Antitumor activity of alectinib (CH5424802/RO5424802) for ALK-rearranged NSCLC with or without prior crizotinib treatment in bioequivalence study.

Nakagawa, Kazuhiko; Hida, Toyoaki; Seto, Takashi; Satouchi, Miyako; Nishio, Makoto; Hotta, Katsuyuki; Murakami, Haruyasu; Ohe, Yuichiro; Takeda, Koji; Tatsuno, Masahiro; Yoshikawa, Naoki; Tanaka, Tomohiro; Tamura, Tomohide

doi:10.1200/jco.2014.32.15_suppl.8103

Cited by 11 publications

(7 citation statements)

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“…The model predicts that if alectinib is dosed within 160 min of the start of a meal, the steady state C max and area under the curve (AUC) will be approximately 80% of the value of a dose given after 30 min. The simulations are consistent with observed patient PK data for alectinib, which showed that steady state C max and AUC did not differ more than 20% following administration within 30 min after a meal or with fasting 2 h before and 1 h after administration [24]. Furthermore, the prediction for the late fed state with dosing up to 240 min after food is that the AUC and C max are reduced to 70 and 60% of the 30-min values, respectively.…”

Section: Prediction Of the Effect Of Time Of Dosing Relative To Food Intakesupporting

confidence: 84%

Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib

Parrott

Takano³

et al. 2016

AAPS J

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Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.

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Section: Prediction Of the Effect Of Time Of Dosing Relative To Food Intakesupporting

confidence: 84%

Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib

Parrott

Takano³

et al. 2016

AAPS J

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“…Also, the place of the second and third generation TKI's (EGFR: afatinib, AZD9291, CO-1686, ALK: ceritinib, alectinib) should be determined as these agents have a better penetration in the CSF compared to first generation TKI's and cranial responses are found with these agents in patients who develop brain metastases when they have already been treated with first generation TKI [15,[60][61][62]. Another option that could be explored in this patient population is the use of SRS without WBRT, even for multiple (five to ten) brain metastases.…”

Section: Discussionmentioning

confidence: 99%

Safety of cranial radiotherapy concurrent with tyrosine kinase inhibitors in non-small cell lung cancer patients: A systematic review

Hendriks¹,

Schoenmaekers²,

Zindler³

et al. 2015

Cancer Treatment Reviews

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Recently, non-small cell lung cancer (NSCLC) has been partly subclassified into molecularly-defined oncogene "addicted" tumors for which targeted agents are available. Tyrosine kinase inhibitors (TKI) are currently approved for patients with an activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement. In these patients, brain metastases are often the first site of progression while on TKI treatment. The TKI may however still be active on extra-cranial sites and clinicians are thus faced with the question if the TKI may be continued during cranial radiotherapy. Advantages of combining TKI with cranial radiotherapy would be a possible synergistic effect on the brain metastases and the prevention of a systemic disease flare-up. A disadvantage is the possibly increased risk of (neuro)toxicity. The present systematic review addresses the toxicity of combining TKI with cranial radiotherapy in NSCLC patients.

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“…Visual effects and gastrointestinal disorders (diarrhea, vomiting, and nausea) were rare. During a phase I study there were an ORR of 60% and good safety profile in patients who are refractory to crizotinib (96): for this reason, a singlearm phase I/II study in crizotinib resistant patients is ongoing (NCT01801111). There is also an ongoing phase III trial comparing alectinib versus crizotinib in advanced NSCLC (NCT02075840).…”

Section: "Second Generation" Alk Inhibitorsmentioning

confidence: 99%

ALK inhibitors for clinical use in cancer therapy

Farina

Gambacorti‐Passerini

2016

Front Biosci

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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase protein implicated in a variety of tumors, both solid and hematological. Few years ago crizotinib, an inhibitor of the receptor tyrosine kinases c-Met and ALK, demonstrated its activity in ALK positive non-small-cell lung cancer and other tumors with excellent toxicity profile. Subsequently several ALK inhibitors have been developed, offering new personalized treatment options. This review addresses some clinical considerations on the use of ALK inhibitors in ALK positive tumors and on the development of resistance to them.

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Antitumor activity of alectinib (CH5424802/RO5424802) for ALK-rearranged NSCLC with or without prior crizotinib treatment in bioequivalence study.

Cited by 11 publications

References 0 publications

Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib

Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib

Safety of cranial radiotherapy concurrent with tyrosine kinase inhibitors in non-small cell lung cancer patients: A systematic review

ALK inhibitors for clinical use in cancer therapy

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