Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Motohashi, Shinya; Mino, Yasuaki; Hori, Kazuyuki; Naito, Takafumi; Hosokawa, Seiji; Furuse, Hiroshi; Ozono, Seiichiro; Mineta, Hiroyuki; Kawakami, Junichi

doi:10.1248/bpb.b12-01086

Cited by 15 publications

(13 citation statements)

References 24 publications

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“…CGRP at the concentration of 10 −7 M induces complete relaxation of human coronary arteries, while pre-incubation with CGRP 8–37 at the concentration of 10 −6 M causes almost perfectly antagonistic effect 127 . Moreover, 10 −6 M of aprepitant, or about 534.4 ng/mL, is well within or below the plasma concentration in cancer patients who took aprepitant to prevent chemotherapy-induced nausea and vomiting: After taking one 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3 128 , the median and interquartile range of plasma concentration of aprepitant 1 day and 3 days were reported to be 768 ng/mL (592–949) and 915 ng/mL (563–1203), respectively 129 . With these considerations, we believe that our choice of doses are well justified.…”

Section: Methodsmentioning

confidence: 99%

Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis

Yan

Liu

Guo

2019

Sci Rep

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Endometriotic lesions are known to be hyperinnervated, especially in lesions of deep endometriosis (DE), which are frequently in close proximity to various nerve plexuses. DE lesions typically have higher fibromuscular content than that of ovarian endometriomas (OE) lesions, but the underlying reason remains elusive. Aside from their traditional role of pain transduction, however, whether or not sensory nerves play any role in the development of endometriosis is unclear. Here, we show that, thorough their respective receptors neurokinin receptor 1 (NK1R), calcitonin receptor like receptor (CRLR), and receptor activity modifying protein 1 (RAMP-1), neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT) and further turn stromal cells into smooth muscle cells (SMCs) in endometriotic lesions, resulting ultimately in fibrosis. We show that SP and CGRP, or the rat dorsal root ganglia (DRG) supernatant, through the induction of NK1R and CGRP/CRLR/RAMP-1 signaling pathways, promoted EMT, FMT and SMM in endometriosis, resulting in increased migratory and invasive propensity, cell contractility, production of collagen, and eventually to fibrosis. Neutralization of NK1R and/or CGRP/CRLR/RAMP-1 abrogated these processes. Extended exposure of endometriotic stromal cells to SP and/or CGRP or the DRG supernatant induced increased expression of α-SMA, desmin, oxytocin receptor, and smooth muscle myosin heavy-chain. Finally, we show that DE lesions had significantly higher nerve fiber density, increased staining levels of α-SMA, NK1R, CRLR, and RAMP-1, concomitant with higher lesional fibrotic content than that of OE lesions. The extent of lesional fibrosis correlated positively with the staining levels of NK1R, CRLR, and RAMP-1, as well as the nerve fiber density in lesions. Thus, this study provides another piece of evidence that sensory nerves play an important role in promoting the development and fibrogenesis of endometriosis. It explains as why DE frequently have higher fibromuscular content than that of OE, highlights the importance of lesional microenvironment in shaping the lesional fate, gives more credence to the idea that ectopic endometrium is fundamentally wounds that go through repeated tissue injury and repair, and should shed much needed light into the pathophysiology of endometriosis.

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Section: Methodsmentioning

confidence: 99%

Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis

Yan

Liu

Guo

2019

Sci Rep

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“…Strategies may include using the lowest effective dose, selecting alternative agents when the risk/benefit ratio for use of a supportive care PIM is too high, and educating patients and caregivers on their potential toxicities. For example, if alternative agents such as NK1 receptor antagonists or serotonin-5-(HT) 3 -receptor antagonists can be used, then these agents should be preferentially considered over agents such as metoclopramide, benzodiazepines, or antipsychotics for emesis prevention [14], as these agents have not been associated with adverse outcomes in older adults [15, 16]. In situations where the use of corticosteroids or diphenhydramine may be necessary, patients and caregivers should be educated regarding the potential side effects and the need for closer monitoring to prevent adverse outcomes such as falls.…”

Section: Discussionmentioning

confidence: 99%

An Analysis of the Inclusion of Medications Considered Potentially Inappropriate in Older Adults in Chemotherapy Templates for Hematologic Malignancies: One Recommendation for All?

