European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objective: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator.

Methods: A 3/8-inch, simulated, ex vivo closed-loop ECMO circuit was prepared with a Quadrox-iD adult oxygenator and primed with fresh whole blood. Cefiderocol was administered into the circuit to achieve a starting concentration of approximately 90 mg/L. Post-oxygenator blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 h after the addition of the drug to determine the loss in the circuit. A glass control jar was prepared with the same blood matrix and maintained at the same temperature to determine drug degradation. The experiment was conducted in triplicate. The rate of cefiderocol loss in the ECMO circuit was compared with that in the control by one-way analysis of variance.

Results: At 0 h, the difference between the pre- and post-oxygenator concentrations was - 4 ± 4% (range 0 to - 7%). After 24 h, the cefiderocol percent reduction was similar between the ECMO circuit and control (50% ± 13 vs. 50% ± 9, p = 1.0).

Conclusions: The degradation rate of cefiderocol did not differ significantly within the ECMO circuit and control, suggesting no loss due to sequestration or adsorption. Pharmacokinetic studies in patients supported by ECMO are warranted to determine final dosing recommendations.

Background and objectives: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers.

Methods: In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics.

Results: The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity (AUC_0-inf) by 104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC_0-inf by 84%.

Conclusion: Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.

Background and objectives: Current anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass‑balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug-drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported.

Methods: The mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [¹⁴C]asundexian) and in BDC rats (intravenous [¹⁴C]asundexian 1 mg/kg).

Results: Overall recovery of radioactivity was 101% for humans (samples collected up to 14 days after dosing), and 97.9% for BDC rats (samples collected in the 24 h after dosing). Radioactivity was mainly excreted into feces in humans (80.3%) and into bile/feces in BDC rats (> 94%). The predominant clearance pathways in humans were amide hydrolysis to metabolite M1 (47%) and non-labeled M9 with subsequent N-acetylation to M10; oxidative biotransformation was a minor pathway (13%). In rats, hydrolysis of the terminal amide to M2 was the predominant pathway. In human plasma, asundexian accounted for 61.0% of total drug-related area under the plasma concentration-time curve (AUC); M10 was the major metabolite (16.4% of the total drug-related AUC). Excretion of unmetabolized drug was a significant clearance pathway in both species (human, ~ 37%; BDC rat, ~ 24%). The near-complete bioavailability of asundexian suggests negligible limitations on absorption and first-pass metabolism. Comparison with radiochromatograms from incubations with human or rat hepatocytes indicated consistency across species and a good overall in vitro/in vivo correlation.

Conclusions: Similar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.

Background and objective: Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells. p-boronophenylalanine (BPA) is widely used in BNCT but is insoluble in water and requires reducing sugar or sugar alcohol as a dissolvent to create an aqueous solution for administration. The purpose of this study was to investigate the pharmacokinetics of ¹⁴C-radiolabeled BPA using sorbitol as a dissolvent, which has not been reported before, and confirm whether neutron irradiation with a sorbitol solution of BPA can produce an antitumor effect of BNCT.

Materials and methods: In this study, we evaluated the sugar alcohol, sorbitol, as a novel dissolution aid and examined the consequent stability of the BPA for long-term storage. U-87 MG and SAS tumor cell lines were used for in vitro and in vivo experiments. We examined the pharmacokinetics of ¹⁴C-radiolabeled BPA in sorbitol solution, administered either intravenously or subcutaneously to a mouse tumor model. Neutron irradiation was performed in conjunction with the administration of BPA in sorbitol solution using the same tumor cell lines both in vitro and in vivo.

Results: We found that BPA in sorbitol solution maintains stability for longer than in fructose solution, and can therefore be stored for a longer period. Pharmacokinetic studies with ¹⁴C-radiolabeled BPA confirmed that the sorbitol solution of BPA distributed through tumors in much the same way as BPA in fructose. Neutron irradiation was found to produce dose-dependent antitumor effects, both in vitro and in vivo, after the administration of BPA in sorbitol solution.

Conclusion: In this report, we demonstrate the efficacy of BPA in sorbitol solution as the boron source in BNCT.

Background: The demand for physiologically based pharmacokinetic (PBPK) model is increasing currently. New drug application (NDA) of many compounds is submitted with PBPK models for efficient drug development. Tissue-to-plasma partition coefficient (K_p) is a key parameter for the PBPK model to describe differential equations. However, it is difficult to obtain the K_p value experimentally because the measurement of drug concentration in the tissue is much harder than that in plasma.

