The Effect of Verapamil, a P‐Glycoprotein Inhibitor, on the Pharmacokinetics of Peficitinib, an Orally Administered, Once‐Daily JAK Inhibitor

Context: Oridonin has been traditionally used in Chinese treatment of various cancers, but its poor bioavailability limits its therapeutic uses. Verapamil can enhance the absorption of some drugs with poor oral bioavailability. Whether verapamil can enhance the bioavailability of oridonin is still unclear. Objective: This study investigated the effect of verapamil on the pharmacokinetics of oridonin in rats and clarified its main mechanism. Materials and methods: The pharmacokinetic profiles of oral administration of oridonin (20 mg/kg) in Sprague-Dawley rats with two groups of six animals each, with or without pre-treatment of verapamil (10 mg/kg/day for 7 days) were investigated. The effects of verapamil on the transport and metabolic stability of oridonin were also investigated using Caco-2 cell transwell model and rat liver microsomes. Results: The results showed that verapamil could significantly increase the peak plasma concentration (from 146.9 ± 10.17 to 193.97 ± 10.53 ng/mL), and decrease the oral clearance (from 14.69 ± 4.42 to 8.09 ± 3.03 L/h/kg) of oridonin. The Caco-2 cell transwell experiments indicated that verapamil could decrease the efflux ratio of oridonin from 1.67 to 1.15, and the intrinsic clearance rate of oridonin was decreased by the pre-treatment with verapamil (40.06 ± 2.5 vs. 36.09 ± 3.7 mL/min/mg protein). Discussion and conclusions: These results indicated that verapamil could significantly change the pharmacokinetic profile of oridonin in rats, and it might exert these effects through increasing the absorption of oridonin by inhibiting the activity of P-gp, or through inhibiting the metabolism of oridonin in rat liver. In addition, the potential drug-drug interaction should be given special attention when verapamil is used with oridonin. Also, the dose of oridonin should be carefully selected in the clinic.

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“…2008; Zhu et al. 2017; Chen et al. 2018), and CYP3A4 also participates in the metabolism of oridonin (Xu et al.…”

Section: Discussionmentioning

confidence: 99%

“…2008; Zhu et al. 2017; Chen et al. 2018), therefore, the absorption of some drugs with poor oral bioavailability could be enhanced (Huang et al.…”

Section: Introductionmentioning

confidence: 99%

Influence of verapamil on the pharmacokinetics of oridonin in rats

Liu

Zhang

et al. 2019

Pharmaceutical Biology

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“…Peficitinib, a new orally JAK blocker that inhibits JAK1, JAK2, JAK3, TYK2 and with a mild selectivity for JAK3 (Zhu et al, 2017). Metabolism and pharmacokinetics of peficitinib are similar to other JAK inhibitors, in which peficitinib was absorbed rapidly with small food effects after single doses (Cao et al, 2016).…”

Section: Clinical Developmentsmentioning

confidence: 99%

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

Hosseini

Gharibi

Marofi

et al. 2020

Journal Cellular Physiology

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Many cytokines are crucial drivers of cancers and autoimmune conditions. These proteins bind to receptors and signal their responses through Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Genetic variations in the JAK-STAT pathway are correlated with the increased risk of cancers, autoimmunity as well as inflammatory diseases. Targeting JAKs and STATs can be a safe and efficacious strategy for treating these diseases. Tofacitinib, as the first JAK inhibitor, is approved for rheumatoid arthritis therapy. Also, many other JAK inhibitors have been proven or are in various phases of clinical trials for various diseases. At present, small-molecule JAK inhibitors are considered as a novel category of drugs in the treatment of cancer and immune-mediated diseases. K E Y W O R D S autoimmune diseases, cancer, Janus kinase inhibitors, novel treatment strategy

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“…14 However, a recent study of peficitinib in combination with verapamil (P-glycoprotein inhibitor) showed increased exposure of peficitinib and its metabolites, suggesting that P-glycoprotein may be involved in peficitinib transport. 15 While the peficitinib PK profile has been described in healthy subjects, 11 it is important to determine the impact of potential comorbidities, such as liver disease, on peficitinib exposure. The burden of liver disease related to hepatitis infection remains high, 16 and there is a rise in nonalcoholic fatty liver disease and its histological phenotype, nonalcoholic steatohepatitis (NASH), which are related to increased obesity and can progress to chronic liver disease.…”

mentioning

confidence: 99%

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function

Miyatake

Shibata

Toyoshima

et al. 2019

Clinical Pharm in Drug Dev

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Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUC inf) and maximum observed concentration (C max) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUC inf and C max , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

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The Effect of Verapamil, a P‐Glycoprotein Inhibitor, on the Pharmacokinetics of Peficitinib, an Orally Administered, Once‐Daily JAK Inhibitor

Cited by 24 publications

References 15 publications

Influence of verapamil on the pharmacokinetics of oridonin in rats

Influence of verapamil on the pharmacokinetics of oridonin in rats

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function

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