2016
DOI: 10.1002/cpdd.298
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Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

Abstract: The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluat… Show more

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Cited by 39 publications
(51 citation statements)
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“…The information that M4 is a major metabolite of alectinib and similarly active was utilized when drug-drug interactions between alectinib and a strong CYP3A inhibitor (posaconazole) and a CYP3A inducer (rifampin) were assessed [26]. Data on the exposure of alectinib and M4 in human were used to set dosing recommendations that ensured inhibitors and inducers had minimal effect on the combined molar exposure of alectinib and M4.…”
Section: Discussionmentioning
confidence: 99%
“…The information that M4 is a major metabolite of alectinib and similarly active was utilized when drug-drug interactions between alectinib and a strong CYP3A inhibitor (posaconazole) and a CYP3A inducer (rifampin) were assessed [26]. Data on the exposure of alectinib and M4 in human were used to set dosing recommendations that ensured inhibitors and inducers had minimal effect on the combined molar exposure of alectinib and M4.…”
Section: Discussionmentioning
confidence: 99%
“…Indeed, PBPK modeling of alectinib absorption predicts a low impact of dissolution in the stomach on oral absorption irrespective of the stomach pH, and no relevant change in exposure is predicted based on a change in gastric pH because of the very low solubility in the stomach at all pH values . Given that alectinib has not shown any perpetrator effects on CYP3A or CYP2C19 enzymes, no confounding influence of potential CYP‐mediated drug–drug interactions with esomeprazole was expected in this assessment. The slight increase observed in alectinib bioavailability with esomeprazole coadministration may be attributed to an (es)omeprazole‐induced decrease in the gastric emptying time of alectinib .…”
Section: Discussionmentioning
confidence: 99%
“…Therefore, the combined exposure of alectinib and M4 (alectinib + M4) steady-state trough concentration adjusted for the individual molecular weights was utilized as the overall alectinib exposure measure (herein C trough,ss ) in the exposure–response analyses. This approach has been utilized for all other alectinib exposure investigations [2225] and similarly utilized for exposure–response assessments for other agents with active metabolites [26–28]. …”
Section: Methodsmentioning
confidence: 99%