Bioavailability and Tolerability of Combination Treatment With Revaprazan 200 mg + Itopride 150 mg: A Randomized Crossover Study in Healthy Male Korean Volunteers

Choi, Hee Youn; Noh, Yook-Hwan; Jin, Seok-Joon; Kim, Yo Han; Kim, Mi-Jo; Jang, Si‐Hyong; Lee, Sung Jae; Bae, Kyun‐Seop; Lim, Hyeong‐Seok

doi:10.1016/j.clinthera.2012.07.004

Cited by 12 publications

(5 citation statements)

References 44 publications

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“…The grey lines represent 20 simulated individual trials, the solid black line is the mean of virtual population and the dashed grey lines represent the 90% confidence interval of the respective simulations. Observed data: (a) mean from 6 healthy Japanese adult subjects (Ganaton, 2016), (b), mean from 23 healthy male Korean subjects, age 23 to 48 years (Yoon et al, ); (c), mean from 27 healthy male Korean subjects, age 20 to 50 years (Choi et al, ); (d) mean from 5 healthy male Japanese subjects, age 24 to 31 years (Katagiri et al, ). (e,f) mean from 6 healthy male Chinese subjects, age 20 to 22 years (Zhou et al, )…”

Section: Resultsmentioning

confidence: 99%

“…The predicted fraction of unbound drug in microsomal incubation ( fu mic = 1) was determined from the itopride physicochemical properties (Turner, Rostami‐Hodjegan, Tucker, & Rowland‐Yeo, ). The developed model was verified with three additional clinical trials in Korean and Japanese subjects (Choi et al, ; Katagiri et al, ; Yoon et al, ). The same trial designs as the clinical studies (dose, number of subjects, age etc.)…”

Section: Methodsmentioning

confidence: 92%

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Development of a physiologically based pharmacokinetic model to predict the effects of flavin‐containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure

Zhou

Humphries

Gardner

et al. 2017

Biopharm & Drug Disp

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Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CL of 9 μl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69 l/h, which was comparable to those observed (55 to 88 l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 92%

Development of a physiologically based pharmacokinetic model to predict the effects of flavin‐containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure

Zhou

Humphries

Gardner

et al. 2017

Biopharm & Drug Disp

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“…In a recent study, the authors compared the bioavailability and tolerability of revaprezan alone to revaprezan plus iotopride. Revaprezan demonstrated bioequivalence to the combination with iotopride without any clinically significant drug-to-drug interaction [49]. Recently, a phase II clinical trial aimed to investigate the safety, tolerability, and efficacy of revaprazan (YH1885L) in NERD patients has been completed.…”

Section: Revaprazanmentioning

confidence: 98%

Novel Upcoming Therapies

Maradey–Romero

Fass

2015

Diagnosis and Treatment of Gastroesophageal Reflux Disease

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“…Combined preparations of prokinetic agents with anti-secretory agents have been studied for FD treatment, based on the rationale that symptom generation may depend on multiple mechanisms in this heterogeneous condition, and that such combination is more likely to address a meaningful mechanisms in the individual patient than a singlemodality therapy (44)(45)(46)(47). However, the available literature has focused on GERD and is less supportive of such gain in FD.…”

Section: Combination Therapiesmentioning

confidence: 99%

Drugs under development for the treatment of functional dyspepsia and related disorders

Tack

Masuy

Houte

et al. 2019

Expert Opinion on Investigational Drugs

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Introduction: Functional dyspepsia (FD), defined as the presence of chronic functional symptoms originating from the gastroduodenum, is one of the most common functional gastrointestinal disorders. FD is subdivided into postprandial distress syndrome (PDS), with meal-related symptoms such as postprandial fullness and early satiation, and epigastric pain syndrome (EPS), with meal-unrelated symptoms such as epigastric pain or burning. In spite of its prevalence, therapeutic options for FD are very limited, probably reflecting the complex pathophysiology which comprises disorders of gastric sensorimotor function as well as low grade duodenal inflammation. Areas covered:This review summarizes recent and ongoing drug development for FD as identified from a literature search was conducted on Pubmed and other sources. Expert opinion:Proton pump inhibitors (PPIs) are the traditional first-line therapy; potassiumcompetitive acid blockers are being studied. Ongoing drug development focuses on gastric motility with prokinetics (dopamine-2 antagonists and 5-HT4 agonists) and fundus relaxant therapies (acotiamide, azapirones), and on sensitivity with peripherally (guanylate cyclase and cannabinoid agonists) and centrally acting neuromodulators.Drugs under development for gastroparesis may also be efficacious in PDS. There are emerging data with pro-and antibiotics and several studies with phytotherapeutic agents. Duodenal low-grade inflammation is a newly emerging target which may respond also to PPIs, histamine and leukotriene receptor blockers.

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Bioavailability and Tolerability of Combination Treatment With Revaprazan 200 mg + Itopride 150 mg: A Randomized Crossover Study in Healthy Male Korean Volunteers

Cited by 12 publications

References 44 publications

Development of a physiologically based pharmacokinetic model to predict the effects of flavin‐containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure

Development of a physiologically based pharmacokinetic model to predict the effects of flavin‐containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure

Novel Upcoming Therapies

Drugs under development for the treatment of functional dyspepsia and related disorders

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