European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objective: Voriconazole is a broad-spectrum antifungal agent whose efficacy and toxicity are closely related to plasma concentrations, which are highly variable between individuals. Therapeutic drug monitoring (TDM) helps optimize its use but is not always available. In this context, machine learning may help predict subtherapeutic or supratherapeutic levels before TDM results are obtained.

Methods: This was a single-center retrospective study conducted between May 2021 and June 2024 in a tertiary hospital in northern Spain. Adult patients treated with voriconazole for at least 3 days and with a steady-state plasma level measurement were included. Clinical, laboratory, and treatment-related variables were collected. Supervised machine learning models (random forest, support vector machines (SVM), XGBoost, etc.) were trained to classify plasma levels as subtherapeutic, therapeutic, or supratherapeutic.

Results: A total of 147 patients were included (65% male; median age 65 years). Therapeutic concentrations were found in 71% of patients, supratherapeutic in 15%, and subtherapeutic in 14%. Significant differences were observed on the basis of route of administration, dosage form, age, liver function, and certain comorbidities. Aspartate aminotransferase (AST), glomerular filtration rate, and administration route were the most relevant predictors in the models. Random forest achieved the best performance (area under the curve (AUC) 0.675), though still below the threshold for clinical applicability.

Conclusions: Although machine learning models identified relevant predictors of voriconazole exposure, their predictive accuracy was limited and insufficient to replace therapeutic drug monitoring. TDM remains essential for individualized and safe dosing. Integrating pharmacogenetic data and hybrid models combining TDM and computational tools may improve predictive performance and clinical applicability.

Background and objective: Fluvoxamine, a potent CYP1A2 inhibitor, increases clozapine serum concentrations by inhibiting its N-dealkylation to norclozapine, thus reducing norclozapine formation and increasing the clozapine/norclozapine ratio. Clinically, fluvoxamine may reduce clozapine tablet burden and mitigate norclozapine-related metabolic side-effects. However, clinical guidance on this co-administration is limited. The current study evaluates the effect of fluvoxamine and its dose on clozapine and norclozapine concentrations and their ratio, while exploring potential influencing factors.

Methods: Patients from long-stay psychiatric wards were included if they had been or were currently receiving clozapine and fluvoxamine, with available steady-state concentrations with and without fluvoxamine coadministraton. Dose-adjusted clozapine and norclozapine concentrations (C/D, ng/mL per mg/day) and their ratios were compared among the two conditions using the Wilcoxon signed-rank test. Median fold increases and associations with clinical variables (e.g. gender, smoking, dosing frequency, baseline clozapine level, fluvoxamine dose), were analysed using Mann-Whitney U tests.

Results: Sixty-seven patients were included. During fluvoxamine co-administration, median C/D clozapine increased from 0.70 to 1.72, C/D norclozapine from 0.43 to 0.80 and the clozapine/norclozapine ratio from 1.66 to 2.16 (all p < 0.001). Median fold increases were 2.51 (clozapine), 1.92 (norclozapine) and 1.27 (clozapine/norclozapine ratio). Greater increases were observed with fluvoxamine doses > 25 mg and baseline clozapine levels < 350 ng/mL, without a significant increase in clozapine/norclozapine ratio. Other factors showed no significant association.

Conclusion: Fluvoxamine significantly increases clozapine and norclozapine concentrations, and their ratio. Doses > 25 mg lead to greater fold increases and more variability. Initiation at 25 mg with a 50% clozapine dose reduction is recommended.

Introduction: Despite dosing protocols and tight therapeutic drug monitoring (TDM), tacrolimus concentrations remain highly variable in pediatric liver transplant (LTx) recipients during the first month post-transplantation. The objective of this study was to describe weight-adjusted tacrolimus concentration-to-dose (C/D/kg) ratios and to identify physical, clinical, and laboratory parameters associated with interpatient pharmacokinetic (PK) variability in hospitalized children during the first month post-LTx.

Methods: In this single-center retrospective cohort study (January 2018-October 2021), we calculated C/D/kg ratios for 36 LTx recipients aged 0-2 years. Descriptive statistics and linear mixed models characterized changes in tacrolimus C/D/kg ratios over time, and we determined the percentage of concentrations within six predefined ranges (0-4, 4-6, 6-8, 8-10, 10-15, and > 15 μg/L).

Results: In total, 524 trough concentrations of orally administered tacrolimus were analyzed. Tacrolimus C/D/kg ratios ranged from 0.19 to 0.75, demonstrating substantial interpatient variability. Time post-transplantation, alanine aminotransferase, aspartate aminotransferase, total bilirubin, coadministration of corticosteroids, spironolactone, fluconazole, fentanyl, amlodipine, flucloxacillin, and ciprofloxacin were significantly associated with interpatient variability (P < 0.05 for all). In the first week, 40.0% tacrolimus trough concentrations were below 4 μg/L, and using TDM the distribution shifted towards the therapeutic mid-range (6-10 μg/L).

