Translational and Clinical Pharmacology最新文献

{"title":"Development of a predictive platform for target concentration intervention of aminoglycosides.","authors":"Kyung Ran Mun, Shi Hyang Lee, Hyeong-Seok Lim","doi":"10.12793/tcp.2026.34.e14","DOIUrl":"10.12793/tcp.2026.34.e14","url":null,"abstract":"<p><p>Aminoglycosides, including gentamicin, are potent bactericidal antibiotics that are widely utilized for the treatment of severe gram-negative bacterial infections. These drugs demonstrate a concentration-dependent bactericidal effect, whereby higher concentrations result in more rapid bacterial elimination. Despite their efficacy, determining optimal dosing regimens is challenging due to significant inter-individual pharmacokinetic (PK) variability and adverse drug reactions, such as nephrotoxicity and ototoxicity. This study developed a simplified, user-friendly PK-predictive system for target concentration intervention of gentamicin. A semi-automatic platform was developed for the generation of patient-specific NONMEM PK datasets using Shiny and the estimation of individual PK parameters using maximum a posteriori Bayesian estimation. The system provides a dosing assessment based on Bayesian PK predictions, with results presented in detailed reports generated via LaTeX. The predictability of the PK model was confirmed via external validation using clinical PK data from 22 patients who underwent therapeutic drug monitoring consultations at the Asan Medical Center. In the external validation the mean prediction error was -0.19 mg/L (95% confidence interval, -0.88 to 0.41) and the root mean squared prediction error was 2.85 mg/L, and 86.4% of observed concentrations fell within the model-predicted 95% prediction interval on the individual prediction check plots. These results support the applicability of the model to this population, within the limits of precision reported, for dose individualisation. The platform architecture may also be adaptable to other drugs with a narrow therapeutic index.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 3","pages":"139-153"},"PeriodicalIF":2.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LC-MS/MS quantification of N-lactoyl-phenylalanine and N-lactoyl-tyrosine in human plasma: method validation and clinical application to metformin administration.","authors":"Ga-Yeong Lee, Yeonseo Jang, Jae-Yong Chung, Joo-Youn Cho","doi":"10.12793/tcp.2026.34.e12","DOIUrl":"10.12793/tcp.2026.34.e12","url":null,"abstract":"<p><p>N-lactoyl amino acids, including N-lactoyl-phenylalanine (Lac-Phe) and N-lactoyl-tyrosine (Lac-Tyr), have recently attracted interest as endogenous metabolites of potential clinical and metabolic relevance. In particular, Lac-Phe has been implicated in appetite regulation and in the metabolic effects of metformin. However, validated analytical methods for the simultaneous quantification of these endogenous metabolites in human plasma remain limited. In this study, a sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of Lac-Phe and Lac-Tyr in human plasma using a simple protein precipitation procedure with a 50-μL sample volume. To minimize interference from endogenous analytes, an eight-point calibration curve was prepared using an artificial surrogate matrix. The assay showed a calibration range of 0.5-100 ng/mL for both analytes, with a lower limit of quantification of 0.5 ng/mL and a total run time of 5.5 minutes. The method demonstrated acceptable analytical performance for both Lac-Phe and Lac-Tyr, with intra- and inter-day precision values of ≤ 8.8% and mean accuracy ranging from 88.0% to 101.4%. The validated assay was successfully applied to plasma samples from healthy volunteers collected before and after metformin administration. This method provides a reliable analytical tool for the simultaneous quantification of Lac-Phe and Lac-Tyr in human plasma and may facilitate future clinical and pharmacological investigations of lactoyl-amino acid metabolism.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT04335526.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 3","pages":"172-181"},"PeriodicalIF":2.