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Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 34913

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Dr. Hirofumi Jono

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Department of Pharmacy, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
Interests: molecular oncology; clinical pharmacology; molecular laboratory medicine; clinical pathology; drug discovery

Special Issue Information

Dear Colleagues,

With innovative advancements in science and technology, large numbers of molecular-targeted agents have recently been developed and widely used in clinical settings, especially for cancer treatment. Although cancer treatment has dramatically improved by developing molecular-targeted agents and precision medicine, identifying eligible patients and maximizing their therapeutic effects remain a great challenge.

Efficacy and safety of pharmacotherapies for cancer patients are determined by complex factors including individual differences of each patient, such as genotype, environmental factor, and lifestyle. In clinical settings, therapeutic drug monitoring is carried out by evaluating plasma or blood drug concentrations in response to individual cancer treatment to improve efficacy and avoid side effects. Moreover, genetic polymorphisms are known to be involved in pharmacokinetics, and cause individual differences in clinical efficacy and adverse events. Thus, to improve the therapeutic outcome in cancer therapy, from the aspects of clinical pharmacology, personalized medicine has to be established by the concepts of pharmacokinetics/pharmacodynamics/pharmacogenetics.

This Special Issue will focus on establishing personalized medicine for cancer therapy based on the clinical pharmacological approach, and provide the latest advances and topics in clinical cancer treatment to achieve better medication for cancer patients.

Dr. Hirofumi Jono
Guest Editor

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Keywords

personalized medicine
pharmacokinetics
pharmacodynamics
pharmacogenetics
cancer chemotherapy
molecular targeted agents
clinical toxicology
therapeutic drug monitoring (TDM)
cancer genomic medicine
molecular oncology

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Published Papers (11 papers)

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Research

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17 pages, 4043 KiB

Open AccessArticle

Formulation and Characterization of Poly (Ethylene Glycol)-Coated Core-Shell Methionine Magnetic Nanoparticles as a Carrier for Naproxen Delivery: Growth Inhibition of Cancer Cells

by Faten Eshrati Yeganeh, Amir Eshrati Yeganeh, Mohammad Yousefi, Bahareh Farasati Far, Iman Akbarzadeh, Dmitry Olegovich Bokov, Kaamran Raahemifar and Madjid Soltani

Cancers 2022, 14(7), 1797; https://doi.org/10.3390/cancers14071797 - 1 Apr 2022

Cited by 18 | Viewed by 2780

Abstract

An efficient and selective drug delivery vehicle for cancer cells can remarkably improve therapeutic approaches. In this study, we focused on the synthesis and characterization of magnetic Ni_1−xCo_xFe₂O₄ nanoparticles (NPs) coated with two layers of methionine and polyethylene glycol to increase the loading capacity and lower toxicity to serve as an efficient drug carrier. Ni_1−xCo_xFe₂O₄@Methionine@PEG NPs were synthesized by a reflux method then characterized by FTIR, XRD, FESEM, TEM, and VSM. Naproxen was used as a model drug and its loading and release in the vehicles were evaluated. The results for loading efficiency showed 1 mg of Ni_1−xCo_xFe₂O₄@Methionine@PEG NPs could load 0.51 mg of the naproxen. Interestingly, Ni_1−xCo_xFe₂O₄@Methionine@PEG showed a gradual release of the drug, achieving a time-release up to 5 days, and demonstrated that a pH 5 release of the drug was about 20% higher than Ni_1−xCo_xFe₂O₄@Methionine NPs, which could enhance the intracellular drug release following endocytosis. At pH 7.4, the release of the drug was slower than Ni_1−xCo_xFe₂O₄@Methionine NPs; demonstrating the potential to minimize the adverse effects of anticancer drugs on normal tissues. Moreover, naproxen loaded onto the Ni_1−xCo_xFe₂O₄@Methionine@PEG NPs for breast cancer cell lines MDA-MB-231 and MCF-7 showed more significant cell death than the free drug, which was measured by an MTT assay. When comparing both cancer cells, we demonstrated that naproxen loaded onto the Ni_1−xCo_xFe₂O₄@Methionine@PEG NPs exhibited greater cell death effects on the MCF-7 cells compared with the MDA-MB-231 cells. The results of the hemolysis test also showed good hemocompatibility. The results indicated that the prepared magnetic nanocarrier could be suitable for controlled anticancer drug delivery. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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19 pages, 3471 KiB

