Dataset Information

Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug.

ABSTRACT: Proton pump inhibitors (PPIs) are the mainstay for treatment of acid-related diseases. This study developed a mechanism-based pharmacokinetic (PK) and pharmacodynamics (PD) model with ilaprazole as case drug, so as to support and accelerate the development of novel PPIs. The model was established and verified using the PK and PD data from 26 subjects receiving 5 to 30 mg of ilaprazole and 22 subjects receiving the loading dose of ilaprazole 20 mg followed by 10 mg once daily for 2 days. The nonlinear mixed-effects modeling approach was performed for the PK/PD model. A two-compartment model with linear elimination and covariates (body weight and gender) described the observed data well. The relationship between plasma concentrations of ilaprazole and gastric acid pH was well quantified with individual variability, in which the synthesis and degradation of H⁺/K⁺-ATPase, the food effect, the circular rhythms of gastric acid secretion, and the irreversible inhibition of H⁺/K⁺-ATPase by ilaprazole were integrated. This PK/PD model well predicted the PK and PD profile of ilaprazole in healthy subjects and patients with duodenal ulcers receiving wide range dose regimens. The mechanism-based PK/PD model provided a potential strategy to accelerate the development of novel PPIs by waiving the unnecessary clinical trials.

SUBMITTER: Jia R

PROVIDER: S-EPMC7998456 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND:Coronary heart disease (CHD) is a common cardiovascular disease accounting for 10-20% mortality by heart disease worldwide. The gold standard treatment to manage CHD is aspirin, which may prevent myocardial infarction and sudden death; however, long-term use of aspirin may increase its side effects. Currently, more and more clinicians are exploring different approaches to use the right combination of medicine to enhance the efficacy and reduce side effects. Salvianolate can significantly inhibit the aggregation and activation of platelets in patients with CHD; however, its optimum combination with western medicine is not established or supported by clinical trial results. METHODS/DESIGN:This trial is a prospectively planned, open-labeled, parallel-grouped, single-centered clinical trial with aggregated pharmacodynamics-pharmacokinetics (PK-PD) data. All treatment courses will last for 10 days and blood sample will be acquired before administration on days 8, 9, and 10, and after administration at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h on day 10. This trial uses PK-PD modeling to provide a description of the concentration-effect relationship and an estimate of pharmacological potency of the medicine. The primary outcome will be changes in aspirin esterase and catechol-o-methyltransferase (COMT) activity at different blood concentrations to determine the PK-PD characteristics of the combination of salvianolate and aspirin, followed by analysis of the correlation between exposure level and pharmacodynamic index of the medicines. DISCUSSION:This trial will aim to evaluate the relationship between changes in the pharmacokinetics and therapeutic effect index in the combined use of salvianolate and aspirin. It also discusses the possible mechanism of medicine combination in the treatment for CHD and provides an experimental basis for a clinically rational medicine combination. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03306550 . Registered on 9 October 2017. ClinicalTrials.gov https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007D8H&selectaction=Edit&uid=U0003QY8&ts=2&cx=oiuc9g.

Project description:Aim: Heavy metal pollution is serious in China, and abscisic acid (ABA) is an important stress hormone. How it regulates plant tolerance to cadmium remains unclear, so we aimed to explore the molecular mechanism responsible for enhanced cadmium resistance in Arabidopsis wild-type and mutant plants and Brassica napus seedlings. Methods: Arabidopsis/B. napus were cultured hydroponically for 28/15 days and then treated with 20/10 μM Cd/Cd+ABA (5 μM) for 3/4 days. Chlorophyll degradation rate, SPAD values, proline, MDA, ABA, NO 3 - , and Cd concentrations were measured in root vacuoles and protoplasts; root to shoot NO 3 - and Cd concentration ratios were determined and NRT1.5-, NRT1.8-, BnNRT1.5-, and BnNRT1.8-related gene expression was studied. Results: Cytoplasmic ABA levels in root cells of bglu10 and bglu18 Arabidopsis mutants were significantly lower than those in the wild-type, apparently making the latter more resistant to Cd. NO 3 - long-distance transporter NRT1.5 responded to ABA signaling by downregulating its own expression, while NRT1.8 did not respond. Concomitantly, proton pump activity in wild-type plants was higher than in the bglu10 and bglu18 mutants; thus, more NO 3 - and Cd accumulated in the vacuoles of wild-type root cells. ABA application inhibited Cd absorption by B. napus. BnNRT1.5 responded to exogenous ABA signal by downregulating its own expression, while the lack of response by BnNRT1.8 resulted in increased amount of NO 3 - accumulating in the roots to participate in the anti-cadmium reaction. Conclusion: NRT1.5 responds to the ABA signal to inhibit its own expression, whereas unresponsiveness of NRT1.8 causes accumulation of NO 3 - in the roots; thus, enhancing Cd resistance. In Arabidopsis, because of proton pump action, more NO 3 - and Cd accumulate in the vacuoles of Arabidopsis root cells, thereby reducing damage by Cd toxicity. However, in B. napus, the addition of exogenous ABA inhibited Cd absorption. Our data provide a sound basis to the theoretical molecular mechanism involved in hormone signaling during response of plants to heavy metal stress.

Dataset Information

Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets