European Journal of Drug Metabolism and Pharmacokinetics最新文献

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.

Background and objective: Cenobamate is an antiseizure medication (ASM) approved for treatment of focal epilepsy in adults. The objective of this study was to characterize the distribution, metabolism, and excretion of cenobamate in adult and pre- and postnatal rats, including pregnant and lactating females and nursing pups.

Methods: Distribution, metabolic, and excretion profiles were determined for ¹⁴C-labeled and unlabeled cenobamate using liquid scintillation counting, radiochromatography, LCMS, and LCMS/MS after oral or intravenous (IV) administration.

Results: Distribution of ¹⁴C-cenobamate-related material in adult male rats was widespread throughout the body, with nearly 1:1 tissue-to-plasma ratios observed for most tissues, including brain. Cenobamate administered to pregnant females was also transferred across the placental barrier into amniotic fluid and fetal plasma. Following administration to lactating F₀ females, cenobamate was detected in breast milk and in plasma of nursing pups. ¹⁴C-cenobamate administered to adult male rats as a single oral dose was extensively metabolized with nine metabolites identified in urine and feces, including a principal dihydrodiol metabolite. Cenobamate was the principal drug-related material in rat plasma. Following a single dose of ¹⁴C-cenobamate to male and female rats, radioactivity was excreted equally into urine and feces, with mass balance achieved by 48 h postdose.

Conclusions: Distribution of cenobamate was widespread into many rat tissues, including brain, amniotic fluid, fetal plasma, breast milk, and breastfeeding rat pups. These distribution findings, along with the results of the metabolism and excretion studies, may help inform treatment decisions for patients with epilepsy being treated with cenobamate, including pregnant or nursing mothers.

Background and objective: Cyclophilin A (CypA) is an isomerase that functions as a chaperone, housekeeping protein, and cyclosporine A (CsA) ligand. Secreted CypA is a proinflammatory factor, chemoattractant, immune regulator, and factor of antitumor immunity. Experimental data suggest clinical applications of recombinant human CypA (rhCypA) as a biotherapeutic for cancer immunotherapy, stimulation of tissue regeneration, treatment of brain pathologies, and as a supportive treatment for CsA-based therapies. The objective of this study is to analyze the pharmacokinetics of rhCypA in a mouse model.

Methods: rhCypA was isotope-labeled with ¹²⁵I and injected intraperitoneally (i.p.) or subcutaneously (s/c) into female mice as a single dose of 100 μg per mouse, equivalent to the estimated first-in-human dose. Analysis of ¹²⁵I-rhCypA biodistribution and excretion was performed by direct radiometry of the blood, viscera, and urine of mice 0.5-72 h following its administration.

Results: rhCypA showed rapid and even tissue-organ distribution, with the highest tropism (f_T = 1.56) and accumulation (maximum concentration, C_max = 137-167 μg/g) in the kidneys, its primary excretory organ. rhCypA showed the lowest tropism to the bone marrow and the brain (f_T = 0.07) but the longest retention in these organs [mean retention time (MRT) = 25-28 h].

Conclusion: This study identified promising target organs for rhCypA's potential therapeutic effects. The mode of rhCypA accumulation and retention in organs could be primarily due to the expression of its receptors in them. For the first time, rhCypA was shown to cross the blood-brain barrier and accumulate in the brain. These rhCypA pharmacokinetic data could be extrapolated to humans as preliminary data for possible clinical trials.

Background and Objectives

Rhubarb anthraquinones contain five main components, that is, rhein, emodin, aloe-emodin, chrysophanol, and physcion, which demonstrate good therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, research on its pharmacokinetics in NAFLD remains lacking. This study aimed to investigate the pharmacokinetic differences of rhubarb anthraquinones in normal and NAFLD rats.

Methods

This study developed an NAFLD rat model by high-fat diet feeding for 6 weeks. Normal and NAFLD groups were orally administered different rhubarb anthraquinones doses (37.5, 75, and 150 mg/kg). The concentration of the rhein, emodin, aloe-emodin, chrysophanol, and physcion in plasma was determined by high-performance liquid chromatography–ultraviolet.

Results

The results revealed significant differences in pharmacokinetic behavior between normal and NAFLD rats. Compared with normal rats, NAFLD rats demonstrated significantly increased maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC_{0 → ∞}) of rhubarb anthraquinones (P < 0.05), as well as significantly prolonged time to reach maximum plasma concentration (T_max), terminal elimination half-life (t_1/2), and mean residence time (MRT) of rhubarb anthraquinones (P < 0.05).

Conclusions

This study indicates significant differences in the pharmacokinetics of rhubarb anthraquinones between the physiological and NAFLD states of rats. Rhubarb anthraquinone demonstrated a longer retention time and slower absorption rate in NAFLD rats and exhibited higher bioavailability and peak concentration. This finding provides important information for guiding the clinical use of rhubarb anthraquinones under pathological conditions.

Background and Objective

There are some potential concerns about the currently marketed solid oral dosage forms of tramadol, including decreased adherence to immediate-release (IR) formulations due to the high number of doses taken each day and the slow rise in the blood tramadol concentration after administration of sustained-release (SR) formulations, which may not achieve a rapid analgesic effect. To overcome these potential concerns, a twice-daily double-layered tablet formulation of tramadol comprising IR and SR layers was developed. This article reports studies that assessed its physicochemical and pharmacokinetic properties.

