European Journal of Drug Metabolism and Pharmacokinetics最新文献

BACKGROUND AND OBJECTIVE: Attention deficit hyperactivity disorder is one of the most common neuropsychiatric conditions in children, and methylphenidate (MPH) is one of the first-line therapies. MPH is available in a variety of extended-release (ER) formulations worldwide, and most formulations are not considered bioequivalent due to differences in pharmacokinetics. It is hypothesized that the current bioequivalence guidelines from the different regulatory bodies may generate inconsistent findings or recommendations when assessing the bioequivalence of ER MPH formulations. This manuscript aims to conduct a comprehensive and narrative critical literature review to analyze pharmacokinetic data pertaining to ER formulations of MPH in order to assess bioequivalence, differences in regulatory guidelines, and additional pharmacokinetic-pharmacodynamic parameters that may help define interchangeability.

Methods: A literature search was conducted in EMBASE, Medline, and Cochrane Library with no time limits. Study characteristics, non-compartmental pharmacokinetic parameters, and bioequivalence data were extracted for analysis.

Results: Thirty-three studies were identified with primary pharmacokinetic data after the administration of ER MPH, of which 10 were direct comparative studies (i.e., at least 2 formulations tested within a single setting) and 23 were indirect comparisons (i.e., different experimental settings). Two formulations were consistently reported as bioequivalent across the regulatory bodies using criteria from their guidance documents, although inconsistencies have been observed. However, when additional kinetic criteria (discussed in this manuscript) were imposed, only one study met the more stringent definition of bioequivalence. Various clinical factors also had inconsistent effects on the pharmacokinetics and interchangeability of the different formulations, which were associated with a lack of standardization for assessing covariates across the regulatory agencies.

Conclusion: Additional pharmacokinetic parameters and consistency in guidelines across the regulatory bodies may improve bioequivalence assessments. Based on our findings, more research is also required to understand whether bioequivalence is an appropriate measure for determining MPH interchangeability. This critical review is suitable for formulation scientists, clinical pharmacologists, and clinicians.

Background and objective: Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats.

Methods: Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software.

Results: After single-dose co-administration of imatinib and metformin on day 1, the AUC_0-24 (area under the plasma concentration-time curve) and C_max (maximum concentration) of imatinib and the MRT (mean residence time) and C_max of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC_0-24 and C_max of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05).

Conclusion: With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.

Background and objectives: Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selective deuteration of TCAs on their pharmacokinetic and pharmacodynamic profile by comparison with their nondeuterated counterparts.

Methods: In the current study, the pharmacokinetic profile and antidepressant behavior of deuterated TCAs were evaluated using the forced swim test (FST) and tail suspension test (TST), using male Wistar rats and male Swiss albino mice, respectively; additionally, a synaptosomal reuptake study was carried out.

Results: Compared with the nondeuterated parent drugs, deuterated forms showed improved efficacy in the behavior paradigm, indicating improved pharmacological activity. The pharmacokinetic parameters indicated increased maximum concentration in the plasma (C_max), elimination half-life (t_1/2), and area under the concentration-time curve (AUC)  in deuterated compounds. This can have a positive clinical impact on antidepressant treatment. Synaptosomal reuptake studies indicated marked inhibition of the reuptake mechanism of serotonin (5-HT) and norepinephrine.

Conclusions: Deuterated TCAs can prove to be potentially better molecules in the treatment of neuropsychiatric disorders as compared with nondeuterated compounds. In addition, we have demonstrated a concept that metabolically active, site-selective deuteration can be beneficial for improving the pharmacokinetic and pharmacodynamic profiles of TCAs. A further toxicological study of these compounds is needed to validate their future clinical use.

Background

Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay.

Objective

The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic–pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters.

Methods

Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P^®). The predictive performance of the previously developed pharmacokinetic–pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed.

Results

The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC₅₀ and E_max values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%).

Conclusion

Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.

Background and objective: The biopharmaceutics drug disposition classification system (BDDCS) categorizes drugs into four classes on the basis of their solubility and metabolism. This framework allows for the study of the pharmacokinetics of transporters and enzymatic metabolization on biopharmaceuticals, as well as drug-drug interactions in the body. The objective of the present study was to develop computational models by neural network models and structural parameters and physicochemical properties to estimate the class of a drug in the BDDCS system.

