European Journal of Drug Metabolism and Pharmacokinetics最新文献

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.

Background and objective: It remains unclear whether sepsis in patients with malignancy interferes with the predictive performance of the dose-estimation formulas. The quick sequential organ failure assessment (qSOFA) score can help identify patients with poor outcomes because of sepsis-associated organ damage. Vancomycin, an important antibiotic, treats systemic infections (sepsis) caused by methicillin-resistant Staphylococcus aureus. We aimed to clarify whether including the qSOFA score in a standard population pharmacokinetic (PopPK) assessment may improve the predictive performance of vancomycin doses in patients with malignancy.

Methods: This was a retrospective, observational study. Serum vancomycin concentration-time datasets were obtained from the therapeutic drug monitoring records of St. Luke's International Hospital (Tokyo, Japan) from January 2011 to August 2016. Clinical and laboratory data of the relevant patients were retrieved from electronic health records. PopPK analysis was performed using the NONMEM program, which includes creatinine clearance (CLCr), blood neutrophil counts, qSOFA scores, and type of malignancy as covariates. We examined the validity of the final PopPK model using bootstrapping, goodness-of-fit plots, and prediction-corrected visual predictive checks.

Results: Six hundred and eight blood samples were obtained from 325 patients. In the final PopPK model, the CLCr and qSOFA scores were selected as covariates of systemic vancomycin clearance (p < 0.05): the population mean value was 2.8 (L/h). Regardless of the CLCr, a qSOFA score of greater than 1 was associated with an approximately 10% reduction in vancomycin clearance.

Conclusions: qSOFA scores might be an additional covariate to CLCr for estimating vancomycin concentrations with a PopPK model in patients with malignancy.

BACKGROUND AND OBJECTIVES: Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute inflammation as represented by interleukin-6 (IL-6) levels on drug clearance, focusing on renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism.

Methods: A physiologically based model incorporating renal and hepatic drug clearance was implemented. Functions correlating IL-6 levels with GFR and in vitro CYP3A4 activity were derived and incorporated into the modeling framework. We then simulated treatment scenarios for hypothetical drugs by varying the IL-6 levels, the contribution of renal and hepatic drug clearance, and protein binding. The relative change in observed area under the concentration-time curve (AUC) was computed for these scenarios.

Results: Inflammation showed opposite effects on drug exposure for drugs eliminated via the liver and kidney, with the effect of inflammation being inversely proportional to the extraction ratio (ER). For renally cleared drugs, the relative decrease in AUC was close to 30% during severe inflammation. For CYP3A4 substrates, the relative increase in AUC could exceed 50% for low-ER drugs. Finally, the impact of inflammation-induced changes in drug clearance is smaller for drugs with a larger unbound fraction.

Conclusion: This analysis demonstrates differences in the impact of inflammation on drug clearance for different drug types. The effects of inflammation status on pharmacokinetics may explain the inter-individual variability in pharmacokinetics in critically ill patients. The proposed model-based analysis may be used to further evaluate the effect of inflammation, i.e., by incorporating the effect of inflammation on other drug-metabolizing enzymes or physiological processes.

Background and objectives: Palovarotene is under development for the treatment of fibrodysplasia ossificans progressiva (FOP). The objectives of this study were to evaluate palovarotene pharmacokinetics under fed versus fasted conditions and its induction potential towards cytochrome P450 3A4 (CYP3A4) substrate, midazolam.

Methods: In this phase I, open-label trial (NCT04829773), palovarotene pharmacokinetics were characterized after repeated once-daily dosing. In one cohort, healthy participants received three doses of palovarotene 20 mg on Days 1, 6, and 11, as whole capsules under fasted or fed conditions, or sprinkled on food under fed conditions. In another cohort, individuals received midazolam 2 mg on Days 1 and 15 and a daily dose of palovarotene 20 mg on Days 2-15. Palovarotene and midazolam pharmacokinetics, including area under the concentration-time curve from time zero to infinity (AUC_(0-∞)) and maximum observed plasma drug concentration (C_max), were assessed. Adverse events (AEs) were recorded.

Results: Overall, 23 participants completed each part. Palovarotene C_max and AUC_(0-∞) increased by 16.5% and 39.7% under fed versus fasted conditions. Pharmacokinetics were comparable between the whole capsule and sprinkled on food, under fed conditions. Midazolam AUC_(0-∞) and C_max decreased by 13.3% and 9.7% upon palovarotene co-administration over 14 days, less than that required to be considered a weak CYP3A4 inducer. Plasma palovarotene exposures were comparable after single and multiple doses. No serious AEs were reported.

Conclusions: These data support palovarotene administration after a meal, as a whole capsule or sprinkled on food. Palovarotene at 20 mg/day is a not a clinical inducer of CYP3A4. These results provide insights into palovarotene pharmacokinetics, aiding optimization of administration for patients with FOP.

Clinical trials registration number: NCT04829773.

Background and objective: All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ in excipients, which may affect corneal drug permeability or stability. This study aimed at comparing corneal penetration of three marketed latanoprost solutions with different excipient formulations in in vitro and in vivo drug permeability studies.

Methods: Three latanoprost formulations were tested under good laboratory practice conditions: a formulation containing benzalkonium chloride (BAK) but no surfactant (Preserved latanoprost); the same formulation except preservative-free (PF) without BAK or surfactant (SF) (PF SF latanoprost); and a different formulation without BAK but containing a non-ionic surfactant (MGHS 40 at 5%) combined with thickening agents (Carbomer 974P, Macrogol 4000) (PF latanoprost). Corneal permeation of latanoprost acid (LAT) was first determined in vitro using a reconstructed human corneal epithelium tissue. Then, in vivo pharmacokinetic studies were performed on pigmented rabbits, for which LAT concentration was measured in the aqueous humour (AH) and iris-ciliary body (ICB).

