Savolitinib is a highly selective small-molecule inhibitor of the mesenchymal–epithelial transition (MET) factor tyrosine kinase, which was approved by the National Medical Products Administration (NMPA) of China for patients with MET exon 14 (METex14)-altered locally advanced or metastatic non-small cell lung cancer (NSCLC). However, the pharmacokinetics profiles of savolitinib and its active metabolite M2 have not been comprehensively characterised in an integrated manner across different studies, tumour types and treatment settings. A non-linear mixed-effects model was developed to characterise the population pharmacokinetics of savolitinib and its active metabolite M2 in patients with advanced solid tumours. The analysis included 7192 savolitinib concentration observations from 704 participants and 7162 M2 concentration observations from 702 participants pooled across eight clinical studies. A joint parent–metabolite model with first-order absorption and two-compartment distribution and elimination for both savolitinib and M2 adequately described the observed concentration-time data. Body weight, alkaline phosphatase, creatinine clearance and total bilirubin were identified as statistically significant covariates for the apparent clearance of savolitinib, whilst body weight and renal impairment categories were retained for apparent M2 clearance. Although these covariates influenced model-predicted pharmacokinetic parameters, the magnitude of the effects was generally modest relative to overall inter-individual variability. The population pharmacokinetics of savolitinib and M2 can be adequately characterised in patients with advanced solid tumours using an integrated parent–metabolite framework. Within the range of this pooled dataset, the identified covariate effects are considered insufficient, on the basis of the present pharmacokinetic analysis, to support routine initial dose adjustment.
The legalization of cannabis in many parts of the USA and worldwide emphasizes the need to study their potential for interaction with drugs. The Cannabis sativa plant contains over 120 phytocannabinoids, with delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) being the most abundant cannabinoids. The aim of this study was to investigate the effect of treatment with individual cannabinoids or mixture of cannabinoids (mix) on the activity and expression of several cytochrome P450 (CYP) enzymes. Primary cultures of human hepatocytes were pretreated with either vehicle or cannabinoids, followed by incubation with a cocktail of CYP substrates. The activity of various CYP enzymes was determined by quantifying the formation of the metabolites of specific CYP substrates using liquid chromatography-tandem mass spectrometry. The messenger RNA (mRNA) expression of various CYP enzymes was determined by quantitative real-time polymerase chain reaction (qrt-PCR). A significant (> 2-fold) increase in CYP1A2 activity was observed after chronic exposure to CBN and mix at 3 µM. Similarly, THC and mix treatments at 3 µM led to a significant (> 2-fold) increase in CYP3A4 activity and expression. No major inducive effects were observed on CYP2D6 and CYP2C9. Acute exposure to CBD, CBN, or mix inhibited CYP1A2 activity in a concentration-dependent manner; mix showed mild CYP3A4 inhibition at 3 µM with no major effects on CYP2D6 and CYP2C9 activity. These data suggest that cannabinoids selectively alter the activity and expression of CYP enzymes, which may lead to change in exposure of coadministered substrates owing to possible metabolic drug–drug interactions (DDI).
Psilocybin, a prodrug that converts to psilocin, exerts psychedelic and antidepressant effects primarily through serotonin 2A (5-HT2A) receptor agonism. Although psilocybin has demonstrated rapid and sustained antidepressant effects in treatment-resistant depression, the optimal dose selection that balances therapeutic benefit and safety remains unclear. This study aims to develop a physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model to predict psilocin exposure, 5-HT2A receptor occupancy, and antidepressant response following a single oral dose of psilocybin. A previously developed PBPK model that simulates psilocin plasma concentrations was coupled to two pharmacodynamic models. A maximum effect model was used to predict 5-HT2A receptor occupancy. A second model combined a turnover model for acute effects and a log-linear function for sustained effects to predict changes in Montgomery-Åsberg Depression Rating Scale (MADRS) scores. This model was applied to simulate MADRS scores at 24 h and 12 weeks after psilocybin doses ranging from 10–30 mg in virtual subjects with moderate to severe depression. The model adequately predicted 5-HT2A receptor occupancy for psilocybin doses ranging from 3–30 mg and reproduced the observed reduction in MADRS scores for the 10- and 25-mg psilocybin doses. Although the model overpredicted MADRS changes in the 1-mg control group and underpredicted changes in the 15-mg dose group from another study, the predicted scores remained within the same depression severity category as the observed data. Simulation analyses illustrate how the model can predict a range of MADRS reductions for psilocybin doses between 10 and 30 mg, with varying baseline depression severities. This approach could potentially guide individualized dose adjustment. This PBPK/PD framework links psilocin exposure to receptor engagement and clinical antidepressant response following psilocybin administration. The model may support dose selection and hypothesis generation for future clinical studies while also highlighting the need for more mechanistic models that integrate neuroplasticity and network-level processes.
