Pharmacoenhancement of Low Crizotinib Plasma Concentrations in Patients with Anaplastic Lymphoma Kinase‐Positive Non‐Small Cell Lung Cancer using the CYP3A Inhibitor Cobicistat

Abstract

The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK-positive non-small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations (C min,ss), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases C min,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK-positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016-002187-14, DRKS00012360) if crizotinib C min,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14-day co-administration of cobicistat to construct the area under the plasma concentration-time curve in the dosing interval from zero to 12 hours (AUC 0-12). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12-lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next-generation ALK-inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased C min,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC 0-12 increased by 78% from 2,210 ng/mL*h to 3,925 ng/mL*h. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost-effective and feasible. Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer and a leading cause of death worldwide. Anaplastic lymphoma kinase (ALK) is a druggable driver mutation of NSCLC. 1 Targeting ALK with the small molecule inhibitor crizotinib demonstrated significant clinical benefit improving progression-free survival, overall response rate (ORR), lung cancer symptoms, and global quality of life. 2,3 Oral crizotinib exhibits substantial variability in steady-state plasma trough concentrations (C min,ss), associated with a concentration-dependent variability in ORR 4 ; the ORR

Novel Therapies for Tongue Squamous Cell Carcinoma Patients with High-Grade Tumors

“…ZINC8214703, namely, unoprostone, could reduce intraocular pressure and treat glaucoma [ 47 ]. ZINC85537014, namely, cobicistat, has the ability to treat human immunodeficiency virus (HIV) infection [ 48 ] and increase the response rates of anticancer drugs [ 49 ]. Because of the anticancer properties of iloprost and unoprostone, these two small molecules might be new drug candidates for TSCC patients [ 50 ].…”

Boosting the oral bioavailability of anticancer drugs through intentional drug–drug interactions

“…However, the clinical trial was terminated because of the approval of alectinib, a next‐generation ALK inhibitor. Nonetheless, in one patient, cobicistat increased crizotinib exposure with no adverse effects 56 . Together, these case studies suggest that cobicistat could boost levels of an oral TKI otherwise unlikely to benefit a patient due to physiologic barriers.…”

“…Two case studies have demonstrated that cobicistat, a potent and allegedly selective CYP3A inhibitor, 22 could boost drug levels of axitinib and crizotinib, respectively 55,56 . Axitinib is an oral multi‐kinase inhibitor metabolised by CYP3A that is approved by the FDA and EMA for metastatic renal cell carcinoma (mRCC).…”

“…If an anticancer drug's therapeutic effects are mediated by active metabolites, then a boosting strategy could negatively impact the therapeutic efficacy of that drug by reducing exposure to those metabolites. Consistent with this idea, a clinical trial investigating PK boosting for crizotinib was terminated and not adapted for alectinib, a next‐generation ALK inhibitor, partially because alectinib has an equipotent active metabolite 56 . While newer, more selective, and/or more potent targeted anticancer agents that may not benefit from a PK boosting strategy are welcome additions to the armamentarium of treatment options for malignancies, the rapid expansion of targeted chemotherapeutics could reduce the feasibility of properly developing a PK boosting strategy for older targeted agents.…”

Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition

“…Recently, there has been a growing interest in the use of this boosting concept as a strategy to improve the pharmacokinetic profile of TKIs already developed and marketed for oral use. Case studies have previously explored the use of cobicistat, to boost levels of TKIs including crizotinib (46) and axitinib (47). Another recent study reported the use of itraconazole, an antifungal drug that is less hepatotoxic than ketoconazole (8), to improve the systemic exposure to ibrutinib in healthy volunteers.…”