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolving landscape of inflammation-related clinical trials: a 25-year registry-based network analysis from a clinical pharmacology perspective.","authors":"Sooyoun Lee, Kyung-Sang Yu, Ki Young Huh","doi":"10.12793/tcp.2026.34.e11","DOIUrl":"10.12793/tcp.2026.34.e11","url":null,"abstract":"<p><p>The longitudinal evolution of inflammation-related clinical research has not been systematically characterized at the registry level, and the differential impact of the coronavirus disease 2019 (COVID-19) pandemic across inflammatory disease domains remains incompletely resolved. We analyzed 15,051 inflammation-related interventional trials registered on ClinicalTrials.gov (2000-2025), stratified into pre-pandemic (≤ 2019; n = 10,366), pandemic (2020-2022; n = 2,356), and post-pandemic (2023-2025; n = 2,329) epochs. We quantified volumetric, phase, and disease-category metrics; assessed thematic evolution using temporally stratified keyword co-occurrence networks; and characterized the static disease-mechanism architecture through bipartite network analysis using the H2' specialization and Nestedness based on Overlap and Decreasing Fill (NODF) nestedness indices. Annual registration sustained near pandemic-era rates through the post-pandemic window, peaking in 2025 (871 trials), alongside a sustained shift toward earlier-stage development. Disease-category composition reorganized into two distinct trajectories: a transient pulmonary surge (13.5%→21.4%→15.3%) and a sustained oncology expansion (12.3%→16.9%→21.3%; 73.2% relative increase), with oncology overtaking rheumatology as the largest category by 2023-2025. Co-occurrence networks underwent structural simplification (density 0.426→0.247; modularity 0.527→0.393), while the betweenness centrality of immune increased monotonically (0.171→0.333), identifying it as a progressively load-bearing bridging concept. Bipartite analysis showed moderate specialization (H2' = 0.415) and substantial nestedness (NODF = 51.07), with cross-domain coupling of immunologic and oncologic vocabularies. Formal artificial intelligence and machine learning (AI/ML) incorporation remained negligible (0.14%). COVID-19 functioned as a discrete inflection point amplifying a longer-term reorientation of inflammation research toward oncology-anchored, immune-centered investigation; AI/ML methodologies have not yet translated into prospective trial design.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 3","pages":"154-171"},"PeriodicalIF":2.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motility-mediated drug interactions with GLP-1 receptor agonists: labeled evidence and a framework for quantitative assessment.","authors":"Jae Yong Chung","doi":"10.12793/tcp.2026.34.e13","DOIUrl":"10.12793/tcp.2026.34.e13","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed, and two additional oral products received US approval in 2025 and 2026. All eleven US labels examined describe delayed gastric emptying as potentially affecting the absorption of co-administered oral medications. Since the exenatide program, no study has evaluated a narrow therapeutic index victim across more than one administration schedule; the original warfarin and digoxin studies each used a single schedule. The omission may reflect an interaction paradigm built around enzymes and transporters. Current frameworks do not routinely trigger motility-specific studies because the standard <i>in vitro</i> screening cascade does not address gastric emptying. Total area under the concentration-time curve (AUC) may also fail to characterize rate-dependent effects in some victim drugs. Once a class warning is established, further study may receive less priority, and interactions managed by routine dose adjustment may go unreported. Of eleven US prescribing-information documents screened, six contributed quantitative data showing that the direction of effect is not uniform: thyroxine, atorvastatin and ramipril exposures have all been reported to increase under specific conditions, so a reduction in exposure should not be assumed. The class is also pharmacologically heterogeneous; ICH M12 places absorption-mediated interactions outside its scope, and the European Medicines Agency has adopted a concept paper proposing guidance covering them. I propose an evaluation framework built on biopharmaceutically stratified probe panels, timing- and titration-explicit designs, selective use of prespecified partial AUC endpoints for rate-sensitive victims, and physiologically based pharmacokinetic models qualified against human gastric emptying data.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 3","pages":"129-138"},"PeriodicalIF":2.