Carbamazepine (CBZ) is a widely used antiepileptic drug with a narrow therapeutic window. Its potential for severe toxicity in overdose is primarily due to its active metabolite, carbamazepine-10,11-epoxide (CBZ-E). In acute CBZ intoxication, sex-specific differences and toxicokinetics are poorly understood, especially the impact on neurological impairment, despite its clinical relevance. The present study aimed to explore the clinical, biochemical, and toxicokinetic data of patients with acute CBZ poisoning to assess the relationship between CBZ exposure and the level of consciousness upon hospital admission and stay and to identify potential sex-based differences in the course and severity of poisoning to develop individualised clinical management strategies for these patients. We conducted a retrospective observational study of 99 adult patients admitted to a national toxicology centre with confirmed acute CBZ poisoning from January 2012 to December 2022. Plasma concentrations of CBZ and CBZ-E were measured using high-performance liquid chromatography. Clinical and biochemical data were analysed regarding sex and level of consciousness on admission and throughout the hospital stay. There were no significant differences between sexes in ingested dose and CBZ initial and peak concentrations. Women exhibited significantly higher peak CBZ-E concentrations and CBZ-E/CBZ ratios, which may be associated with a nonsignificant trend toward longer hospital stay. Men had higher baseline haematological and biochemical parameters, consistent with known physiological differences. Females more frequently required dopamine support for hypotension, while head injuries occurred exclusively in males. A strong dose-response relationship was observed between CBZ and CBZ-E exposure and impaired consciousness. Multivariate regression analysis confirmed that both CBZ and CBZ-E Cmax were independent predictors of consciousness impairment, with CBZ-E Cmax showing a slightly stronger association than the parent drug. Early toxicokinetic assessment is clinically important in acute CBZ poisoning, particularly considering the significant sex-related differences in CBZ metabolism and toxicity. Monitoring the active metabolite CBZ-E may provide additional clinical value, especially in female patients. CBZ and CBZ-E plasma concentrations are valuable biomarkers of poisoning severity.
Nerandomilast, a preferential phosphodiesterase 4B inhibitor, is approved for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis in some countries. The objective of this study was to evaluate the safety and pharmacokinetics of nerandomilast in healthy volunteers through single- and multiple-rising-dose studies, and a human mass balance study evaluating absorption, distribution, metabolism, and excretion. Healthy participants received oral nerandomilast doses ranging from 0.02 mg to 24 mg in the single-rising-dose trial, 1 mg or 6 mg twice daily for 14 days in the multiple-rising-dose trial, and a single oral dose of 18 mg [14C]-labeled nerandomilast in the mass balance trial. In each trial, pharmacokinetic blood samples were collected for determination of nerandomilast plasma concentrations. In the mass balance study, urine, feces, and blood samples were collected, and [14C]-radioactivity was quantified from these matrices. All pharmacokinetic parameters were calculated via noncompartmental analysis. Nerandomilast was rapidly absorbed postadministration, with peak plasma concentrations occurring between 0.5 and 1.25 h postdose before declining in a multiphasic manner. Nerandomilast exposure increased dose proportionally following single- and multiple-dose administrations. Steady state was reached by day 7 after twice-daily dosing with up to 1.69-fold drug accumulation. Following a single oral dose administration of [14C]nerandomilast, 58.0
Multidrug-resistant (MDR) Gram-negative infections pose significant therapeutic challenges, with limited evidence guiding optimal polymyxin B dosing in patients with renal impairment. This systematic review aimed to identify key covariates influencing polymyxin B pharmacokinetic and inform dosing strategies in this population. A comprehensive search of PubMed, Scopus, Embase, and Cochrane library was conducted from inception to May 2025. Population–pharmacokinetic (pop-PK) studies evaluating polymyxin B in adult patients in adult patients with renal impairment, with or without renal replacement therapy (RRT) were included. Study quality was assessed using a validated critical appraisal of clinical pharmacokinetic studies tool (CACPK). Eleven pop-PK studies (603 patients) were included. Considerable interindividual variability in clearance and volume of distribution was noted. Creatinine clearance (CrCL), RRT modality, and disease severity were key covariates influencing drug exposure. Convective RRT modalities (CVVH, CVVHDF) were associated with increased clearance and lower exposure, whereas diffusive modalities (CVVHD) showed variable effects. However, the clinical relevance of CrCL-based dose adjustment alone remains uncertain and should be interpreted alongside other clinical factors. Polymyxin B dosing in renal impairment requires an individualized approach integrating renal function, RRT modality, and disease severity. While a loading dose of 150 mg is appropriate, maintenance dosing should be guided by clinical context, with higher doses in convective RRT and cautious dosing in diffusive modalities. Therapeutic drug monitoring (TDM), where available, is recommended to optimize efficacy and minimize toxicity.
