Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects

Lau, Yvonne; Gu, Wen; Lin, Tsang Long; Song, Dongweon; Yu, Ruey J.; Scott, Jeffrey W.

doi:10.1002/jcph.619

Cited by 41 publications

(35 citation statements)

References 20 publications

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“…The absolute bioavailability of oral ceritinib is not known 66. Two studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg and another study with a light snack at 750 mg 69. Higher plasma concentrations for ceritinib were achieved when it was administered under fed conditions (low- and high-fat meals).…”

Section: Ceritinib: Overcoming Crizotinib Resistancementioning

confidence: 99%

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

Santarpía¹,

Daffinà²,

D’Aveni³

et al. 2017

DDDT

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The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib’s efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse. Different mechanisms of acquired resistance have been identified, including secondary ALK mutations, ALK copy number alterations and activation of bypass tracks. Different highly potent and brain-penetrant next-generation ALK inhibitors have been developed and tested in NSCLC patients with ALK rearrangements. Ceritinib, a structurally distinct and selective ALK inhibitor, showed 20 times higher potency than crizotinib in inhibiting ALK and had activity against the most common crizotinib-resistant mutations, including L1196M and G1269A, in preclinical models. In Phase I and II studies, ceritinib demonstrated pronounced activity in both crizotinib-naïve and crizotinib-refractory patients, with responses observed regardless of the presence of ALK resistance mutations. Ceritinib was the first ALK inhibitor to be approved for the treatment of crizotinib-refractory, ALK-rearranged NSCLC, and recent results from a Phase III study have demonstrated superior efficacy compared to standard chemotherapy in the first- and second-line setting. We provide an extensive overview of ceritinib from the design of the compound through preclinical data until efficacy and toxicity results from Phase I–III clinical studies. We review the molecular alterations associated with resistance to ceritinib and highlight the importance of obtaining tumor biopsy at progression to tailor therapy based upon the underlying resistance mechanism. We finally provide an outlook on novel rational therapeutic combinations.

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Section: Ceritinib: Overcoming Crizotinib Resistancementioning

confidence: 99%

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

Santarpía¹,

Daffinà²,

D’Aveni³

et al. 2017

DDDT

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“…Although the recommended daily ceritinib dose of 750 mg taken under fasting conditions, a report has shown ceritinib administered at non-fasted state that suggest decreased toxicity in gastrointestinal symptoms, such as nausea [36]. Notably, ceritinib at a dose of 750 mg administered under non-fasting conditions is expected to result in increased systemic exposure and may increase exposure-dependent adverse drug reactions, which is associated with a higher frequency of grade ≥ 3 hepatotoxicity [37].…”

Section: Discussionmentioning

confidence: 99%

Pooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLC

Zhu

Weng

et al. 2017

BMC Cancer

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BackgroundThe anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear.MethodsWe performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs’ inception to May 2016 to identify clinical trials. Severe adverse events (AEs) (grade ≥ 3) based on the ALK-TKI type were analysed.ResultsSeventeen trials published between 2011 and 2016, including a total of 1826 patients, were eligible for analysis. Patients in 10 trials (n = 1000) received crizotinib, patients in 5 trials (n = 601) received ceritinib and patients in 2 trials (n = 225) received alectinib. The overall frequencies of treatment-related death and AEs due to treatment withdrawal were 0.9% (12/1365) and 5.5% (85/1543), respectively. Moreover, the frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib or alectinib, especially for hepatotoxicity, fatigue and some of gastrointestinal symptoms. Additionally, significant difference in the elevated lipase and amylase levels (grade ≥ 3) were detected between ceritinib and crizotinib/alectinib, whereas neutropenia was less frequent.ConclusionsALK-TKIs were safe for ALK-positive patients. Moreover, statistically significant differences in some severe AEs among ceritinib, crizotinib and alectinib were detected in present study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3405-3) contains supplementary material, which is available to authorized users.

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“…31,44,45 Absorption of ceritinib is affected by food, and it should be taken on an empty stomach ideally 2 h after a meal. 31,45,52 A ceritinib dose of 600 mg or greater taken with a meal is expected to result in systemic exposure exceeding the 750 mg recommended dose taken under fasting conditions. 32,45,52 Ceritinib is 97% bound to plasma proteins.…”

Section: Clinical Pharmacology In Humansmentioning

confidence: 99%

“…31,45,52 A ceritinib dose of 600 mg or greater taken with a meal is expected to result in systemic exposure exceeding the 750 mg recommended dose taken under fasting conditions. 32,45,52 Ceritinib is 97% bound to plasma proteins. After a single dose of 750 mg, the volume of distribution is 4230 L. The half-life of ceritinib is 41 h. After a single 750 mg dose of ceritinib, 82% of the parent compound remained in human plasma, and 92.3% and 1.3% of ceritinib were recovered in feces and urine, respectively.…”

Section: Clinical Pharmacology In Humansmentioning

confidence: 99%

Ceritinib: A primer for pharmacists

Cavalieri

Stenehjem

2016

J Oncol Pharm Pract

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Clinical pharmacists are important contributors to the care of patients with cancer; it is therefore critical for oncology clinical pharmacists to stay current with new anticancer therapies. This review summarizes the epidemiology and pathogenesis of non-small cell lung cancer, including the most common genetic alterations, as well as the mechanism of action, clinical development, pharmacodynamics and pharmacokinetics of the anaplastic lymphoma kinase inhibitor ceritinib for the treatment of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer. Targeted therapies based on the presence of specific mutations are an important development in the treatment of non-small cell lung cancer. However, acquired resistance to the first anaplastic lymphoma kinase-inhibitor approved by the U.S. Food and Drug Administration, crizotinib, is observed in almost half of patients treated with it. Ceritinib is an oral anaplastic lymphoma kinase-inhibitor that has demonstrated more potent antitumor activity than crizotinib in preclinical models. It was granted accelerated approval in 2014 to treat anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer patients who have progressed on or are intolerant to crizotinib. Ceritinib represents an important alternative second-line therapy for patients with metastatic non-small cell lung cancer who have traditionally limited treatment options.

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Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects

Cited by 41 publications

References 20 publications

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

Pooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLC

Ceritinib: A primer for pharmacists

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