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Pharmacokinetic Study of Oral ¹⁴C-Radiolabeled Hyzetimibe, A New Cholesterol Absorption Inhibitor.

ABSTRACT: Background and objectives: Hyzetimibe is a candidate drug being investigated as the second-in-class cholesterol absorption inhibitor; it lowers plasma levels of low-density lipoprotein cholesterol (LDL-C) by blocking the Niemann-Pick C1-like 1 protein, a transporter mainly expressed in the intestine that allows dietary cholesterol to enter the body from the intestinal lumen. Previous studies on the metabolism of hyzetimibe in healthy volunteers were not enough to show the biotransformation and excretion pathway; in particular, whether hyzetimibe maintains pharmacological action for duration sufficient to pass through the hepatic-intestinal circulation remains unknown. Furthermore, it remains unclear whether the differences between the chemical structures of ezetimibe and hyzetimibe would result in different pharmacokinetic characteristics. Given that the molecular target is in the intestine and the substantial hepatic-intestinal circulation is a metabolic characteristic of the drug, a study of hyzetimibe as an oral ¹⁴C-radiolabeled drug, compared with routinely metabolized drugs, would play an important role in uncovering pharmacokinetic details. Methods: After an overnight fast and before taking medication, six healthy male volunteers swallowed an investigational product suspension containing 20 mg/∼100 μCi of ¹⁴C-labeled hyzetimibe as a single dose. Whole-blood, plasma, urine, and fecal samples were collected, and hyzetimibe and its metabolites were measured. Pharmacokinetic variables of hyzetimibe and its metabolites were calculated and statistically analyzed according to obtained concentration data. Safety data were collected throughout the study. Results: The major metabolite detected in plasma was hyzetimibe-glucuronide, which accounted for 97.2% of the total plasma radioactivity. The mean cumulative excretion of total radioactivity of the dose was 16.39% in urine and 76.90% in feces. Unchanged drug and hyzetimibe-glucuronide were identified as the major components in the feces and the urine, respectively. The main metabolic conversions of hyzetimibe were glucuronidation (M1), mono-oxidation (M4), and mono-oxidation with additional sulfonation (M7). Hyzetimibe was considered generally safe and well tolerated. Conclusion: This study of ¹⁴C-radiolabeled hyzetimibe provides a full profile of the biotransformation and excretion routes of hyzetimibe to improve the understanding of the pharmacokinetic characteristics of hyzetimibe. The changed hydroxyl group in the hyzetimibe structure made it easier for that drug, compared with ezetimibe, to combine with glucuronic acid and subsequently increased the urinary excretion of hyzetimibe vs. ezetimibe. These differences highlight the need to investigate in more detail the different pharmacokinetic impacts on the efficacy and safety of hyzetimibe and ezetimibe.

SUBMITTER: Liao J

PROVIDER: S-EPMC8194275 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesPhysiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib.MethodsA PBPK model was built in GastroPlus® that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution.ResultsThe inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state.ConclusionsFully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.

Project description:BackgroundAlmonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Here, we investigated the pharmacokinetic characteristics and safety profile of almonertinib following a single oral dose (110 mg/50 µCi) in healthy Chinese male participants.MethodsTotal radioactivity (TRA) in whole blood, plasma, urine, and feces was measured by utilizing a liquid scintillation counter to obtain almonertinib substance balance data. The pharmacokinetic parameters of [14C]almonertinib and the parent drug almonertinib in whole blood and plasma were analyzed with noncompartmental analysis in the WinNonlin software (Pharsight Corp). The major metabolites in plasma, urine, and feces were analyzed by high-performance liquid chromatography (HPLC) coupled with an online or offline isotope detector. The safety of the drug was evaluated after administration.ResultsThe safety and tolerability of a single oral dose of 110 mg/50 µCi [14C] almonertinib suspension were good in healthy Chinese male participants. There was no significant abnormality or special adverse reaction. TRA peaked quickly in plasma, with a Tmax of 4.0 h; however, TRA was cleared slowly in vivo, with a mean terminal elimination phase (half-life, T1/2) of up to 863 h. In addition to the parent drug, a total of 26 metabolites in blood, urine, and feces were analyzed. In plasma, parent drug was the major drug-related component, accounting for 69.97% of TRA, and M440 (almonertinib-M2 demethyl product) was the major metabolite, accounting for 5.08% of TRA; in urine, parent drug accounted for 0.48% of the dose administered and HAS-719 was the major metabolite, accounting for 1.20% of the administered dose; in feces, parent drug was about 8.61% of the dose administered and HAS-719 was the major metabolite, accounting for 12.33% of the administered dose, which was followed by M541a/M470a and M617/M575, accounting for 11.8% and 6.76% of the administered dose, respectively.ConclusionsAlmonertinib has a good safety profile, with parent drug as its main circulating component. almonertinib is extensively metabolized in vivo before excretion and is excreted as a parent drug and metabolites mainly via feces.Trial registrationThe trial registration number: CTR20192291.

Project description:BackgroundDexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation may broaden the use and benefits of dexmedetomidine to numerous care settings. The authors hypothesized that oral dexmedetomidine (300 mcg to 700 mcg) would result in plasma concentrations consistent with sedation while maintaining hemodynamic stability.MethodsThe authors performed a single-site, open-label, phase I dose-escalation study of a solid oral dosage formulation of dexmedetomidine in healthy volunteers (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg). The primary study outcome was hemodynamic stability defined as lack of hypertension, hypotension, or bradycardia. The authors assessed this outcome by analyzing raw hemodynamic data. Plasma dexmedetomidine concentrations were determined by liquid chromatograph-tandem mass spectrometry. Nonlinear mixed effect models were used for pharmacokinetic and pharmacodynamic analyses.ResultsOral dexmedetomidine was associated with plasma concentration-dependent decreases in heart rate and mean arterial pressure. All but one subject in the 500-mcg group met our criteria for hemodynamic stability. The plasma concentration profile was adequately described by a 2-compartment, weight allometric, first-order absorption, first-order elimination pharmacokinetic model. The standardized estimated parameters for an individual of 70 kg was V1 = 35.6 [95% CI, 23.8 to 52.8] l; V2 = 54.7 [34.2 to 81.7] l; CL = 0.56 [0.49 to 0.64] l/min; and F = 7.2 [4.7 to 14.4]%. Linear models with effect sites adequately described the decreases in mean arterial pressure and heart rate associated with oral dexmedetomidine administration. However, only the 700-mcg group reached plasma concentrations that have previously been associated with sedation (>0.2 ng/ml).ConclusionsOral administration of dexmedetomidine in doses between 300 and 700 mcg was associated with decreases in heart rate and mean arterial pressure. Despite low oral absorption, the 700-mcg dose scheme reached clinically relevant concentrations for possible use as a sleep-enhancing medication.Editor’s perspective

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Pharmacokinetic Study of Oral ¹⁴C-Radiolabeled Hyzetimibe, A New Cholesterol Absorption Inhibitor.

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Pharmacokinetic Study of Oral 14C-Radiolabeled Hyzetimibe, A New Cholesterol Absorption Inhibitor.

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Pharmacokinetic Study of Oral ¹⁴C-Radiolabeled Hyzetimibe, A New Cholesterol Absorption Inhibitor.