Hemorrhagic shock (HS) remains a leading cause of trauma-related mortality, primarily due to severe hypovolemia and systemic hypoperfusion. These pathophysiological changes may profoundly affect the pharmacokinetics of fentanyl, an opioid widely used for analgesia in trauma care. Previous studies, predominantly based on fixed-pressure shock models, may not adequately reflect clinically relevant hemodynamic conditions. Therefore, we employed a fixed-volume HS model as an alternative approach to reflect hypovolemia-associated perfusion deficits influencing fentanyl disposition. This study aimed to evaluate the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, in an experimental model of fixed-volume HS. Male Wistar rats were randomly divided into two groups: a control group (C; n = 6) and a fixed-volume hemorrhagic shock group (HS; n = 6). In the HS group, hemorrhage was induced by withdrawal of 30
Type 2 diabetes mellitus (T2DM) is a group of metabolic diseases characterized by chronic hyperglycemia, primarily caused by insulin resistance and/or pancreatic beta cell dysfunction. Glibenclamide, a second-generation sulfonylurea oral hypoglycemic agent, plays a crucial role in managing T2DM. Our objective was to establish a population pharmacokinetic model of glibenclamide in Chinese healthy volunteers and use this model to guide the adjustment of individualized dosage regimens. We collected 476 concentration observations of glibenclamide from 20 Chinese healthy volunteers in a phase I clinical trial. A fundamental three-compartment pharmacokinetic model with instantaneous zero-order absorption and linear elimination was developed using the first-order conditional estimation method by NONMEM software. A covariate model was developed by screening for relevant covariates based on the base model. Internal validation of the final model was performed using visual predictive checks and bootstrap methods. The reference standard for the final model was used to assess the quality of the simulated doses. A PopPK model of glibenclamide in Chinese healthy volunteers was successfully established. Age significantly impacted the apparent distribution volume of the central compartment. Validation results indicate that the final model is stable. Simulation results indicate that the model has good goodness of fit. The established population model accurately represents the pharmacokinetics of glibenclamide in Chinese healthy volunteers and based on this model, can be further extrapolated to inform individualized medication strategies for glibenclamide in the treatment of T2DM in the future.
Vepdegestrant is a selective, oral PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader in development for the treatment of ER-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. The current study was conducted to estimate the relative bioavailability of single 200-mg doses of commercially representative vepdegestrant tablets (2 × 100-mg strength and 1 × 200-mg strength) compared with a single 200-mg dose of the pivotal phase 3 vepdegestrant tablets (2 × 100-mg strength). This phase 1, randomized, open-label, three-period, three-treatment, six-sequence, crossover, single-dose study in healthy adults was conducted according to bioequivalence standards. Participants were to receive three vepdegestrant treatments over three treatment periods. Serial pharmacokinetic blood samples were collected up to 168 h after vepdegestrant administration in each period. Fifty-two participants were enrolled and treated in the study. Following administration, vepdegestrant plasma concentration–time curves for both commercially representative tablets (test) and the pivotal phase 3 tablets (reference) were nearly superimposable. The 90
Amikacin remains an important agent in managing severe Gram-negative infections in children. However, its clinical use is limited by a narrow therapeutic index and pronounced pharmacokinetic (PK) variability. Population pharmacokinetic (PopPK) modeling offers a framework for individualized dosing, yet evidence in non-neonatal pediatric populations remains fragmented. A scoping review was conducted across PubMed, Scopus, and Web of Science (last updated July 2025) to identify PopPK studies evaluating intravenous amikacin in children aged 1 month to 18 years. Eligible studies applied nonlinear mixed effects modeling and reported structural models, PK parameters, and covariate analyses. Methodological quality was assessed using a 38-item checklist adapted from established guidelines. Of 783 records screened, 8 studies met the inclusion criteria. Most were retrospective, with sparse PK sampling from routine therapeutic drug monitoring (TDM) data. Body weight was the most consistently identified predictor, while renal function, age, and disease state were retained in selected models. Burn, cystic fibrosis, and oncology populations demonstrated consistently higher clearance and/or volume of distribution, often requiring higher doses for pharmacodynamic target attainment. None of the included studies performed external validation, limiting generalizability. Amikacin PK in children is highly variable and disease-specific. Conventional weight-based dosing is frequently insufficient. Integration of model-informed precision dosing (MIPD) with TDM is essential to optimize amikacin therapy in pediatric practice, particularly in high-risk subpopulations.
Lapatinib, an oral tyrosine kinase inhibitor used to treat breast cancer, is associated with cardiotoxicity. Therefore, cardioprotective agents, including calcium channel blockers, are often co-prescribed, creating a potential for pharmacokinetic drug-drug interactions that need to be evaluated. The current study assessed the effects of calcium channel blockers on P-glycoprotein-mediated efflux, CYP3A4 (cytochrome P450-3A4)-regulated metabolism, and the overall pharmacokinetics of lapatinib using an ex vivo everted gut sac model, in vitro metabolic stability assays, and in vivo pharmacokinetic interaction studies in rats. Calcium channel blockers such as verapamil and nicardipine increased the apparent permeability of lapatinib 1.92- and 1.68-fold, respectively. Furthermore, lapatinib’s metabolic clearance in human liver microsomes was decreased by 15.78- and 9.47-fold in the presence of nicardipine and diltiazem, respectively, at a concentration of 100 µM. In vivo, the Cmax (maximum plasma concentration) of lapatinib was increased by 29.30
Efavirenz is associated with frequent adverse effects, mainly hepatotoxicity and central nervous system disturbances. The cytochrome P450 enzyme CYP2B6 plays a key role in efavirenz metabolism and is strongly linked to these toxicities. This study aimed to evaluate the effect of the CYP2B6 c.516 G>T polymorphism on efavirenz plasma concentrations by comparing individuals with GG, GT, and TT genotypes. A systematic review of four databases was conducted to identify studies published up to March 2025 evaluating the association between the CYP2B6 c.516 G>T polymorphism and efavirenz plasma concentrations. Pooled mean differences with 95