Open AccessArticle

The Tumour Suppressor CYLD Is Required for Clathrin-Mediated Endocytosis of EGFR and Cetuximab-Induced Apoptosis in Head and Neck Squamous Cell Carcinoma

by Rin Liu, Satoru Shinriki, Manabu Maeshiro, Mayumi Hirayama, Hirofumi Jono, Ryoji Yoshida, Hideki Nakayama and Hirotaka Matsui

Cancers 2022, 14(1), 173; https://doi.org/10.3390/cancers14010173 - 30 Dec 2021

Cited by 6 | Viewed by 3036

Abstract

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and is a target for the therapeutic antibody cetuximab (CTX). However, because only some patients have a significant clinical response to CTX, identification of its predictive biomarkers and potentiation of CTX-based therapies are important. We have recently reported a frequent downregulation of cylindromatosis (CYLD) in primary HNSCC, which led to increased cell invasion and cisplatin resistance. Here, we show that CYLD located mainly in lipid rafts was required for clathrin-mediated endocytosis (CME) and degradation of the EGFR induced by EGF and CTX in HNSCC cells. The N-terminus containing the first cytoskeleton-associated protein-glycine domain of CYLD was responsible for this regulation. Loss of CYLD restricted EGFR to lipid rafts, which suppressed CTX-induced apoptosis without impeding CTX’s inhibitory activity against downstream signalling pathways. Disruption of the lipid rafts with cholesterol-removing agents overcame this resistance by restoring CME and the degradation of EGFR. Regulation of EGFR trafficking by CYLD is thus critical for the antitumour activity of CTX. Our findings suggest the usefulness of a combination of cholesterol-lowering drugs with anti-EGFR antibody therapy in HNSCC. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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12 pages, 1462 KiB

Open AccessArticle

Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury

by Shinji Kobuchi, Miyu Kai and Yukako Ito

Cancers 2021, 13(24), 6382; https://doi.org/10.3390/cancers13246382 - 20 Dec 2021

Cited by 2 | Viewed by 2677

Abstract

Acute kidney injury (AKI) complicates the dosing strategies of oxaliplatin (L-OHP) and the requirement for L-OHP dose reduction in patients with renal failure remains controversial. The objective of this study is to assess the impact of AKI on the pharmacokinetics (PK) of intact L-OHP and simulate the relationship between the degree of renal function and intact L-OHP exposures using a population PK model. Intact L-OHP concentrations in plasma and urine after L-OHP administration were measured in mild and severe AKI models established in rats through renal ischemia-reperfusion. Population PK modeling and simulation were performed. There were no differences among rats in the area under the plasma concentration–time curve of intact L-OHP after intravenous L-OHP administrations. Nevertheless, the amount of L-OHP excretion after administration of 8 mg/kg L-OHP in mild and severe renal dysfunction rats was 63.5% and 37.7%, respectively, and strong correlations were observed between biochemical renal function markers and clearance of intact L-OHP. The population PK model simulated well the observed levels of intact L-OHP in AKI model rats. The population PK model-based simulation suggests that dose reduction is unnecessary for patients with mild to moderate AKI. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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10 pages, 1831 KiB

Open AccessArticle

Relationship between Serum Bortezomib Concentration and Emergence of Diarrhea in Patients with Multiple Myeloma and/or AL Amyloidosis

by Yuki Fujimoto, Shikiko Ueno, Kazutaka Oda, Nao Gunda, Yumi Shimomura, Yuka Nishimura, Ayami Yamaguchi, Akari Kuwano, Yuki Ito, Yusuke Baba, Aina Nishigaki, Natsumi Michiwaki, Shota Uchino, Kayo Kurogi, Yawara Kawano, Masao Matsuoka, Hideyuki Saito, Yutaka Okuno and Hirofumi Jono

Cancers 2021, 13(22), 5674; https://doi.org/10.3390/cancers13225674 - 12 Nov 2021