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and safety of nafamostat and its metabolites following single- and multiple-dose oral administration of nafamostat mesylate in healthy male participants.","authors":"Jun Ki Hong, Hyun Chul Kim, In-Jin Jang, SeungHwan Lee","doi":"10.12793/tcp.2026.34.e7","DOIUrl":"10.12793/tcp.2026.34.e7","url":null,"abstract":"<p><p>Nafamostat mesylate, a serine protease inhibitor, is a potential antiviral agent that inhibits the intracellular entry of severe acute respiratory syndrome coronavirus-2. An oral formulation is under development to improve patient compliance over the existing intravenous formulation. This study evaluated the pharmacokinetics (PKs) and safety of oral nafamostat mesylate following single and multiple doses in healthy male participants. An open-label, single-dose and multiple ascending dose (MAD) study was conducted. In the single-dose study, 8 participants were administered 200 mg of nafamostat mesylate. In the MAD study, 8 participants in each dose group received nafamostat mesylate 100, 200, or 400 mg every 6 hours (QID) for 7 days. PKs were assessed for nafamostat in the single-dose study, and for nafamostat, 6-amidino-2-naphthol (AN) and 4-guanidinobenzoic acid (GBA) in the MAD study. The safety and tolerability were evaluated throughout the study. The median time to maximum concentration at steady state was 0.50-0.88 hours for nafamostat, 1.75-2.00 hours for AN, and 2.50-3.50 hours for GBA. Terminal elimination half-life ranged 0.61-3.84, 21.24-31.44, and 8.28-14.70 hours respectively. The accumulation ratio of nafamostat was 23.86 at 400 mg QID, with no accumulation at 100 and 200 mg QID. The mean accumulation ratios were 7.43-13.73 for AN and 1.84-2.11 for GBA. Nafamostat exposure showed a more than dose-proportional increase, whereas metabolites exposures were dose-proportional. No serious adverse events were reported. Multiple doses of oral nafamostat mesylate were well-tolerated up to 400 mg QID in healthy male participants.</p><p><strong>Trial registration: </strong>Clinical Research Information Service Identifier: KCT0005647.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 2","pages":"88-99"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13338761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implementation of decentralized clinical trials in Korea from a resource-based perspective.","authors":"Ki Young Huh, Gaeun Kang, Kye Hun Kim","doi":"10.12793/tcp.2026.34.e9","DOIUrl":"10.12793/tcp.2026.34.e9","url":null,"abstract":"<p><p>Clinical trials in South Korea are heavily concentrated in Seoul, limiting patient access in other regions. We conducted a cross-sectional ecological study of 17 Korean administrative divisions to assess regional infrastructure readiness for decentralized clinical trial (DCT) implementation, using data from the Health Insurance Review and Assessment Service (2024), the National Health Insurance Service (2024), and the Ministry of Food and Drug Safety (2024 to 2025). Provincial densities for four resource domains (specialists, nurses, beds, and medical equipment) were calculated per 100,000 patients and normalized to Seoul (= 1.00). Area-specific composite indices for four therapeutic areas were computed as the capped geometric mean of specialist and equipment densities, and an overall infrastructure index as the capped geometric mean of all four domain densities. Trial density was derived from 1,924 approved trials yielding 7,760 trial-center pairs (99% mapping rate). Among the 16 non-Seoul provinces, bed density was the most dispersed (coefficient of variation [CV] = 0.39, range 0.58 to 2.91), whereas specialist density was the most Seoul-concentrated of the four domains: no non-Seoul province reached 80% of Seoul's level (CV = 0.23, range 0.42 to 0.79). The four therapeutic-area composite indices showed comparable dispersion (CV 0.15 to 0.23; composite infrastructure CV 0.16; Pearson <i>r</i> = 0.72). Gwangju exhibited the largest gap between infrastructure capacity (index 0.94) and trial activity (density ratio 0.18). Clinical trial activity in Korea is disproportionately low relative to infrastructure, and region-specific DCT strategies matched to local resource profiles can provide a practical framework for balanced trial participation.