Objective: Instead of experiments, many researchers have sought in silico methods. Today, most of the models for K_p prediction are using in vitro and in vivo parameters as explanatory variables. We thought of physicochemical descriptors that could improve the predictability. Therefore, we aimed to develop the two-dimensional quantitative structure-activity relationship (2D-QSAR) model for K_p using physicochemical descriptors instead of in vivo experimental data as explanatory variables.

Methods: We compared our model with the conventional models using 20-fold cross-validation according to the published method (Yun et al. J Pharmacokinet Pharmacodyn 41:1-14, 2014). We used random forest algorithm, which is known to be one of the best predictors for the 2D-QSAR model. Finally, we combined minimum in vitro experimental values and physiochemical descriptors. Thus, the prediction method for K_p value using a few in vitro parameters and physicochemical descriptors was developed; this is a multimodal model.

Results: Its accuracy was found to be superior to that of the conventional models. Results of this research suggest that multimodality is useful for the 2D-QSAR model [RMSE and % of two-fold error: 0.66 and 42.2% (Berezohkovsky), 0.52 and 52.2% (Rodgers), 0.65 and 34.6% (Schmitt), 0.44 and 61.1% (published model), 0.41 and 62.1% (traditional model), 0.39 and 64.5% (multimodal model)].

Conclusion: We could develop a 2D-QSAR model for K_p value with the highest accuracy using a few in vitro experimental data and physicochemical descriptors.

Background and objective: Lu-177 DOTATATE (Lutathera^®) is a radiolabeled analog of somatostatin administered intravenously in patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Biodistribution of Lu-177 DOTATATE in tumor and healthy tissues can be monitored by serial post-injection scintigraphy imaging. Patient exposure to the drug is variable with the recommended fixed dosage, and hence there is a variable response to treatment. The aim of this work was to study the pharmacokinetics of Lu-177 DOTATATE by a population modeling approach, based on single-photon emission computed tomography (SPECT)/computed tomography (CT) images used as surrogate of plasma concentrations to study the interindividual variability and finally optimize an individual dosage.

Methods: From a retrospective study, SPECT/CT images were acquired at 4 h, 24 h, 72 h, and 192 h postadministration. From these images, volumic activities were calculated in blood and bone marrow. An individual non-compartmental pharmacokinetic analysis was performed, and the mean pharmacokinetic parameters of each tissue were compared together and with reference data. Blood volumic activities were then used to perform a population pharmacokinetic analysis (NONMEM).

Results: The pharmacokinetic parameters (non-compartmental analysis) obtained from blood (clearance [CL] = 2.65 L/h, volume of distribution at steady state [Vss] = 309 L, elimination half-life [t_1/2] = 86.3 h) and bone marrow (CL =1.68 L/h, Vss = 233 L, t_1/2 = 98.8 h) were statistically different from each other and from reference values (CL = 4.50 L/h, Vss = 460 L, t_1/2 = 71.0 h) published in the literature. SPECT/CT blood images were used as a surrogate of plasma concentrations to develop a population pharmacokinetic model. Weight was identified as covariate on volume of the central compartment, reducing the interindividual variability of all population pharmacokinetic parameters.

Conclusion: This study is a proof of concept that obtaining pharmacokinetic parameters with image-based blood concentration is possible. Obtaining observed concentrations from SPECT/CT images, without the need for blood sampling, is a real advantage for the patient and the drug monitoring. Pharmacokinetic modeling could be combined with a deep learning model for automatic contouring and allow precise patient-specific dose adjustment in a non-invasive manner.

Background and objective: Taohong Siwu Decoction (TSD) is a classic traditional Chinese medicine (TCM) compound with pharmacological effects such as vasodilation and hypolipidemia. Paeoniflorin (PF) is one of the active ingredients of TSD. The aim of this study was to evaluate the pharmacokinetics of PF in herbal extracts and their purified forms in rats.

Method: A sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method for the determination of PF in rat plasma was developed. Rats were divided into three groups, and given PF solution, water extract of white peony root (WPR), or TSD by gavage. At different predetermined timepoints after gavage, blood was collected from the orbital vein. The pharmacokinetic parameters of PF in the plasma of rats in the three groups was determined.

Results: The pharmacokinetic studies showed that the time to reach maximum concentration (T_max) of PF in the purified forms group was relatively high, while the half-lives (T_½) of PF in the TSD and WPR groups were longer. Among the three groups, PF in the purified forms group had the maximum area under the concentration-time curve (AUC_0-t = 732.997 µg/L·h) and the largest maximum concentration (C_max = 313.460 µg/L), which showed a significant difference compared with the TSD group (P < 0.05). Compared with the purified group, the clearance (CL_z/F = 86.004 L/h/kg) and the apparent volume of distribution (V_z/F = 254.787 L/kg) of PF in the TSD group increased significantly (P < 0.05).