Cited by 1 | Viewed by 1962

Abstract

(1) Background: multiple myeloma patients have benefited from bortezomib therapy, though it has often been discontinued owing to diarrhea. The objective of this study was to verify serum bortezomib concentration in the emergence of diarrhea. (2) Methods: this prospective, observational case-control, and monocentric study was performed with an approval by the Ethics Committee of Kumamoto University Hospital in 2015 (No. 1121) from February 2015 to April 2017. (3) Results: twenty-four patients with bortezomib therapy were recruited; eight patients (33.3%) developed diarrhea at day 3 as median. Median measured trough bortezomib concentration at 24 h after first or second dose for patients with or without diarrhea was 0.87 or 0.48 ng/mL, respectively (p = 0.04, Wilcoxon signed rank test). Receiver operation characteristic (ROC) analysis produced the cut-off concentration of 0.857 ng/mL (area under the ROC curve of 0.797, sensitivity of 0.625, specificity of 0.875). The survival curves between patients with and without diarrhea were similar (p = 0.667); those between patients with higher and lower concentration than median value (0.61 ng/mL) were also similar (p = 0.940). (4) Conclusions: this study indicated the possible involvement of serum bortezomib concentration in the emergence of diarrhea in bortezomib therapy in patients with multiple myeloma. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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12 pages, 1199 KiB

Open AccessArticle

Development and Validation of an HPLC Method for Analysis of Topotecan in Human Cerebrospinal Fluid and Its Application in Elimination Evaluation of Topotecan after Intraventricular Injection

by Naoki Yoshikawa, Ai Yamada, Tsubasa Yokota, Yusei Yamada, Mariko Kinoshita, Hiroshi Moritake and Ryuji Ikeda

Cancers 2021, 13(18), 4643; https://doi.org/10.3390/cancers13184643 - 16 Sep 2021

Cited by 4 | Viewed by 2653

Abstract

Intrathecal administration of anticancer drugs is an effective dosage strategy, but the elimination of intraventricular drugs is not uniform in all patients. For safety, a system to evaluate local pharmacokinetics in the ventricles after administration is desired. In this study, we developed a simple and reproducible method to measure topotecan concentration in the cerebrospinal fluid (CSF) and confirmed its clinical applicability. High-performance liquid chromatography (HPLC) analysis was performed using a C18 column to measure the total topotecan concentration in the CSF. Clinical CSF samples were obtained from a 1-year old child with poor CSF absorption and stagnation. The patient received topotecan via an intraventricular subcutaneous reservoir. The HPLC method complied with the validation criteria. The lower limit of quantitation of this method was 0.04 µM. Using the developed method, we could determine the difference in topotecan CSF concentrations at 24 and 48 h after administration. The patient’s topotecan elimination rate was extremely low, and signs of adverse effects were observed at high CSF concentration of topotecan. The developed method could detect the delay in topotecan elimination after intrathecal injection. The findings of this study are valuable for the development of personalized treatments for the intrathecal administration of anticancer drugs. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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10 pages, 796 KiB

Open AccessArticle

High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction

by Takayuki Takahashi, Hideyuki Terazono, Takayuki Suetsugu, Hideki Sugawara, Junko Arima, Mina Nitta, Toru Tanabe, Kayu Okutsu, Ryuji Ikeda, Keiko Mizuno, Hiromasa Inoue and Yasuo Takeda

Cancers 2021, 13(14), 3425; https://doi.org/10.3390/cancers13143425 - 8 Jul 2021

Cited by 4 | Viewed by 2862

Abstract

Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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13 pages, 1459 KiB

Open AccessArticle

Population Pharmacokinetics of Oxycodone and Metabolites in Patients with Cancer-Related Pain

by Bram C. Agema, Astrid W. Oosten, Sebastiaan D.T. Sassen, Wim J.R. Rietdijk, Carin C.D. van der Rijt, Birgit C.P. Koch, Ron H.J. Mathijssen and Stijn L.W. Koolen

Cancers 2021, 13(11), 2768; https://doi.org/10.3390/cancers13112768 - 2 Jun 2021

Cited by 5 | Viewed by 3443

Abstract

Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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13 pages, 980 KiB

Open AccessArticle

Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups

by Anna Mueller-Schoell, Robin Michelet, Lena Klopp-Schulze, Madelé van Dyk, Thomas E. Mürdter, Matthias Schwab, Markus Joerger, Wilhelm Huisinga, Gerd Mikus and Charlotte Kloft

Cancers 2021, 13(10), 2432; https://doi.org/10.3390/cancers13102432 - 18 May 2021