Conclusion: TDM of tacrolimus is often not enough to obtain the concentrations in the therapeutic range. Identifying cofounders for variability a priori is essential for guiding efficient and accurate dosing, shifting the focus from reactive TDM towards better dosing strategies that improve PK predictions and ultimately improve therapy for pediatric LTx recipients.

Background: Coenzyme Q₁₀ (CoQ₁₀) plays a vital role in mitochondrial bioenergetics and functions as a potent endogenous antioxidant. Low CoQ₁₀ levels have been associated with various neurodegenerative, metabolic, muscular, and cardiovascular disorders. Early intervention with high-dose oral CoQ₁₀ (5-50 mg/kg/day) can mitigate disease progression and delay the onset of renal disease. We recently developed an emulgel matrix that facilitates the ingestion of high-dose, oil-dissolved CoQ₁₀ for patients with CoQ₁₀ deficiency and secondary dysphagia.

Objective: To evaluate the bioavailability and cellular compatibility of this novel CoQ₁₀ emulgel.

Methods: Two exploratory studies were conducted in healthy adults: a randomized cross-over single-dose trial (n = 6) and a 14-day repeated-dose trial (n = 12) comparing 1 g of CoQ₁₀ administered as emulgel (25 g serving) or solid capsules (2 × size-00). Plasma CoQ₁₀ concentrations were determined by validated HPLC-UV and pharmacokinetic parameters were analyzed using noncompartmental methods. Cellular compatibility was assessed in Vero cells.

Results: The single-dose study in healthy adults demonstrated equivalent bioavailability of 1 g CoQ₁₀ administered via emulgel (25 g serving) and solid capsules (1 g CoQ₁₀ in two size-00 capsules). However, CoQ₁₀ in the emulgel exhibited faster and more efficient absorption. A 14-day repeated-dose study revealed significant higher plasma CoQ₁₀ concentrations with emulgel administration, potentially achieving therapeutic levels. A cellular compatibility assay confirmed the safety of the emulgel.

Conclusions: These findings indicate that the emulgel matrix does not compromise the bioavailability of oil-dissolved CoQ₁₀ and offers a promising, safe, and comfortable alternative for patients with dysphagia requiring long-term, high-dose CoQ₁₀ supplementation.

Background: The incidence of pediatric inflammatory bowel disease (IBD) rises yearly. Infliximab, a cornerstone of treatment, often has limited efficacy owing to high pharmacokinetic variability. Therapeutic drug monitoring and model-based precision dosing (MIPD) can improve optimal drug exposure.

Objective: This study aimed to evaluate the predictive performance of available pediatric infliximab population pharmacokinetic (popPK) models implemented in specialized software during the induction phase of IBD treatment.

Methods: This retrospective observational cohort study included patients from January 2021 to December 2024. Plasma trough concentrations of infliximab were measured using an enzyme immunoassay. Pharmacokinetic simulations were performed with TDMx software, applying eight different pediatric popPK models. Metrics used to evaluate predictive performance included root mean squared error (RMSE), mean squared error (MSE), mean absolute error (MAE), mean absolute percentage error (MAPE), coefficient of determination, and relative bias.

Results: A total of 29 patients were included (Crohn's disease, n = 24; ulcerative colitis, n = 5; 52% female). Median (range) age was 12 (1-18) years and weight was 32 (7-62) kg. During the induction phase, patients received a median infliximab dose of 6.1 (4.6-10.2) mg/kg per infusion. The model by Dubinsky showed the best performance, including MSE, RMSE, MAE, and R², followed by the models of Wojciechowski and Xiong.

Conclusions and relevance: Pharmacotherapeutic assistance using MIPD software for infliximab precision dosing during induction in pediatric IBD is feasible and sufficiently accurate for clinical practice. In our population, the Dubinsky model was optimal for integration into dosing systems, balancing predictive performance with reliable PK representation.

Introduction: Cachexia is a complex multi-organ syndrome characterized by systemic alterations that could impact drug pharmacokinetics. This scoping review aims to examine and synthesize existing research on the pathophysiological changes in cachexia that may influence drug pharmacokinetics.

Methods: A comprehensive literature search was conducted across five databases from inception to December 2024. Study selection was refined using the population, concept, and context (PCC) framework. The population included humans and animals with cachexia, the concept focused on cachexia-induced pathophysiological changes in relation to drug pharmacokinetics, and the context encompassed any clinical, healthcare setting, or laboratory settings.

Results: Out of 2684 identified studies, 53 met the inclusion criteria: 25 were based on human data, 18 on animal data, and 10 were reviews. The findings suggest that cachexia may impair drug absorption due to reduced skinfold thickness, gut dysbiosis, and structural and functional alterations in the gastrointestinal (GI) tract. Similarly, drug distribution may also be affected by changes in body composition and decreased serum albumin levels.

Conclusions: Pathophysiological changes in cachexia may lead to alterations in drug absorption and distribution, contributing to variability in drug bioavailability. However, the lack of controlled clinical trials directly linking cachexia-induced physiological changes to specific drug pharmacokinetics renders these findings tentative.

