Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

Morcos, Peter N.; Cleary, Yumi; Guerini, Elena; Dall, Georgina; Bogman, Katrijn; Petris, Luigi De; Viteri, Santiago; Bordogna, Walter; Yu, Li; Martin‐Facklam, Meret; Phipps, Alex

doi:10.1002/cpdd.298

Cited by 39 publications

(51 citation statements)

References 49 publications

(135 reference 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%

Metabolites of alectinib in human: their identification and pharmacological activity

Sato-Nakai¹,

Kawashima²,

Nakagawa³

et al. 2017

Heliyon

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Two metabolites (M4 and M1b) in plasma and four metabolites (M4, M6, M1a and M1b) in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.

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Section: Discussionmentioning

confidence: 99%

Metabolites of alectinib in human: their identification and pharmacological activity

Sato-Nakai¹,

Kawashima²,

Nakagawa³

et al. 2017

Heliyon

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“…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%

Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects

Morcos

Guerini

Parrott

et al. 2016

Clinical Pharm in Drug Dev

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Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2-treatment (A, fasted conditions; B, following a high-fat meal), 2-sequence (AB or BA) crossover assessment, separated by a 10-day washout. In group 2 (n = 24), subjects were enrolled in a 2-period, fixed-sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high-fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%-393%) and 311% (90%CI, 273%-355%) for C and AUC , respectively, versus fasted conditions. Coadministration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4. Alectinib should be administered under fed conditions to maximize its bioavailability, whereas no restrictions are required with antisecretory agents.

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“…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 [22–25] and similarly utilized for exposure–response assessments for other agents with active metabolites [26–28]. …”

Section: Methodsmentioning

confidence: 99%

Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

Morcos

Nueesch

Jaminion

et al. 2018

Cancer Chemother Pharmacol

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PurposeAlectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.MethodsA semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3).ResultsOverall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs.ConclusionAlectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.Electronic supplementary materialThe online version of this article (10.1007/s00280-018-3597-5) contains supplementary material, which is available to authorized users.

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Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

Cited by 39 publications

References 49 publications

Metabolites of alectinib in human: their identification and pharmacological activity

Metabolites of alectinib in human: their identification and pharmacological activity

Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects

Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

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