A double-site absorption model fits to pharmacokinetic data of repaglinide in man

Liu, X. D.; Ji, Hui; Xie, Lin; Yan, Ming; Zhang, L.; Huang, Xin

doi:10.1007/bf03190077

Cited by 4 publications

(6 citation statements)

References 3 publications

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“…Aspartate amino transferase transient elevation was reported in one patient in the absorption of eltrombopag occurs along the gastrointestinal tract. 15,16 Enterohepatic circulation could also be a potential mechanism. 17 The plasma exposure (AUC 0-24 h and C max ) of hetrombopag in CITP patients increased greater than dose-proportional over the dose range of 2.5 to 7.5 mg/d, which was consistent with our previous observation in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

“…The absorption phase of drug concentration‐time curve showed a double peak phenomenon. The possible reason is that absorption rate varies in different regions of the gut, such as zero or very low absorption in the jejunum, quick absorption in the duodenum and ileum, indicating that absorption of eltrombopag occurs along the gastrointestinal tract 15,16 . Enterohepatic circulation could also be a potential mechanism 17 …”

Section: Discussionmentioning

confidence: 99%

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First‐in‐patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura

Wang

Chen

Zhang

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Idiopathic thrombocytopenic purpura (ITP) especially refractory and (or) relapsed ITP, is a serious and global health burden and its clinical treatment is far from being satisfied. Hetrombopag is a novel, small-molecule thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura (CITP). Objectives: This first-in-patient study aimed to investigate the safety, pharmacokinetics, and anticipated therapeutic dose of hetrombopag in CITP patients. Methods: In this multicenter, first-in-patient study, CITP patients received hetrombopag in a dose escalation (2.5 mg/day, 5 mg/day, or 7.5 mg/day) cohort. All patients received hetrombopag in fasting condition once daily for 2 weeks. Results: Of 44 patients screened, 32 were enrolled and treated. Most adverse events were graded 1 to 2 (ie, mild to moderate), and the incidence and severity were similar for three study cohorts. The pharmacokinetics of hetrombopag were found to be nonlinear with greater than dose-proportional: 12.5% of patients (1/8) in the 2.5 mg/d cohort, 58.3% of patients (7/12) in the 5 mg/d cohort, 66.7% of patients (8/12) in the 7.5 mg/d cohort reached the primary study endpoint of a platelet count exceeding 50 × 10 9 /L on day 28. Conclusion: Hetrombopag was well tolerated and preliminarily efficacious. Efficacy, safety, and pharmacokinetic data suggest that 7.5 mg hetrombopag once daily was the anticipated therapeutic dose of hetrombopag in CITP patients and has been recommended for investigation in a later confirmatory clinical study of hetrombopag.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

First‐in‐patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura

Wang

Chen

Zhang

et al. 2020

Journal of Thrombosis and Haemostasis

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“…The fast absorption may be related to the proper lipophilicity of steroidal alkaloids. With regard to the phenomenon of the second peak, some studies have shown that it is associated with enterohepatic circulation [16], and suggested that it is caused by the different absorption mechanisms of drugs in the gastrointestinal tract [17]. Notably, the phenomenon of enterohepatic circulation was first observed in jervine, but not other veratrum alkaloids like veratramine [3,10] or cyclopamine [15].…”

Section: Pharmacokinetic Studymentioning

confidence: 99%

Pharmacokinetics and enterohepatic circulation of jervine, an antitumor steroidal alkaloid from Veratrum nigrum in rats

Zheng

Wang

Song

et al. 2019

Journal of Pharmaceutical Analysis

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Jervine, a novel steroidal alkaloid from Veratrum nigrum L., exhibits both antitumor effect and potential toxicity. The aim of study was to characterize the pharmacokinetic behaviors and enterohepatic circulation of jervine in rats. A rapid and simple ultra-high performance liquid chromatography-tandem mass spectrometric method was developed and validated for quantification of jervine and alpinetin (internal standard) in rat plasma. After extraction from rat plasma by a simple protein-precipitation method, the analyte was separated on a C 18 column (2.1 mm Â 50 mm, 1.7 mm) using water with 0.1% formic acid and acetonitrile as the mobile phase delivered at a flow rate of 0.4 mL/min. Jervine and alpinetin were determined in the positive mode with multiple reaction monitoring (MRM) of the ion transitions at m/z 426.3 / 108.8 and m/z 271.0 / 166.9, respectively. Molecular docking method was used to investigate the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase. The method was well validated within acceptance limits including specificity, matrix effect, recovery, precision, accuracy, and stability, and was successfully applied to the pharmacokinetic study of jervine after oral and intravenous administration to rats. Jervine presented a small volume of distribution, fast absorption, high oral bioavailability, and enterohepatic circulation. The enterohepatic circulation was first observed in veratrum alkaloids, and was further investigated by molecular docking studies, which was related to the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase. The pharmacokinetic properties and enterohepatic circulation of jervine in rats provided a significant basis for the drug-drug interaction and toxicity study in the future.

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“…PK models incorporating dual absorption compartments have been used to describe complicated absorption kinetics. [21][22][23] The model-estimated proportion in the first absorption compartment was 56% and an estimated lag time in the second absorption compartment was ∼3.7 hours. These results suggest that the absorption of heptanoate is staged with approximately 50% of heptanoate absorbed from the GI tract immediately after the dosing and the remaining portion absorbed approximately 4 hours later when the next meal is served.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long‐Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin

Lee

Gosselin

Jomphe

et al. 2022

Clinical Pharm in Drug Dev

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Triheptanoin is an odd‐carbon, medium‐chain triglyceride consisting of three fatty acids with seven carbons each on a glycerol backbone, indicated for the treatment of adult and pediatric patients with long‐chain fatty acid oxidation disorders (LC‐FAOD). A total of 562 plasma concentrations of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, from 13 healthy adult subjects and 30 adult and pediatric subjects with LC‐FAOD were included in the population pharmacokinetic (PK) analyses. Multiple peaks of heptanoate observed in several subjects were characterized by dual first‐order absorption with a lag time in the second absorption compartment. The disposition of heptanoate in human plasma was adequately described by one‐compartmental distribution with a linear elimination. The apparent clearance (CL/F) and apparent volume of distribution were allometrically scaled with body weight to describe PK data across a wide range of age groups in subjects with LC‐FAOD. The typical CL/F in adult subjects with LC‐FAOD was ≈19% lower than that in healthy subjects. Model‐estimated elimination half‐life for LC‐FAOD patients was ∼1.7 hours, supporting a recommended dosing frequency of ≥4 times per day. Covariate analyses indicate that age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate.

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A double-site absorption model fits to pharmacokinetic data of repaglinide in man

Cited by 4 publications

References 3 publications

First‐in‐patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura

First‐in‐patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura

Pharmacokinetics and enterohepatic circulation of jervine, an antitumor steroidal alkaloid from Veratrum nigrum in rats

Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long‐Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin

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