Background and objectives: Tapentadol is a novel, centrally acting, potent analgesic with a dual mechanism of action on µ-opioid receptors and noradrenaline reuptake in the central nervous system. This study was conducted to compare the pharmacokinetics, preliminary pharmacodynamics, and safety of single-dose tapentadol hydrochloride intravenous infusion (IV) with tapentadol hydrochloride oral immediate-release (IR) and tapentadol hydrochloride oral extended-release (ER).

Methods: In this randomized, open-label, multicenter, active-controlled, parallel-group phase 1 trial, 28 Chinese patients with moderate noncancer pain were randomly assigned in a 1:1:1 ratio to receive a single dose of either tapentadol IV (0.5 mg/kg), tapentadol IR (100 mg), or tapentadol ER (100 mg). Adverse events were monitored, serum samples were collected for pharmacokinetic analysis, and 11-point numeric rating scale (NRS) scores were recorded for preliminary pharmacodynamic evaluation during the study.

Results: The geometric mean (geomean) absolute bioavailability of tapentadol IR and ER after a single-dose administration under fasting conditions was 44.3% (90% confidence interval [CI] 37.5-52.3) and 34.0% (90% CI 27.1-52.3), respectively. The NRS scores demonstrated a decreasing trend across all three groups. Treatment-related adverse event (TRAE) occurred in 50.0% (tapentadol IV), 70% (tapentadol IR), and 50.0% (tapentadol ER) of patients. No events led to dose adjustment or interruption or necessitated additional concomitant medication, and there were no serious adverse events (SAEs), withdrawals, or deaths.

Conclusions: Tapentadol IV exhibits precise pharmacokinetics, promising pharmacodynamic properties, and a favorable safety profile compared with IR and ER routes for patients with moderate noncancer pain, supporting further clinical research and development of tapentadol injection.

Trial registration: http://www.chinadrugtrials.org.cn/ ; CTR20212327 2021-09-27.

Background and objective: Sunitinib malate is used to treat advanced renal cell carcinoma, gastrointestinal stromal, and pancreatic tumors. Wide variability in drug exposure is reported for both sunitinib and its active metabolite (SU12662). This review aimed to summarize reported population pharmacokinetics studies of sunitinib and to identify the factors affecting the pharmacokinetics of sunitinib and SU12662.

Methods: A systematic search was undertaken using Scopus, Web of Science, and PubMed databases following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were included in the review if population pharmacokinetic modeling approach was used for sunitinib and/or SU12662 in adult and/or pediatric population. Data quality was assessed using the percent compliance rate of each study.

Results: A total of 1820 articles were retrieved, and subsequently, 14 studies that met the inclusion criteria were included in the systematic review. Most of the studies reported two-compartment model with first-order absorption and elimination to describe sunitinib and SU12662. Body surface area, age, sex, ethnicity, tumor type, and ABCB1 and ABCG2 genotype were the significant covariates that affected the pharmacokinetics of sunitinib and SU12662.

Conclusions: According to the published data from the reported studies, various covariates alter sunitinib and SU12662 exposure and thus have the potential to influence the clinical outcome of sunitinib treatment. Predictive performance assessment of these published models should be performed before implementing these models during the routine clinical practice. The summarized significant covariates affecting pharmacokinetics (PK) of sunitinib and SU12662 will facilitate model-informed precision dosing of sunitinib therapy in a clinical setting.

Remimazolam, an ultrashort-acting benzodiazepine, has emerged as a promising sedative agent for procedural sedation and general anesthesia. It combines the favorable properties of traditional benzodiazepines with a rapid onset and offset of action, largely due to its unique metabolism via hepatic carboxylesterases rather than cytochrome P450 enzymes. This metabolism allows for predictable pharmacokinetics, reducing the risk of prolonged sedation and drug accumulation, particularly in patients with hepatic or renal impairment. Clinically, remimazolam demonstrates non-inferiority to midazolam and propofol, with advantages including a lower incidence of hypotension and respiratory depression. Multiple randomized controlled trials have shown its efficacy in various procedural settings, including endoscopy and bronchoscopy, with high procedural success rates and faster recovery times compared to midazolam. Additionally, remimazolam is reversible with flumazenil, further enhancing its safety profile. Pharmacokinetic studies indicate a rapid distribution phase, a short terminal half-life of approximately 37-53 min, and a clearance rate significantly higher than midazolam. Pharmacodynamic analyses confirm dose-dependent sedation effects, making remimazolam suitable for tailored sedation levels across patient populations. Special population studies suggest minimal impact of age, renal function, or mild-to-moderate hepatic impairment on drug disposition. However, rare cases of anaphylaxis and re-sedation following flumazenil administration have been reported. Given its rapid onset, predictable clearance, and favorable safety profile, remimazolam represents a valuable alternative to existing sedatives in procedural and anesthetic applications. Further research is warranted to explore its long-term safety, expanded clinical applications, and potential role in high-risk populations.