Methods: In this study, deep learning methods were utilized to explore the potential of artificial and convolutional neural networks (ANNs and CNNs) in predicting the BDDCS class of 721 substances. The structural parameters and physicochemical properties [Abraham solvation parameters, octanol-water partition (log P) and over the pH range 1-7.5 (log D), number of rotatable bonds, hydrogen bond acceptor numbers, as well as hydrogen bond donor count] are calculated with various software. These compounds were then split into a training set consisting of 602 molecules and a test set of 119 compounds to validate the models.

Results: The results of this study showed that neural network models using applied parameters of the drug, i.e., log D and Abraham solvation parameters, are able to predict the class of solubility and metabolism in the BDDCS system with good accuracy.

Conclusions: Neural network models are well equipped to deal with the relations between the structural parameters and physicochemical properties of drugs and BDDCS classes. In addition, log D is a more suitable parameter compared with log P in predicting BDDCS.

Aim: 4-Hydroxybenzaldehyde (4-HBd) is used for the treatment of headaches, dizziness, and convulsions. The objective of this study was to characterize the pharmacokinetics of 4-HBd in cerebral ischemia-reperfusion injury (CIRI) rats by microdialysis technology with high-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS).

Methods: Microdialysis was used to collect blood, feces, and urine of normal and CIRI model rats. Pharmacokinetic parameters were determined using HPLC-DAD and 4-HBd metabolites were determined using UPLC-MS.

Results: After gavage of 4-HBd in normal and middle cerebral artery occlusion/reperfusion (MCAO/R) rats, it was widely distributed to all tissues (heart, liver, spleen, lung, kidney, and brain) in both the equilibrium and elimination phases, and the distribution pattern was basically the same; the highest concentration was found in the brain. The absolute bioavailability of 4-HBd was 5.33%; however, after intragastric administration in normal and MCAO/R rats, fecal and urinary excretion of 4-HBd accounted for 0.02% and 0.01% and for 0.01% and 0.03% of the dosage, respectively. Furthermore, 4-HBd was rapidly metabolized into 4-hydroxybenzoic acid (4-HBA) after administration in both the control and MCAO/R groups. Compared with the control, the peak time of 4-HBd plasma concentration in the MCAO/R rats decreased from 10.67 min to 8.83 min, the area under the concentration-time curve decreased significantly, and the half-life increased from 31.81 min to 78.85 min.

Conclusions: The rapid absorption and low absolute bioavailability of 4-HBd by gavage in rats are followed by rapid and wide distribution to various tissues and organs, including the brain. The prototype drug is excreted in the feces and urine in low amounts, and it is metabolized to 4-HBA in large amounts in vivo; the pathological state of the MCAO/R model mainly affects its absorption degree and metabolism rate.

Background: Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization.

Methods: In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects (n = 6) received a single dose of 50 mg eliapixant blended with 3.7 MBq [¹⁴C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human in vitro systems and metabolizing enzymes were also investigated.

Results: After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2 h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3 h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3-99.4%) within 14 days, with 86.3% (84.8-88.1%) excreted via feces and 11.6% (9.5-13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈ 0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the in vitro experiments were similar to those identified in vivo.

Conclusion: Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (> 90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~ 1% of dose).

Clinical trial registration: ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017).

Background and objective: Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for patients with rheumatic diseases, is sparse on cytochrome P450 (CYP)-mediated metabolism. We have shown that pre-treatment with pantoprazole does not alter HCQ absorption in healthy volunteers. In this paper, we report the effects of a single 400 mg dose of HCQ on specific CYP3A and CYP2D6 substrates in healthy volunteers.

Methods: In the trial, participants were randomized into two groups (HCQ plus a 9-day course of pantoprazole, or HCQ only). As a secondary endpoint, the effects of a single oral dose of HCQ on the exposure of the oral microdosed CYP3A probe drug midazolam (30 μg) and the oral microdosed CYP2D6 probe drug yohimbine (50 μg) were studied in 23 healthy volunteers (EudraCT no. 2020-001470-30, registered 31 March 2020).

Results: The exposure of the probe drugs after intake of HCQ compared with baseline values was quantified by the partial area under the plasma concentration-time curve 0-6 h after administration (AUC_0-6 h) for yohimbine and the partial AUC_2-4 h for midazolam. Under HCQ, yohimbine AUC_0-6 h was unchanged, independent of CYP2D6 genotypes and pantoprazole exposure. Midazolam AUC_2-4 h was 25% higher on the day of HCQ administration than at baseline (p = 0.0007). This significant increase was driven by the pantoprazole subgroup, which showed a 46% elevation of midazolam AUC_2-4 h as compared with baseline (p < 0.0001). The ratio of midazolam to 1-OH-midazolam partial AUC_2-4 h significantly increased from 3.03 ± 1.59 (baseline) to 3.60 ± 1.56 (HCQ) in the pantoprazole group (p = 0.0026).