Methods

Dissolution tests of five bilayer tablet formulations (designated tablets A–E) and pharmacokinetic studies of tablets A and B were conducted to investigate the appropriate ratio of the IR/SR layers in the double-layered tablet. Additionally, pharmacokinetic studies of three finished dosage formulations (tablets C–E) were performed in healthy adult males to investigate the effect of food intake on drug absorption.

Results

Adjusting the excipients and tramadol content in the IR and SR layers of tablets A–E altered their dissolution profiles in a manner that could be predicted based on their compositions. The IR layer was released within 15 min, and the SR layer was slowly released over 10 h. In the pharmacokinetic study, the time to maximum plasma concentration (t_max) of tramadol after administration of tablets A (IR:SR: 20:80 mg) and B (40:60 mg) was shorter than that of a commercially available SR tablet, and the half-life (t_1/2) was longer than that of a commercially available IR tablet. For tablets C–E, administration after food did not affect the area under the concentration-time curve (AUC) or maximum drug concentration (C_max) of tramadol, but the t_max was prolonged by about 1 h compared with administration in fasting conditions. The mean ± standard deviation t_max and t_1/2 for tablet D (IR:SR: 35:65 mg) in the fasting condition was 1.09 ± 0.56 h and 7.82 ± 0.85 h, respectively. The respective values in the fed condition were 2.47 ± 1.06 h and 7.12 ± 0.85 h, respectively.

Conclusions

To address the potential concerns regarding existing formulations of tramadol, a twice-daily, extended-release bilayer formulation of tramadol consisting of an IR and SR layer was developed. Pharmacokinetic studies confirmed that the plasma tramadol concentration increased quickly after administration and was maintained over a long period of time.

Background: In patients with kidney or hepatic diseases, an increment of circulating pasireotide is also expected. Therefore, this open-label, phase I study aimed to evaluate the pharmacokinetic profiles and safety of subcutaneous (SC) and long-acting release (LAR) intramuscular injections of pasireotide in male Taiwanese volunteers who are hyperendemic hepatitis B/C and chronic kidney disease (CKD).

Methods: A total of 45 male volunteers were randomized to receive one of nine treatment sequences, involving a single subcutaneous injection of 300, 600, or 900 μg pasireotide, a multiple SC injection of the same dosage of pasireotide [300, 600, or 900 μg, twice daily (b.i.d.) for 4 days and a single dose for 1 day], and a single dose of 20, 40, or 60 mg LAR pasireotide intramuscular injection. The pasireotide SC and LAR formulations were prepared and supplied to the study center by Novartis. Pharmacokinetic parameters were assessed from both formulations. All adverse events that occurred in participants throughout the study period, including abnormalities in fasting levels of glucose, insulin, and glucagon, as well as laboratory measurements and electrocardiograms, were recorded.

Results: Analysis of plasma concentration over time revealed a rapid absorption of pasireotide, with a maximal concentration at 0.5 h after SC injection(s) of pasireotide (300-900 µg). Following a single dose of pasireotide LAR (20-60 mg), a sustained release was observed following an initial increase on day 1, a plateau around day 20, and a decline over the next 7 weeks.

Conclusions: Both pasireotide formulations showed dose-proportional pharmacokinetics and 300-900 μg of SC pasireotide and 20-60 mg LAR pasireotide treatment showed favorable safety profiles and was well-tolerated when administered in male Taiwanese volunteers who are hyperendemic hepatitis B/C and CKD.

Background and objectives: MYL-1402O is a bevacizumab (Avastin^®) biosimilar. Pharmacokinetic and safety similarity of MYL-1402O and reference Avastin^® authorized in the European Union (EU-Avastin^®) and the US (US-Avastin^®) was demonstrated in healthy subjects (phase I, NCT02469987). The key objectives of this study were to establish a population pharmacokinetic (PopPK) model on pooled data from the phase I and phase III clinical studies to assess pharmacokinetic linearity of MYL-1402O and Avastin^® across dose ranges, to assess the pharmacokinetic similarity of MYL-1402O and Avastin^® in patients with non-squamous non-small cell lung cancer (nsNSCLC), and to explore potential covariates to account for systematic sources of variability in bevacizumab exposure.

Methods: Efficacy and safety of MYL-1402O compared with EU-Avastin^® was investigated in a multicenter, double-blind, randomized, parallel-group study in patients with stage IV nsNSCLC (phase III, NCT04633564). PopPK models were developed using a nonlinear mixed effects approach (NONMEM^® 7.3.0).

Results: The pharmacokinetics of Avastin^® and MYL-1402O were adequately described with a two-compartment linear model. Fourteen covariates were found to be statistically significant predictors of bevacizumab pharmacokinectics. The impact of each covariate on area under the concentration-time curve, half-life, and maximum plasma concentration was modest, and ranges were similar between the treatment groups, MYL-1402O and EU-Avastin^®, in patients with nsNSCLC. The pharmacokinectics of bevacizumab appeared to be linear.

Conclusions: PopPK analysis revealed no significant differences between pharmacokinetics of MYL-1402O and Avastin^® in patients with nsNSCLC. The developed PopPK model was considered robust, as it adequately described bevacizumab pharmacokinetics in healthy participants and nsNSCLC patients.