European Journal of Drug Metabolism and Pharmacokinetics最新文献

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: Acquired hemophilia A (AHA) is a rare blood disorder with high morbidity and even mortality as severe bleeding can occur in up to 90% of affected patients. Unlike congenital hemophilia which presents with intra-articular bleeding, acquired hemophilia causes bleeding into the skin, muscle, mucous membranes and soft tissues.

Case presentation: We report an unusual case of upper airway hematoma in a 61-year-old man who presented with acute onset dysphagia and shortness of breath. There were bruises on his neck and blood clots on the floor of mouth when he was examined. Endoscopic examination revealed an extensive laryngeal hematoma. A prolonged activated partial thromboplastin time (APTT) prompted us to investigate for factor VIII deficiency leading to the diagnosis of AHA. He recovered completely after a treatment regime instituted by the hematology team without suffering any grave debilitating events.

Conclusion: AHA with laryngeal hematoma is a rare condition with only a handful of cases reported. Although a life-threatening disease, it is easily reversed with early recognition and administration of medical therapy involving the hematology team.

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.

Background and objective: HSK21542, a synthetic short-chain polypeptide, is a selective peripheral kappa opioid receptor (KOR) agonist. In this single-centre, non-randomized, open-label study, the pharmacokinetics, mass balance, metabolism and excretion of HSK21542 were investigated.

Methods: A single intravenous dose of 2 μg/0.212 μCi/kg [¹⁴C]HSK21542 was administered to six healthy male subjects. Samples of blood, urine and faeces were collected for quantitative determination of total radioactivity and unchanged HSK21542, and identification of metabolites.

Results: The mean total recovery was 81.89% of the radiolabelled dose over 240 h post-dose, with 35.60% and 46.30% excreted in faeces and urine, respectively. The mean maximum concentration (C_max), the half-life (t_1/2) and the area under the concentration-time curve (AUC_0-t) of total radioactivity (TRA) in plasma were 20.4 ±4.16 ng Eq./g, 1.93 ± 0.322 h and 21.8 ± 2.93 h·ng Eq./g, respectively, while the C_max, t_1/2 and the AUC_0-t of unchanged HSK21542 were 18.3 ± 3.36 ng/mL, 1.66 ± 0.185 h and 18.4 ± 2.24 h·ng/mL, respectively. The blood-to-plasma ratios of TRA at several times ranged from 0.46 to 0.54. [¹⁴C]HSK21542 was detected as the main circulating substance in plasma, accounting for 92.17% of the AUC of TRA. The unchanged parent compound was the only major radioactive chemical in urine (100.00% of TRA) and faeces (93.53% of TRA). Metabolites were very minor components.

Conclusions: HSK21542 was barely metabolized in vivo and mainly excreted with unchanged HSK21542 as its main circulating component in plasma. It was speculated that renal excretion was the principal excretion pathway, and faecal excretion was the secondary pathway.

Clinical trial registration number: NCT05835934.

Background and objectives: Ripretinib was developed to target a whole range of KIT proto-oncogene mutations and platelet-derived growth factor receptor A (PDGFR-A) kinases found in certain cancers and myeloproliferative neoplasms, particularly gastrointestinal stromal tumours (GISTs). This study investigated the effect of verapamil, a potential inhibitor of P-glycoprotein-1 (P-gp1) and cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics of ripretinib in rats when administered orally together. This study also assessed the metabolic stability and in vitro cellular absorption of ripretinib in the presence of verapamil.

Methods: A novel sensitive time-saving liquid chromatography tandem mass spectometry (LC-MS/MS) technique for determining ripretinib in rat plasma was developed and validated. A Zorbax SB C18 column was used for the separation and analysis of ripretinib with a mobile phase consisting of 50:50 (%v/v) acetonitrile and 10 mM ammonium formate buffer at a flow rate of 0.4 mL/min. Imatinib was used as an internal standard (IS) in the method. The pharmacokinetic characteristics of ripretinib were evaluated in Wistar rats by successfully administering an oral dosage of 5 mg/kg body weight of ripretinib in the presence of verapamil (10 mg/kg body weight). Subsequently, rat liver microsomes were used to assess the effect of verapamil on ripretinib metabolic stability, and absorption was tested using a Caco-2 cell transwell model.

Results: Ripretinib and IS were identified using multiple reaction monitoring (MRM) modes by mass spectrometry and showed ion transitions of 510.09→94.06 m/z and 494.26→ 394.16 m/z, respectively. The high-performance liquid chromatography (HPLC) method successfully eluted ripretinib and IS at retention times of 0.91 and 0.68 min, respectively, and the method was validated for all parameters and met the criteria for acceptance. Co-administration of verapamil increased the maximum concentration (C_max) of ripretinib from 437 ± 84 ng/mL to 492 ± 50 ng/mL (12%), and the area under the concentration-time curve from 0 to the last sampling time t (AUC_0-t) increased by approximately 40.6%. Verapamil significantly reduced the basolateral-to-apical transfer of ripretinib through Caco-2 cells. Findings also showed that verapamil increased the metabolic stability of ripretinib.

Conclusion: The study results indicate that the co-administration of ripretinib with CYP3A4 and/or P-gp1 inhibitors is associated with significant drug-drug interactions that affect the pharmacokinetics of ripretinib. Further research in human subjects is suggested to confirm dosage adjustment and therapeutic drug monitoring of ripretinib when administered along with P-gp1/CYP3A4 inhibitors ensuring patient safety and optimizing the therapeutic benefits of ripretinib.