Cited by 1 | Viewed by 2337

Abstract

Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (C_{SS,min ENDX}) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower C_SS,min _ENDX. In the Women’s Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget C_{SS,min ENDX} at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget C_{SS,min ENDX} in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget C_{SS,min ENDX} at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget C_{SS,min ENDX}. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget C_{SS,min ENDX}). Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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13 pages, 1052 KiB

Open AccessReview

Dose Optimization in Oncology Drug Development: The Emerging Role of Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics

by Apostolos Papachristos, Jai Patel, Maria Vasileiou and George P. Patrinos

Cancers 2023, 15(12), 3233; https://doi.org/10.3390/cancers15123233 - 18 Jun 2023

Cited by 7 | Viewed by 5044

Abstract

Drugs’ safety and effectiveness are evaluated in randomized, dose-ranging trials in most therapeutic areas. However, this is only sometimes feasible in oncology, and dose-ranging studies are mainly limited to Phase 1 clinical trials. Moreover, although new treatment modalities (e.g., small molecule targeted therapies, biologics, and antibody-drug conjugates) present different characteristics compared to cytotoxic agents (e.g., target saturation limits, wider therapeutic index, fewer off-target side effects), in most cases, the design of Phase 1 studies and the dose selection is still based on the Maximum Tolerated Dose (MTD) approach used for the development of cytotoxic agents. Therefore, the dose was not optimized in some cases and was modified post-marketing (e.g., ceritinib, dasatinib, niraparib, ponatinib, cabazitaxel, and gemtuzumab-ozogamicin). The FDA recognized the drawbacks of this approach and, in 2021, launched Project Optimus, which provides the framework and guidance for dose optimization during the clinical development stages of anticancer agents. Since dose optimization is crucial in clinical development, especially of targeted therapies, it is necessary to identify the role of pharmacological tools such as pharmacogenomics, therapeutic drug monitoring, and pharmacodynamics, which could be integrated into all phases of drug development and support dose optimization, as well as the chances of positive clinical outcomes. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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20 pages, 606 KiB

Open AccessReview

Pharmacogenomics Testing in Phase I Oncology Clinical Trials: Constructive Criticism Is Warranted

by Tristan M. Sissung and William D. Figg

Cancers 2022, 14(5), 1131; https://doi.org/10.3390/cancers14051131 - 23 Feb 2022

Cited by 1 | Viewed by 2288

Abstract

While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24–31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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24 pages, 1308 KiB

Open AccessSystematic Review

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy in Children with Cancer: A Systematic Review and Meta-Analysis

by Aniek Uittenboogaard, Céline L. G. Neutel, Johannes C. F. Ket, Festus Njuguna, Alwin D. R. Huitema, Gertjan J. L. Kaspers and Mirjam E. van de Velde

Cancers 2022, 14(3), 612; https://doi.org/10.3390/cancers14030612 - 26 Jan 2022

Cited by 17 | Viewed by 4217

Abstract

Vincristine-induced peripheral neuropathy (VIPN) is a debilitating side-effect of vincristine. It remains a challenge to predict which patients will suffer from VIPN. Pharmacogenomics may explain an individuals’ susceptibility to side-effects. In this systematic review and meta-analysis, we describe the influence of pharmacogenomic parameters on the development of VIPN in children with cancer. PubMed, Embase and Web of Science were searched. In total, 1597 records were identified and 21 studies were included. A random-effects meta-analysis was performed for the influence of CYP3A5 expression on the development of VIPN. Single-nucleotide polymorphisms (SNPs) in transporter-, metabolism-, cytoskeleton-, and hereditary neuropathy-associated genes and SNPs in genes previously unrelated to vincristine or neuropathy were associated with VIPN. CYP3A5 expression status was not significantly associated with VIPN. The comparison and interpretation of the results of the included studies was limited due to heterogeneity in the study population, treatment protocol and assessment methods and definitions of VIPN. Independent replication is essential to validate the clinical significance of the reported associations. Future research should aim for prospective VIPN assessment in both a discovery and a replication cohort. Ultimately, the goal would be to screen patients upfront to determine optimal vincristine dosage with regards to efficacy and risk of VIPN. Full article

(This article belongs to the Special Issue Pharmacokinetics/Pharmacodynamics/Pharmacogenetics Based Personalized Medicine for Cancer Therapy)

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