Boosting axitinib exposure with a CYP3A4 inhibitor, making axitinib treatment personal

Lubberman, Floor J E; Erp, Nielka P. van; Heine, Rob ter; Herpen, Carla M.L. van

doi:10.1080/0284186x.2017.1311024

Cited by 16 publications

(19 citation statements)

References 10 publications

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“…This concept could be applied to other tyrosine kinase inhibitors in cases where the victim drug’s clearance significantly depends on CYP3A activity, major active metabolites are not critically reduced by inhibition of this pathway, and where a close relationship between plasma exposure and response is established (e.g., in the cases of imatinib, sunitinib, or axitinib). While conducting our trial, a similar approach was reported in a patient with renal cancer under the treatment with axitinib, in whom excessive cobicistat doses helped achieving therapeutic axitinib exposure 19 . In addition, whereas we demonstrated feasibility and safety of pharmacoenhancement, the 14‐day period was too short to answer the question of whether increasing drug exposure will improve antitumor reponse to the drug.…”

Section: Discussionmentioning

confidence: 85%

“…While conducting our trial, a similar approach was reported in a patient with renal cancer under the treatment with axitinib, in whom excessive cobicistat doses helped achieving therapeutic axitinib exposure. 19 In addition, whereas we demonstrated feasibility and safety of pharmacoenhancement, the 14-day period was too short to answer the question of whether increasing drug exposure will improve antitumor reponse to the drug.…”

Section: Limitationsmentioning

confidence: 93%

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

Hohmann

Bozorgmehr

Christopoulos

et al. 2020

Clinical Translational Sci

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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

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Section: Discussionmentioning

confidence: 85%

Section: Limitationsmentioning

confidence: 93%

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

Hohmann

Bozorgmehr

Christopoulos

et al. 2020

Clinical Translational Sci

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition

Eisenmann

Muhowski

et al. 2021

Cancer Research Communications

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Ibrutinib (Imbruvica; PCI-32765) is an orally administered inhibitor of Bruton's tyrosine kinase that has transformed the treatment of B-cell malignancies. However, ibrutinib has very low oral bioavailability that contributes to significant variability in systemic exposure between patients, and this has the potential to affect both efficacy and toxicity. We hypothesized that the oral bioavailability of ibrutinib is limited by CYP3A isoform–mediated metabolism, and that this pathway can be inhibited to improve the pharmacokinetic properties of ibrutinib. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms (CYP3A−/−) that received ibrutinib alone or in combination with CYP3A inhibitors cobicistat or ketoconazole. Computational modeling was performed to derive doses of ibrutinib that, when given after a CYP3A inhibitor, results in therapeutically relevant drug levels. Deficiency of CYP3A in mice was associated with an approximately 10-fold increase in the AUC of ibrutinib. This result could be phenocopied by administration of cobicistat before ibrutinib in wild-type mice, but cobicistat did not influence levels of ibrutinib in CYP3A−/− mice. Population pharmacokinetic and prospectively validated physiologically based pharmacokinetic models established preclinical and clinical doses of ibrutinib that could be given safely in combination with cobicistat without negatively affecting antileukemic properties. These findings signify a dominant role for CYP3A-mediated metabolism in the elimination of ibrutinib, and suggest a role for pharmacologic inhibitors of this pathway to intentionally modulate the plasma levels and improve the therapeutic use of this clinically important agent. Significance: Ibrutinib has limited oral bioavailability, which contributes to significant interindividual pharmacokinetic variability. Using engineered mouse models, we here report a causal relationship between CYP3A-mediated metabolism and ibrutinib's bioavailability and drug–drug interaction with cobicistat. These results offer a mechanistic basis for reported pharmacokinetic interactions with ibrutinib, and in conjunction with a newly developed computational model, allow for the rational design of clinical trials aimed at improving the therapeutic use of ibrutinib.

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“…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).…”

Section: Intentional Use Of Drug–drug Interactions To Increase Bioavailabilitymentioning

confidence: 99%

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

Eisenmann

Talebi

Sparreboom

et al. 2021

Basic Clin Pharma Tox

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Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability of anticancer drugs is due to both pharmaceutical limitations and physiological barriers. Pharmacokinetic boosting is a strategy to enhance the oral bioavailability of a therapeutic drug by inhibiting physiological barriers through an intentional drug–drug interaction (DDI). This type of strategy has proven effective across several therapeutic indications including anticancer treatment. Pharmacokinetic boosting could improve anticancer drugs lacking or with otherwise unacceptable oral formulations through logistic, economic, pharmacodynamic and pharmacokinetic benefits. Despite these benefits, pharmacokinetic boosting strategies could result in unintended DDIs and are only likely to benefit a limited number of targets. Highlighting this concern, pharmacokinetic boosting has mixed results depending on the boosted drug. While pharmacokinetic boosting did not significantly improve certain drugs, it has resulted in the commercial approval of boosted oral formulations for other drugs. Pharmacokinetic boosting to improve oral anticancer therapy is an expanding area of research that is likely to improve treatment options for cancer patients.

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Boosting axitinib exposure with a CYP3A4 inhibitor, making axitinib treatment personal

Cited by 16 publications

References 10 publications

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

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

Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition

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

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