High-dose methotrexate (HDMTX) is an essential agent in hematological malignancies, the use of which is complicated by toxicities related to delayed elimination. Existing thresholds to define delayed elimination vary widely, creating inconsistencies in clinical practice. This multicenter retrospective study evaluated adult non-Hodgkin Lymphoma patients from Malaysia to establish a locally relevant delayed elimination threshold and identify factors influencing it. Patients who received HDMTX ≥ 500 mg/m2 were included. Data extracted from medical records were HDMTX regimen, supportive therapy, renal and liver function, full blood count, MTX concentrations, and MTX-related toxicities. MTX thresholds at 48 h were assessed based on their association with post-treatment clinical outcomes. The selected threshold was subsequently used to categorize patients into delayed and nondelayed elimination groups, and factors associated with delayed elimination were evaluated using logistic regression. A toxicity-based receiver operating characteristic (ROC) approach identified ≥ 0.2 µmol/L at 48 h as the concentration at which lymphocyte count and alanine aminotransferase (ALT) worsened by 50
Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is transported into hepatocytes via OATP1B1, which is encoded by the SLCO1B1 gene. Although interindividual variability in vadadustat pharmacokinetics (PK) has been reported, the influence of SLCO1B1 polymorphisms and the clinical relevance of coproporphyrin-I (CP-I) as a biomarker of OATP1B1 activity on vadadustat exposure remain unclear in Japanese patients with chronic kidney disease-related anemia. This study evaluated the effects of SLCO1B1 polymorphisms on vadadustat plasma concentration in this population. A prospective observational study was conducted in 11 patients who received vadadustat. Plasma concentrations at 12 h post administration (C12) were measured using high-performance liquid chromatography with ultraviolet detection, and dose-adjusted concentrations (C12/D) were calculated. CP-I, an endogenous biomarker of OATP1B1 activity, was quantified simultaneously. SLCO1B1 c.388A>G and c.521T>C were genotyped, and haplotypes were assigned. Associations between SLCO1B1*15, vadadustat C12/D, and CP-I were analyzed. A total of 71 samples were analyzed. C12/D was significantly higher in SLCO1B1*15 carriers than in noncarriers (median: 60.3 versus 37.6 µg/mL/g, P = 0.009). CP-I concentrations were also higher in SLCO1B1*15 carriers (median: 0.72 versus 0.36 ng/mL, P = 0.030). A significant correlation was observed between C12/D and CP-I (ρ = 0.627, P = 0.039). SLCO1B1*15 significantly influenced vadadustat concentration, and CP-I was associated with vadadustat C12/D, suggesting an association with OATP1B1-related transporter function. These findings provide insights into variability in vadadustat PK and support the larger studies to clarify the clinical utility of therapeutic drug monitoring strategies that incorporate pharmacogenomic and biomarker information. Video abstract available in online supplementary file.
Calaspargase pegol (CalPEG) is a PEGylated conjugate of L-Asparaginase (L-Asp) and an asparagine specific enzyme approved by the Food and Drug Administration (FDA) as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) in children and young adults. Although CalPEG is an established and effective treatment for childhood ALL, its potential in solid tumors is still underexplored. Recent reports illustrated that L-Asp may also have potential for the treatment of certain aggressive solid tumors, including hepatocellular carcinoma (HCC)[1–5]. In order to investigate this potential, clinical and preclinical data were integrated using model-informed drug development (MIDD) approaches, which are among the most adequate tools to facilitate the translation of preclinical into clinical data [6–9]. This work explores the potential of pharmacokinetic/pharmacodynamic tumor growth inhibition (PKPD TGI) modeling to maximize the use of in vivo preclinical data and PK data in patients with ALL for translation of preclinical observed antitumor activity to clinical efficacy. A PKPD TGI model was developed that described tumor volumes (TVs) versus time in a preclinical hypermethylated xenograft mouse model relevant for HCC. Translation of the PKPD TGI model to human was performed by linking the structural TGI model developed in mice with human PK model of CalPEG. This model was developed on PK data, i.e., plasma Asp activity (PAA), obtained in pediatric and adult patients with ALL and was used to predict TGI profiles of CalPEG in adult patients with HCC. The developed PKPD TGI model adequately described the TV versus time profiles in tumor bearing (TB) mice and quantified the PKPD relationship between PAA and TGI in TB mice. The structural mouse TGI model was linked to predicted human PK parameters and this human PKPD TGI model was used to perform simulations and to predict antitumor activity of CalPEG at different doses/schedule in patients with HCC. The results indicate that PKPD TGI modeling can be used to build a preclinical to clinical translational framework to predict the exposure–response relationship in patients with HCC and to inform dosing strategies or trial designs for solid tumors.
