokinetic model, alternative dosing regimens to the current every 12 h regimen were explored using Monte Carlo simulations. Results: A two-compartment model with first-order absorption through transit compartments and first-order elimination incorporating a circadian rhythm effect best described radotinib pharmacokinetics. Disease status significantly affected apparent clearance; it was slower by 39.2% in CML patients compared with HVs (23.0 L/h versus 37.9 L/h), resulting in a longer terminal half-life (28.8 h versus 17.5 h). Age was negatively associated with volume of distribution in the central compartment, with an estimated slope of −0.0129 L/year. A 400 mg once-daily regimen was predicted to provide comparable systemic exposures to those of other TKIs with similar physiochemical and pharmacological properties to radotinib, and a 36% lower exposure than that of the current 300 mg twice-daily regimen. Conclusions: The model developed in this study adequately describes the population pharmacokinetics of radotinib and provides a basis for optimal, individualized radotinib therapy for patients with CML. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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12 pages, 1107 KB  
Article
The Effects of Ritonavir on the Pharmacokinetics of Tofacitinib in Rats
by Sung-yoon Yang, Hyunjung Lee, Tham Thi Bui, Quyen Thi Tran, Lien Thi Ngo, Hwi-yeol Yun, Sangkeun Jung and Jung-woo Chae
Pharmaceuticals 2025, 18(10), 1561; https://doi.org/10.3390/ph18101561 - 16 Oct 2025
Viewed by 573
Abstract
Background and Objective: Tofacitinib (TOF), an oral Janus kinase inhibitor used to treat rheumatoid arthritis (RA), is extensively metabolized by cytochrome P450 (CYP) 3A4. Ritonavir (RTV), a protease inhibitor, is commonly used as a pharmacokinetic (PK) enhancer due to its potent CYP3A4 [...] Read more.
Background and Objective: Tofacitinib (TOF), an oral Janus kinase inhibitor used to treat rheumatoid arthritis (RA), is extensively metabolized by cytochrome P450 (CYP) 3A4. Ritonavir (RTV), a protease inhibitor, is commonly used as a pharmacokinetic (PK) enhancer due to its potent CYP3A4 inhibitory effects. Considering the prevalence of comorbidities in RA patients, it is possible to use TOF and RTV concurrently, raising concerns about potential drug–drug interactions (DDIs). The current study aims to assess the potential DDIs between RTV and TOF. Methods: An in vivo rat study was conducted to investigate the impacts of RTV on the PK of TOF. Rats were randomly divided into three groups: vehicle, RTV 10 mg/kg, and RTV 20 mg/kg, each undergoing four days of pretreatment. On the test day, TOF (10 mg/kg) was administered following co-administration of the respective RTV doses. Blood samples were collected at the pre-specified time points. Plasma concentrations of TOF were quantified using liquid chromatography coupled with mass spectrometry, and PK parameters were analyzed using non-compartmental analysis. Results: RTV (10 and 20 mg/kg) increased the area under the curve of TOF by 2.53-fold (95% CI: 1.64–3.43) and 5.39-fold (95% CI: 4.47–6.33), respectively, and the maximum concentration by 1.47-fold (95% CI: 0.99–2.00) and 2.86-fold (95% CI: 2.39–3.37), respectively. Whereas the half-life (t1/2) remained unchanged. Conclusions: RTV substantially increased TOF exposure in rats. These results suggest the need for dose adjustments of TOF during co-administration with RTV in clinical settings. Further clinical research is needed to confirm these findings. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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14 pages, 1249 KB  
Article
Model-Based Evaluation of HangAmDan-B1 and Afatinib Combination Therapy in HCC827 Xenograft Mice with Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
by Sung-yoon Yang, Lien Thi Ngo, Soyoung Lee, Hwi-yeol Yun, Tham Thi Bui, Dong-Hyeon Kim, Jung-woo Chae and Sojung Park
Pharmaceuticals 2025, 18(5), 748; https://doi.org/10.3390/ph18050748 - 19 May 2025
Viewed by 1354
Abstract
Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to [...] Read more.
Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to quantitatively examine the exposure–response relationship and synergistic interactions through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: A PK/PD model was established and validated based on tumor growth profiles from a xenograft mouse study of gefitinib-resistant HCC827. Model-based simulations were performed to predict and assess therapeutic effects across different treatment groups. Results: The PK/PD model confirmed HAD-B1 enhances the potency of AFT by 1.45-fold. Model-based simulations predicted that combination treatment maintains a lower tumor size compared to AFT monotherapy. Conclusions: This study quantitatively demonstrated the synergistic interaction between HAD-B1 and AFT. The developed PK/PD model provides insights into potential dosing strategies to treat NSCLC resistant to EGFR-TKIs. Further clinical trials are warranted to validate these findings and refine dosing strategies to improve therapeutic outcomes. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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11 pages, 1084 KB  
Communication
A Successful Experience of Individualized Vancomycin Dosing in Critically Ill Patients by Using a Loading Dose and Maintenance Dose
by Jorge S. Amador, Álvaro Vega, Patricio Araos, Luis A. Quiñones and Cristián A. Amador
Pharmaceuticals 2025, 18(5), 677; https://doi.org/10.3390/ph18050677 - 2 May 2025
Viewed by 1962
Abstract
Background/Objective: Vancomycin, a hydrophilic glycopeptide antibiotic with bactericidal activity against Gram-positive microorganisms, is one of the most commonly used antibiotics un the intensive care unit (ICU). Different efforts have been made to achieve a therapeutically effective plasma concentration of vancomycin by using loading [...] Read more.
Background/Objective: Vancomycin, a hydrophilic glycopeptide antibiotic with bactericidal activity against Gram-positive microorganisms, is one of the most commonly used antibiotics un the intensive care unit (ICU). Different efforts have been made to achieve a therapeutically effective plasma concentration of vancomycin by using loading and subsequent maintenance doses on an individual basis, but this remains subject to debate. Our objective was to individualize a dosage regimen in a Chilean ICU to optimize the pharmacological treatment of vancomycin by using a population pharmacokinetic model. Methods: A quantitative descriptive study was carried out in 51 patients at the adult ICU, San Borja Arriarán Clinical Hospital in Santiago, Chile. The dose of vancomycin was calculated by using a population pharmacokinetic software, the Antibiotic Kinetics®, and was subsequently validated with plasma trough levels of the drug through a patient sample. Results: The most commonly prescribed loading dose was 1500 mg and the most commonly used maintenance dose was 1000 mg, three times a day. The measured blood plasma concentrations of each patient (16.98 ± 5.423 μg/mL) were compared with the concentrations calculated through the population pharmacokinetic model (14.33 ± 4.630 μg/mL, p < 0.05). In addition, a correlation was found between the software-calculated trough concentration versus the measured trough concentration for vancomycin, with a positive correlation between both variables established (R2 = 0.65; p < 0.0001). No renal side effects were observed in the treated patient group. Conclusions: In the present study, a vancomycin dosing model for critically ill patients, based on a population pharmacokinetic model, was successfully implemented for routine clinical practice. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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17 pages, 3974 KB  
Article
Development of a Population Pharmacokinetic Model of Levofloxacin in Healthy Adults and Identification of Optimal Dosing Regimens
by Yun-Jung Lee, Gaeun Kang, Dae-Young Zang and Dong-Hwan Lee
Pharmaceuticals 2025, 18(5), 621; https://doi.org/10.3390/ph18050621 - 25 Apr 2025
Viewed by 1682
Abstract
Background/Objectives: Levofloxacin dosing guidelines recommend adjustments only when the creatinine clearance (CrCl) is <50 mL/min. We hypothesized that further dose stratification based on CrCl could improve therapeutic outcomes, even when the CrCl ≥ 50 mL/min. This study aimed to develop a population [...] Read more.
Background/Objectives: Levofloxacin dosing guidelines recommend adjustments only when the creatinine clearance (CrCl) is <50 mL/min. We hypothesized that further dose stratification based on CrCl could improve therapeutic outcomes, even when the CrCl ≥ 50 mL/min. This study aimed to develop a population pharmacokinetic (PK) model of levofloxacin in healthy adults and identify optimal dosing regimens. Methods: In this prospective, open-label study, 12 healthy adults received a single dose of levofloxacin. Plasma concentrations were measured using liquid chromatography–tandem mass spectrometry. A population PK model was developed with nonlinear mixed-effects modeling, and Monte Carlo simulations were performed to identify optimal dosing regimens. Results: A two-compartment model with first-order kinetics best described the levofloxacin PK profiles. The CrCl was associated with a variation in clearance and lean body mass, with a variation in peripheral volume of distribution. Simulations identified optimal regimens, defined as those achieving a probability of target attainment of at least 90% for the target unbound 24-hour area under the curve at steady state to minimum inhibitory concentration ratio (fAUC/MIC), which differed by pathogen (≥30 for Gram-positive bacteria; ≥100 for Gram-negative bacteria). For the ratio fAUC/MIC ≥ 30 and an MIC of 0.5 mg/L, 500 mg daily was optimal for patients with a CrCl of 50–89 mL/min. For the ratio fAUC/MIC ≥ 100, 1000 mg daily was required in the same CrCl range and MIC value. Conclusions: The population PK model incorporating CrCl and lean body mass improved the prediction of levofloxacin PKs. Refining current dosing recommendations by incorporating stratified CrCl and MIC values could optimize therapeutic outcomes, particularly for patients with a CrCl ≥ 50 mL/min. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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25 pages, 6309 KB  
Systematic Review
Population Pharmacokinetics of Risperidone and Paliperidone in Schizophrenia: A Systematic Review
by Ana Carrascosa-Arteaga, Ricardo Nalda-Molina, Patricio Más-Serrano and Amelia Ramon-Lopez
Pharmaceuticals 2025, 18(5), 698; https://doi.org/10.3390/ph18050698 - 8 May 2025
Cited by 1 | Viewed by 4002
Abstract
Background: The primary treatment of schizophrenia is pharmacotherapy with antipsychotic agents, such as risperidone and paliperidone. Population pharmacokinetic (PopPK) modelling plays a crucial role in optimising therapy by predicting of plasma concentrations, therapeutic efficacy, and the risk of adverse effects using model informed [...] Read more.