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 2","pages":"100-115"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13338760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and evaluation of automated screening algorithms for pre-analytical errors in pharmacokinetic data: a simulation-based study.","authors":"Minsub Shim, Jaegu Kang, Kyung-Sang Yu, Ki Young Huh","doi":"10.12793/tcp.2026.34.e10","DOIUrl":"10.12793/tcp.2026.34.e10","url":null,"abstract":"<p><p>Pre-analytical errors such as sample mix-ups can compromise the integrity of pharmacokinetic (PK) data. We simulated vancomycin PK data and introduced two error types: intra-individual time point swap (TS) errors and inter-individual concentration swap (CS) errors. This study developed and validated two automated detection approaches-a run-test-based non-parametric method and a Mahalanobis distance-based method with leave-one-out cross-validation (LOOCV)-for identifying pre-analytical errors in PK datasets. Performance was evaluated using 12,500 simulated profiles comparing the two methods. The distance-based method demonstrated significantly higher error detection rate (79.7% vs. 59.6%, <i>p</i> < 0.001) and greater area under the receiver operating characteristic curve (0.856; 95% confidence interval [CI], 0.816-0.889 vs. 0.574; 95% CI, 0.541-0.610) compared to the run-test, while maintaining reasonable specificity (76.4% vs. 84.0%). For TS errors, the distance-based method achieved higher recall (80.4% vs. 71.9%) and modestly higher F1-score (0.530 vs. 0.515). For CS errors, the distance-based method demonstrated superior precision (86.1% vs. 59.8%) with comparable F1-score (0.572 vs. 0.564). Detection was robust across alternative PopPK models, a structurally different drug (theophylline), training-set contamination (with the minimum covariance determinant estimator recommended for non-curated training), missing data (with sub-vector marginal handling), and sampling-time jitter. Overall, the distance-based method with LOOCV outperformed the conventional run-test across key performance metrics and can serve as a practical quality control tool for ensuring PK data integrity in clinical pharmacology research.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 2","pages":"71-87"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13338758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of pharmacokinetics and safety of fixed-dose versus loose combination of atorvastatin/fenofibrate 10/145 mg in healthy Korean participants.","authors":"Hyungji Jang, Juyoung Khwarg, Ki Young Huh, Dong-Min Park, Heejung Park, Kyung-Sang Yu","doi":"10.12793/tcp.2026.34.e8","DOIUrl":"10.12793/tcp.2026.34.e8","url":null,"abstract":"<p><p>Dyslipidemia is a risk factor for cardiovascular disease. Atorvastatin and fenofibrate are co-administered to treat mixed dyslipidemia, a subtype requiring long-term control of low-density lipoprotein cholesterol and triglycerides; fixed-dose combinations (FDCs) could improve adherence. This study compared the pharmacokinetics and safety of an FDC formulation of atorvastatin/fenofibrate 10/145 mg with the corresponding loose combination in healthy Korean participants. Given that atorvastatin is a highly variable drug, a randomized, two-sequence, four-period replicated crossover study was conducted. Plasma concentrations of atorvastatin and 2-hydroxy (2-OH) atorvastatin were measured for 48 h in all periods, and fenofibric acid for 72 hours in the first two periods. Pharmacokinetic parameters were calculated using noncompartmental analysis. Log-transformed maximum plasma concentration (C_max) and area under the plasma concentration-time curve to the last time point (AUC_last) were analyzed using a linear mixed-effects model to obtain geometric mean ratios (GMRs) and 90% confidence intervals (CIs). Using the reference-scaled average bioequivalence approach, the acceptance limits for atorvastatin C_max were widened based on the intrasubject variability. Of 40 randomized participants, 36 completed the study. The GMRs and 90% CIs for C_max and AUC_last were, respectively, 1.0595 (0.9565-1.1735) and 0.9530 (0.9045-1.0041) for atorvastatin; 0.9459 (0.8903-1.0243) and 0.9560 (0.9151-0.9986) for 2-OH atorvastatin; and 0.9589 (0.9020-1.0193) and 0.9861 (0.9585-1.0146) for fenofibric acid. In conclusion, the FDC of atorvastatin/fenofibrate 10/145 mg demonstrated comparable pharmacokinetics to the loose combination. The findings support its use as an alternative to improve medication adherence in patients with mixed dyslipidemia requiring dual lipid-modifying therapy.</p><p><strong>Trial registration: </strong>Clinical Research Information Service Identifier: KCT0010666.