To establish pharmacokinetic bioequivalence and assess the safety of a single-dose administration of fixed-dose combination (FDC) tablet containing dapagliflozin 10 mg + pioglitazone 15 mg (JLP-2008) compared with a single-dose administration of their individual tablets. In this randomized, open-label, two-period crossover study, 49 healthy Korean adults were enrolled, 48 received at least one dose and 45 completed both periods. Participants received either one JLP-2008 tablet or separate dapagliflozin + pioglitazone tablets under fasting conditions, then the alternate treatment after a 7-day washout. Blood samples collected predose to 48 h were quantified by ultra-fast liquid chromatography–tandem mass spectrometry. Primary endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from zero until the last measurable concentration (AUClast) for each analyte; bioequivalence was concluded if 90
Amiloride, an acid-sensing ion channel (ASIC) blocking agent with demonstrated anti-panic effects in preclinical models, is a promising candidate for rapid treatment of panic attacks. Intranasal administration enables rapid systemic uptake, and single-dose pharmacokinetics (PK) of intranasal amiloride in healthy adults have been described, but its population PK (PopPK) properties, including variability and absorption pathways, remain undefined. This study aimed to develop a PopPK model in healthy adults to characterize intranasal amiloride absorption kinetics and systemic exposure. Healthy volunteers (n = 15) randomized equally to three dose groups (n = 5 per group) received 0.2, 0.4, or 0.6 mg intranasal amiloride via a mucosal atomization device, and plasma samples were collected over 24 h. PopPK modelling was performed in NONMEM® using first-order conditional estimation. Structural models, covariates, variability, and residual error were evaluated with goodness-of-fit plots and prediction-corrected visual predictive checks. Simulations explored systemic exposure across 10–80 mg doses. A first-order parallel dual absorption model with rapid nasal uptake and a slower secondary route via a transit compartment, combined with two-compartment disposition, best described the data. Key parameter estimates included a slow absorption rate constant of 0.136 h−1, an apparent clearance of 19 L/h and apparent central volume of distribution of 9.83 L, and a nasal bioavailability fraction of 0.133. Intranasal amiloride pharmacokinetics are best described by a dual-pathway absorption model with rapid and delayed uptake. This PopPK model provides a quantitative foundation for dose selection and further clinical development as a rapid-acting treatment for panic attacks.
Community-acquired pneumonia (CAP) remains a major global health burden, with antibacterial therapy as the primary treatment strategy. In clinical practice, plasma drug concentrations are often used to guide therapy, yet they may not reliably reflect effective pulmonary exposure, which is particularly critical for older adults, patients with comorbidities, and critically ill populations. In recent years, targeted pulmonary pharmacokinetics/pharmacodynamics (PK/PD) studies have gained increasing attention and have become an important reference for guiding precision antimicrobial therapy in clinical settings. This review provides a comprehensive overview of the pulmonary PK characteristics of key antibiotics commonly used for CAP, including macrolides, fluoroquinolones, β-lactams, tetracyclines, and the pleuromutilin agent lefamulin. Major factors influencing drug distribution in the lung are summarized. The significance of pulmonary PK/PD targets in antibiotic selection, dose adjustment, and individualized treatment is discussed, aiming to support improved clinical outcomes, rational antibiotic use, and resistance management. A deeper understanding of pulmonary PK/PD properties is essential to advance evidence-based and optimized treatment for CAP.
Entrectinib, a multi-target tyrosine kinase inhibitor (TKI) against TRK, ROS1, and ALK, is clinically approved for genetically-defined solid tumors. The prevalence of drug–drug interactions (DDIs) with increased use indicates the need for further research. This present study aimed to screen 32 cardiovascular drugs for inhibitory effects on entrectinib metabolism and to elucidate the pharmacokinetic interaction with nicardipine. We utilized rat liver microsomes to screen cardiovascular drugs and identify potent inhibitors. The inhibition kinetics of nicardipine were determined in vitro, and molecular docking to the primary entrectinib-metabolizing cytochrome P450 isoform was performed to investigate a potential mechanism for the observed interaction. Furthermore, in vivo pharmacokinetic studies were conducted in rats to evaluate the impact of nicardipine on entrectinib exposure. In rat liver microsomes, nicardipine was identified as a moderately potent inhibitor with a half-maximal inhibitory concentration (IC50) of 1.43 µM, inhibiting entrectinib metabolism through dual competitive and noncompetitive mechanisms (inhibition constants: Ki = 1.28 µM; αKi = 1.92 µM). In vivo studies showed that nicardipine significantly increased the area under the curve (AUC) and maximum plasma concentration (Cmax) of entrectinib by 1.5-fold, while reducing clearance (CLz/F) and volume of distribution (Vz/F) (p < 0.05). These findings in rat models and in silico docking indicate that nicardipine increases entrectinib exposure. While these results underscore the risk of significant DDIs, further clinical studies in humans are required to confirm this interaction and determine if entrectinib dose adjustments are necessary to mitigate adverse events.
