Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers

ABSTRACTPosaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drug-drug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.

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Population Pharmacokinetic Analysis of Diurnal and Seasonal Variations of Plasma Concentrations of Cilostazol in Healthy Volunteers

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000077 ◽

2014 ◽

Vol 36 (6) ◽

pp. 771-780 ◽

Cited By ~ 3

Author(s):

Donghwan Lee ◽

Hankil Son ◽

Lay A. Lim ◽

Kyungsoo Park

Keyword(s):

Healthy Volunteers ◽

Seasonal Variations ◽

Plasma Concentrations ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic

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Population Pharmacokinetic Analysis of Cefaclor in Healthy Korean Subjects

Pharmaceutics ◽

10.3390/pharmaceutics13050754 ◽

2021 ◽

Vol 13 (5) ◽

pp. 754

Author(s):

Seung-Hyun Jeong ◽

Ji-Hun Jang ◽

Hea-Young Cho ◽

Yong-Bok Lee

Keyword(s):

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Factors Affecting ◽

Population Pharmacokinetic Study ◽

Final Population ◽

Subject Variability

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor’s final population pharmacokinetic model was validated and some of the population’s pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients.

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Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients with Chronic Hepatitis C Virus Infection

10.22541/au.160193339.96141209/v1 ◽

2020 ◽

Author(s):

Xiao duo Guan ◽

Xian ge Tang ◽

Ying jun Zhang ◽

Hong ming Xie ◽

Lin Luo ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Infection ◽

Healthy Volunteers ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Hepatitis C Virus Infection ◽

Chronic Hepatitis C Virus

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Population Pharmacokinetic Analysis of Tiropramide in Healthy Korean Subjects

Pharmaceutics ◽

10.3390/pharmaceutics12040374 ◽

2020 ◽

Vol 12 (4) ◽

pp. 374

Author(s):

Seung-Hyun Jeong ◽

Ji-Hun Jang ◽

Hea-Young Cho ◽

Yong-Bok Lee

Keyword(s):

Digestive System ◽

Genetic Factors ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Factors Affecting ◽

First Order ◽

Basic Model ◽

Dosing Algorithm ◽

Subject Variability

The purpose of this study was to perform population pharmacokinetic (PPK) analysis of tiropramide in healthy Korean subjects, as well as to investigate the possible effects of various covariates on pharmacokinetic (PK) parameters of tiropramide. Although tiropramide is commonly used in digestive system-related diseases as an antispasmodic, PPK reporting and factors affecting PKs are not clearly reported. Thus, this study for healthy subjects is very significant because it could find new covariates in patients that had not been reported before or predict PPK for patients in the clinic by establishing PPK in healthy adults. By using Phoenix NLME, PK, demographic, and genetic data (collected to explain PK diversity of tiropramide in population) analyses were performed. As a basic model, a one-compartment with first-order absorption and lag-time was established and extended to include covariates that influenced the inter-subject variability. The total protein significantly influenced the distribution volume and systemic clearance of tiropramide, but genetic factors such as ABCB1 (1236C>T, 2677G>T/A, and 3435C>T), CYP2D6 (*1 and *10), OCT2 (808G>T), and PEPT1 (1287G>C) genes did not show any significant association with PK parameters of tiropramide. The final PPK model of tiropramide was validated, and suggested that some of the PK diversity in the population could be explained. Herein, we first describe the establishment of the PPK model of tiropramide for healthy Korean subjects, which may be useful as a dosing algorithm for the diseased population.

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