Background: The primary treatment of schizophrenia is pharmacotherapy with antipsychotic agents, such as risperidone and paliperidone. Population pharmacokinetic (PopPK) modelling plays a crucial role in optimising therapy by predicting of plasma concentrations, therapeutic efficacy, and the risk of adverse effects using model informed precision dosing. Objectives: This systematic review examined the PopPK models of risperidone and paliperidone in patients diagnosed with schizophrenia based on the available scientific evidence. Methods: A systematic review of the health science databases was conducted. The inclusion criteria were original articles published in peer-reviewed journals, studies focusing on the development of original PopPK models of risperidone and paliperidone, and clinical studies. The exclusion criteria were full-text articles that could not be retrieved; studies not including subjects diagnosed with schizophrenia or schizoaffective disorders; and studies that did not investigate risperidone or paliperidone. Results: A total of 19 studies developing PopPK models were analysed, including one- or two-compartment PopPK model structures. Interindividual variability in the pharmacokinetic parameters was shown to be influenced by factors such as CYP2D6 activity, renal function, body mass index, and sex. Parameter estimation revealed high variability in clearance and volume of distribution. Conclusion: Numerous PopPK models for risperidone and paliperidone have been published with a detailed characterisation of absorption, metabolism, and elimination. Therefore, future research should focus on the external validation of these models to facilitate their integration into clinical practice and optimise individualised dosing, ultimately improving treatment efficacy and safety across diverse patient populations. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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11 pages, 1225 KB  
Systematic Review
Exploring the Pharmacokinetics of Drugs in Disabled Saudi Patients: A Systematic Review
by Faleh Alqahtani, Saeed A. Al Awadh and Muhammad Fawad Rasool
Pharmaceuticals 2025, 18(4), 582; https://doi.org/10.3390/ph18040582 - 16 Apr 2025
Viewed by 1171
Abstract
Background/Objectives: Disability is a term that involves mental, intellectual, or sensory impairment resulting in the loss of one’s ability to walk or perform the activities necessary to live in a society. This study aims to collect all the data regarding the absorption, [...] Read more.
Background/Objectives: Disability is a term that involves mental, intellectual, or sensory impairment resulting in the loss of one’s ability to walk or perform the activities necessary to live in a society. This study aims to collect all the data regarding the absorption, distribution, and disposition of drugs in disabled Saudi patients, i.e., patients suffering from epilepsy, cancer, cardiovascular diseases, etc., and then compare these results with data reported in other ethnicities. Methods: An exhaustive online search used the key terms in Google Scholar, PubMed, Cochrane Library, and Science Direct to extract all articles that met the eligibility criteria. All research studies containing pharmacokinetic (PK) parameters (area under the curve from 0 to infinity (AUC0–∞), maximal plasma concentration (Cmax), clearance (CL), volume of distribution, time to reach maximum plasma concentration, and half-life) were included in this review. Results: In pediatric epileptic patients, carbamazepine showed a notable decrease in Cmax with increasing age, which may be due to ontogenetic changes in its disposition. The AUC0–∞ of busulphan in adult hematopoietic stem cell transplantation patients was recorded as 4392.5 ± 1354.65 μg·h/mL, with high inter-individual variability. Moreover, the CL of vancomycin was reported to be 25% higher among cancer patients in comparison to non-cancer subjects. Conclusions: The complications in disabled patients due to alterations in cytochrome P450 enzymes, pathophysiology, genetics, and ethnicity emphasize the significance of patient-centered drug dosing. These findings may aid healthcare physicians in refining therapeutic care in this population. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)
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