et al. 2018

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Background: There remains a paucity of data regarding the use of potentially inappropriate medications (PIMs) in the supportive management of older adults undergoing chemotherapy. Raising awareness among healthcare providers of the frequency of their use and potential toxicities may help to minimize the risks to patients. Objective: To evaluate the frequency of six specific classes of medications considered PIMs by the American Geriatrics Society Beers Criteria that are commonly included in the National Comprehensive Cancer Network (NCCN) chemotherapy order templates for hematologic malignancies. The six PIMs evaluated are first generation antihistamines, benzodiazepines, corticosteroids, H2-receptor antagonists, metoclopramide, and antipsychotics. Methods: A total of 311 unique chemotherapy order templates published online by the NCCN for treatment of hematologic malignancies were reviewed to determine the frequency that these six specific PIMs were recommended for supportive care. Results: Approximately 45 percent of the NCCN chemotherapy templates for hematologic malignancies specifically recommended the use of at least one of the six PIMs examined. The remainder of the templates evaluated referred exclusively to the (NCCN Guidelines®) Oncology for Antiemesis, which also included the use of at least one of the six PIMs evaluated. Conclusions: These findings demonstrate that PIMs are frequently used as supportive therapy in the treatment of hematologic malignancies. Increasing healthcare provider awareness of their potential side effects may minimize the risks associated with their use in older adults with hematologic malignancies undergoing chemotherapy.

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“…A study of aprepitant plasma pharmacokinetics in 44 Japanese cancer patients receiving cisplatin de novo, with oral aprepitant 125 mg administered before chemotherapy on day 1 and aprepitant 80 mg given on days 2 and 3, found that plasma aprepitant exposure was not correlated with age or sex [63]. In contrast, another pharmacokinetic study in a larger sample of 315 Japanese cancer patients reported that age had a mild effect on the oral clearance of aprepitant [64].…”

Section: Special Populationsmentioning

confidence: 98%

Aprepitant and Fosaprepitant: A 10-Year Review of Efficacy and Safety

et al. 2015

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Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with anticancer treatment that can have a significant adverse impact on patient health-related quality of life and that can potentially undermine the effectiveness of chemotherapy. Traditional regimens to prevent CINV generally involved a combination of a corticosteroid plus a 5-hydroxytryptamine (5HT 3 ) receptor antagonist (RA). In the past 10 years, antiemetic treatment has greatly advanced with the availability of the neurokinin-1 receptor antagonist (NK 1 RA) aprepitant and its prodrug fosaprepitant. NK 1 RAs have a different mechanism of action in CINV than corticosteroids and 5HT 3 RAs, thus their use can complement traditional antiemetic drugs and can enhance control of CINV.This review examined accumulated data regarding the safety and efficacy of aprepitant and fosaprepitant over the decade since the first regulatory approval. Data from key studies of aprepitant and fosaprepitant in the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy were explored, as were recommendations in currently available guidelines for their use. In addition, their use as antiemetic therapy in special patient populations was highlighted. Future perspectives on potential uses of aprepitant and fosaprepitant for indications other than CINV are presented. The Oncologist 2015; 20:450-458 Implications for Practice: Aprepitant (and its prodrug fosaprepitant) is a neurokinin-1 receptor antagonist approved more than a decade ago for the prevention of chemotherapy-induced nausea and vomiting (CINV). Its alternative mechanism of action complements traditional antiemetic drugs, enhancing control of CINV.This review examined safety and efficacy data for aprepitant and fosaprepitant accumulated since the first regulatory approval and explores recommendations in current guidelines for their use. The review serves as a useful reminder for the practitioner that aprepitant and fosaprepitant are valuable additions to the therapeutic armamentarium for the prevention of CINV. Future perspectives on potential uses of aprepitant and fosaprepitant for indications other than CINV are discussed.

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Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Cited by 15 publications

References 24 publications

Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis

Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis

An Analysis of the Inclusion of Medications Considered Potentially Inappropriate in Older Adults in Chemotherapy Templates for Hematologic Malignancies: One Recommendation for All?

Aprepitant and Fosaprepitant: A 10-Year Review of Efficacy and Safety

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