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 2","pages":"116-127"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13338759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploratory comparative pharmacokinetic study of a fixed-dose combination of telmisartan/amlodipine/chlorthalidone: half-dose (20/2.5/6.25 mg) versus conventional dose (40/5/12.5 mg).","authors":"Kyungrin Chang, Heejae Won, Taewon Lee, Soonkeun Kwon, Seung Hwan Lee, Joo-Youn Cho, Kyung-Sang Yu","doi":"10.12793/tcp.2026.34.e5","DOIUrl":"10.12793/tcp.2026.34.e5","url":null,"abstract":"<p><p>Low-dose combination therapies are recommended when monotherapy fails to control hypertension. This exploratory study aimed to compare the pharmacokinetics (PK) of 2 fixed-dose combinations (FDCs) of telmisartan, amlodipine, and chlorthalidone: half-dose test FDC (20/2.5/6.25 mg) and a conventional-dose reference FDC (40/5/12.5 mg). A randomized, open-label, single-dose, parallel-group study was conducted in healthy participants. Each participant received a single oral dose of either the test or reference FDC. Serial blood samples for telmisartan, amlodipine, and chlorthalidone were collected up to 72 hours post-dose, and PK parameters were calculated using noncompartmental analysis. The mean maximum plasma concentrations (C_max) of telmisartan, amlodipine, and chlorthalidone were 41.34 and 155.75 μg/L, 1.74 and 4.42 μg/L, and 39.36 and 104.86 μg/L for the test and reference FDCs, respectively. The mean area under the concentration-time curves to the last measurable time point (AUC_last) were 659.93 and 1,673.51 h·μg/L for telmisartan, 57.98 and 128.75 h·μg/L for amlodipine, and 831.73 and 1,826.86 h·μg/L for chlorthalidone. The test FDC demonstrated systemic exposure levels ranging from 0.27- to 0.39-fold for telmisartan, 0.39- to 0.44-fold for amlodipine, and 0.38- to 0.46-fold for chlorthalidone, compared to the reference FDC. In conclusion, the PK profiles of the half-dose test FDC were consistent with the known characteristics of the individual components. These provide the first PK data for this half-dose test FDC and may support its potential as an alternative treatment option for hypertension. However, as this was an exploratory study, the results should be interpreted with caution.</p><p><strong>Trial registration: </strong>Clinical Research Information Service Identifier: KCT0010166.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"45-57"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pH factor: unraveling drug-drug interactions in protein kinase inhibitors through the regulatory lens.","authors":"Simona Stankeviciute, Ariel Tsai, Noha Rayad, Matthias Kruse","doi":"10.12793/tcp.2026.34.e6","DOIUrl":"10.12793/tcp.2026.34.e6","url":null,"abstract":"<p><p>Drug-drug interactions (DDIs) are a significant concern in clinical practice, DDIs might be relevant when drugs with pH-dependent solubility are co-administered with gastric acid-reducing agents (ARAs) such as histamine, H2-receptor antagonists and proton pump inhibitors. One class prone to such DDI at the absorption phase are the weakly basic protein kinase inhibitors (PKIs). The aim of this work is to review recent Food & Drug Administration (FDA) and European Medicines Agency (EMA) submissions for PKIs and evaluate the various approaches by drug developers to characterize pH-dependent DDI liability potentially affecting efficacy in this class of drugs and assess how this impacts the labelling. For this purpose, 32 FDA New Drug Applications (NDAs) and 25 EMA Market Authorization Applications of PKIs in the last 5 years (2019 through 2024) were reviewed More than two-thirds of the submissions included a dedicated clinical DDI studies with an ARA, which remains the most frequent approach to evaluating gastric pH-dependent DDIs among the PKIs investigated, albeit model-informed drug development approaches are also attempted by applicants in about 20% of the submissions. In cases where no clinical DDI study was submitted and alternative approaches taken, this was accepted by the approving agencies. Only the complete absence of data on the DDI potential triggered the request to provide the information post-marketing. A risk-based approach, considering the drug's properties and patient population, is crucial for determining the need for a clinical DDI study and should be discussed with the agencies during drug development.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"1-14"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}