Conclusion: In conclusion, we observed an increased midazolam exposure most likely related to pantoprazole.

Background and objective: Imatinib is a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML). The area under the concentration-time curve (AUC) is a pharmacokinetic parameter that symbolizes overall exposure to a drug, which is correlated with complete cytogenetic and treatment responses to imatinib, as well as its side effects in patients with CML. The limited sampling strategy (LSS) is considered a sufficiently precise and practical method that can be used to estimate pharmacokinetic parameters such as AUC, without the need for frequent, costly, and inconvenient blood sampling. This study aims to investigate the pharmacokinetic parameters of imatinib, develop and validate a reliable and practical LSS for estimating imatinib AUC_0-24, and determine the optimum sampling points for predicting the imatinib AUC after the administration of once-daily imatinib in Palestinian patients with CML.

Method: Pharmacokinetic profiles, involving six blood samples collected during a 24-h dosing interval, were obtained from 25 Palestinian patients diagnosed with CML who had been receiving imatinib for at least 7 days and had reached a steady-state level. Imatinib AUC_0-24 was calculated using the trapezoidal rule, and linear regression analysis was performed to assess the relationship between measured AUC_0-24 and concentrations at each sampling time. All developed models were analyzed to determine their effectiveness in predicting AUC_0-24 and to identify the optimal sampling time. To evaluate predictive performance, two error indices were employed: the percentage of root mean squared error (% RMSE) and the mean predictive error (% MPE). Bland and Altman plots, along with mountain plots, were utilized to assess the agreement between measured and predicted AUC.

Results: Among the one-timepoint estimations, predicted AUC_0-24 based on concentration of imatinib at the eighth hour after administration (C₈-predicted AUC_0-24) demonstrated the highest correlation with the measured AUC (r² = 0.97, % RMSE = 6.3). In two-timepoint estimations, the model consisting of C₀ and C₈ yielded the highest correlation between predicted and measured imatinib AUC (r² = 0.993 and % RMSE = 3.0). In three-timepoint estimations, the combination of C₀, C₁, and C₈ provided the most robust multilinear regression for predicting imatinib AUC_0-24 (r² = 0.996, % RMSE = 2.2). This combination also outperformed all other models in predicting AUC. The use of a two-timepoint limited sampling strategy (LSS) for predicting AUC was found to be reliable and practical. While C₀/C₈ exhibited the highest correlation, the use of C₀/C₄ could be a more practical and equally accurate choice. Therapeutic

BACKGROUND AND OBJECTIVE: Platelets play a pivotal role in thrombotic events associated with acute coronary syndrome (ACS), making oral antiplatelet therapy a cornerstone in antithrombotic strategies. The dosing regimen for the oral antiplatelet drug ticagrelor warrants evaluation to ensure its appropriateness in clinical practice. Therefore, this study aimed to investigate the real-world clinical application of ticagrelor by determining the optimal therapeutic concentration of ticagrelor in Chinese patients undergoing percutaneous coronary intervention (PCI).

Methods: We enrolled a cohort of 912 patients who underwent PCI with drug-eluting stent implantation for the treatment of ACS. We measured steady-state plasma drug concentrations using high-performance liquid chromatography-tandem mass spectrometry. The therapeutic drug concentration range at steady state was established on the basis of clinical pharmacodynamic indices, with verification of reliability through concentration-effect analysis and receiver operating characteristic curve assessment.

Results: Analysis of plasma samples from the 912 patients revealed significant variations in the steady-state trough concentration of ticagrelor associated with factors such as gender, age, hypertension, and hyperlipidemia. On the basis of this analysis, the optimal therapeutic range for steady-state trough concentration was determined to be 240.65-335.83 ng/mL. Furthermore, the upper limit values for steady-state concentration were established at 439.97 ng/mL for male patients and 347.06 ng/mL for female patients.

Conclusions: This study provides robust and reliable insights into the optimal therapeutic steady-state trough concentrations of ticagrelor in Chinese patients with post-percutaneous coronary intervention. These findings have significant implications for guiding the rational use of antiplatelet drugs and facilitating precise drug administration in Chinese patients undergoing percutaneous coronary intervention.