Results: In vitro, the cumulative transport of LAT was linear between 1 h and 4 h for preserved latanoprost and PF SF latanoprost, and LAT concentrations matched exactly at each timepoint. By contrast, the permeation of PF latanoprost was linear between 2 h and 12 h and was significantly lower than that of preserved latanoprost and PF SF latanoprost at 4 and 8 h (p < 0.001). In rabbits, the concentrations of LAT in AH and ICB were not statistically different between preserved latanoprost and PF SF latanoprost at each timepoint, except at 1 h in ICB (p = 0.005). By comparison, the LAT concentration of PF latanoprost was statistically (p < 0.05) lower than that of preserved latanoprost and PF SF latanoprost in AH and ICB from 0.5 to 3 h.

Conclusion: BAK did not influence the corneal penetration of latanoprost in in vitro and in vivo studies. The formulation containing a non-ionic surfactant resulted in lower and slower ocular penetration compared with preserved or PF SF formulations. This raises questions about the relevance of BAK and some surfactants in enhancing corneal penetration of ocular formulations.

Background: Moderate malnutrition is a common problem in young children. It is observed that severe malnutrition affects the pharmacokinetics of chemotherapy drugs in pediatric cancer patients, but moderate malnutrition is not well studied in this context.

Objectives: In this study, we aimed to understand how moderate malnutrition affects the pharmacokinetics of two chemotherapy drugs, etoposide and vincristine, using a murine model of early age moderate malnutrition.

Methods: We developed a murine model of moderate childhood malnutrition by subjecting freshly weaned Sprague-Dawley rats to 8% protein diet for 8 weeks. In two separate experiments, we administered etoposide and vincristine (N = 8 for etoposide and N = 12 for vincristine each in protein deficient and control groups) through tail vein injection for pharmacokinetics study.

Results: We found ~ 60% increase in area under the concentration-time curve (AUC) of etoposide in malnourished animals as compared to well-nourished animals. Furthermore, clearance, volume of distribution, and half-life were decreased by ~ 37, 53, and 24%, respectively, in malnourished animals. Pharmacokinetic parameters of vincristine showed only marginal differences between well-nourished and malnourished groups.

Conclusions: Our results suggest that while moderate malnutrition significantly affects the pharmacokinetics of etoposide, pharmacokinetics of vincristine remain unchanged. Since chemotherapy drugs have a narrow therapeutic index, the difference in AUC observed in our study might explain the increased toxicity of etoposide in malnourished pediatric cancer patients. This brings forth a need for robust clinical studies to validate our findings and optimize dose for malnourished patients.

Background: Cytochrome P450 (CYP) metabolizes arachidonic acid to produce bioactive metabolites such as EETs and HETEs: mid-chain, subterminal, and terminal HETEs. Recent studies have revealed the role of CYP1B1 and its associated cardiotoxic mid-chain HETE metabolites in developing cardiac hypertrophy and heart failure. Subterminal HETEs have also been involved in various physiological and pathophysiological processes; however, their role in cardiac hypertrophy has not been fully defined.

Objective: The objective of the current study is to determine the possible effect of subterminal HETEs, R and S enantiomers of 16-HETE, on CYP1B1 expression in vitro using human cardiomyocytes RL-14 cells.

Methods: In the study, RL14 cell line was treated with vehicle and either of the 16-HETE enantiomers for 24 h. Subsequently, the following markers were assessed: cell viability, cellular size, hypertrophic markers, CYP1B1 gene expression (at mRNA, protein, and activity levels), luciferase activity, and CYP1B1 mRNA and protein half-lives.

Results: The results of the study showed that 16-HETE enantiomers significantly increased hypertrophic markers and upregulated CYP1B1 mRNA and protein expressions in RL-14 cell line. The upregulation of CYP1B1 by 16-HETE enantiomers occurs via a transcriptional mechanism as evidenced by transcriptional induction and luciferase reporter assay. Furthermore, neither post-transcriptional nor post-translational modification was involved in such modulation since there was no change in CYP1B1 mRNA and protein stabilities upon treatment with 16-HETE enantiomers.

Conclusion: The current study provides the first evidence that 16R-HETE and 16S-HETE increase CYP1B1 gene expression through a transcriptional mechanism.

Background: In pediatric drug development, the selection of first-in-pediatric dose is of immense importance. Generally, the pharmacokinetic information and a safe and efficacious dose of a drug in adults are already known and this information can then be used to select first-in-pediatric dose. The objective of this study was to predict the pediatric dose of antimalarial drugs and compare the predicted dose with the recommended dose.

Methods: In this study, two simple methods to project a first-in-pediatric dose to initiate a clinical trial for antimalarial drugs were evaluated. These two methods were Salisbury Rule and allometric scaling. The predicted doses of antimalarial drugs by the two methods were compared with the observed doses recommended by the World Health Organization (WHO) or the US Food and Drug Administration (FDA).

Results: In this study, 15 antimalarial drugs with 88 observations (different body weight groups) were evaluated. From allometric scaling, all 88 observations were within 0.5-1.5-fold and 0.7-1.3-fold prediction error. From Salisbury Rule, all 88 observations were within 0.5-1.5-fold and 86 observations were within 0.7-1.3-fold prediction error.

Conclusions: The proposed methods are simple and quite accurate in their predictive power. These methods can be developed on a spreadsheet or a calculator in a very short period of time and are applicable to first-in-pediatric clinical trials or even in a clinical setting.