Conclusions: A highly specific, sensitive, and rapid HPLC-MS-MS method was developed and applied for the determination of PF in rat plasma. It was found that TSD and WPR can prolong the action time of paeoniflorin in the body.

Background and objective: Pethidine (meperidine) can decrease labor pain-associated mother's hyperventilation and high cortisol-induced newborn complications. However, prenatal transplacentally acquired pethidine can cause side effects in newborns. High pethidine concentrations in the newborn brain extracellular fluid (bECF) can cause a serotonin crisis. Therapeutic drug monitoring (TDM) in newborns' blood distresses them and increases infection incidence, which can be overcome by using salivary TDM. Physiologically based pharmacokinetic (PBPK) modeling can predict drug concentrations in newborn plasma, saliva, and bECF after intrauterine pethidine exposure.

Methods: A healthy adult PBPK model was constructed, verified, and scaled to newborn and pregnant populations after intravenous and intramuscular pethidine administration. The pregnancy PBPK model was used to predict the newborn dose received transplacentally at birth, which was used as input to the newborn PBPK model to predict newborn plasma, saliva, and bECF pethidine concentrations and set correlation equations between them.

Results: Pethidine can be classified as a Salivary Excretion Classification System class II drug. The developed PBPK model predicted that, after maternal pethidine intramuscular doses of 100 mg and 150 mg, the newborn plasma and bECF concentrations were below the toxicity thresholds. Moreover, it was estimated that newborn saliva concentrations of 4.7 µM, 11.4 µM, and 57.7 µM can be used as salivary threshold concentrations for pethidine analgesic effects, side effects, and the risk for serotonin crisis, respectively, in newborns.

Conclusion: It was shown that saliva can be used for pethidine TDM in newborns during the first few days after delivery to mothers receiving pethidine.

Background and objectives: Understanding predictive potential of parameters to perform early bioequivalence (BE) risk assessment is crucial for good planning and risk mitigation during product development. The objective of the present study was to evaluate predictive potential of various biopharmaceutical and pharmacokinetic parameters on the outcome of BE study.

Methods: Retrospective analysis was performed on 198 Sandoz (Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526 Ljubljana, Slovenia) sponsored BE studies [52 active pharmaceutical ingredients (API)] where characteristics of BE study and APIs were collected for immediate-release products and their predictive potential on the study outcome was assessed using univariate statistical analysis.

Results: Biopharmaceutics Classification System (BCS) was confirmed to be highly predictive of BE success. BE studies with poorly soluble APIs were riskier (23% non-BE) than with highly soluble APIs (0.1% non-BE). APIs with either lower bioavailability (BA), presence of first-pass metabolism, and/or being substrate for P-glycoprotein substrate (P-gP) were associated with higher non-BE occurrence. In silico permeability and time at peak plasma concentrations (T_max) were shown as potentially relevant features for predicting BE outcome. In addition, our analysis showed significantly higher occurrence of non-BE results for poorly soluble APIs with disposition described by multicompartment model. The conclusions for poorly soluble APIs were the same on a subset of fasting BE studies; for a subset of fed studies there were no significant differences between factors in BE and non-BE groups.

Conclusion: Understanding the association of parameters and BE outcome is important for further development of early BE risk assessment tools where focus should be first in finding additional parameters to differentiate BE risk within a group of poorly soluble APIs.

Background and objectives: The role of therapeutic drug monitoring for ustekinumab in the treatment of Crohn's disease has not been defined. This study aimed to explore the relationship of serum ustekinumab trough concentration (UTC) with clinical and biochemical disease outcomes in a real-world setting.

Methods: We performed a retrospective analysis of Crohn's disease patients treated at a single tertiary centre. Ustekinumab was given as a single intravenous induction dose, followed by maintenance subcutaneous injections every 4 to 8 weeks. Rates of clinical remission (Harvey-Bradshaw Index ≤ 4), biochemical remission (C-reactive protein < 5 mg/l and faecal calprotectin < 150 μg/g) and complete remission were assessed at baseline and at the time of UTC testing during maintenance therapy. The association between baseline variables and UTC was tested using linear regression. We also performed an external validation analysis of UTC cut-offs established in four previously published studies.

Results: This study included 43 patients. Compared to 8-weekly dosing, a 2.49- and 2.65-fold increase in UTC was associated with 6-weekly and 4-weekly dosing respectively. However, there was no significant difference in clinical, biochemical or complete remission among the dosing groups. An external validation of previously published optimal UTC cut-offs found low predictive value for our patient population.

Conclusions: In this study, dosing interval was the only determinant significantly associated with a higher UTC for patients on maintenance ustekinumab therapy. While a higher UTC may be achieved with dose escalation, it was not associated with improved rates of clinical or biochemical response in our cohort.