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

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 (Cmin,ss ), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases Cmin,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 Cmin,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 (AUC0-12 ). 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 Cmin,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC0-12 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.

Atazanavir sulfate + cobicistat for the treatment of HIV infection.

INTRODUCTION: During last two decades several drugs were developed to offer long-term benefits in terms of virologic efficacy, favourable tolerability and toxicity profiles in treatment of HIV infection. Pharmacokinetics boosting of protease inhibitor allows a higher genetic barrier, as few or no drug-resistant mutations are detected in patients with virologic failure. Areas covered: Atazanavir sulfate + cobicistat (ATV/c) was recently approved for the treatment of HIV-1 infection. Bioequivalence between cobicistat (COBI) and ritonavir (RTV) as a pharmacoenhancer of ATV was established. Additionally, randomized clinical trials demonstrated that ATV/c and ATV/ritonavir had comparable efficacy and safety profiles. Low rates of virologic failure and no ATV resistance mutations were observed in these clinical trials. Therefore, COBI shows increased advantages over RTV, such as no activity against HIV, fewer drug-drug interactions and better solubility, which promotes coformulation strategies with less pill burden, better tolerability, and, potentially, higher life-long treatment adherence. Expert commentary: ATV/c regimen supports its useas an effective treatment option for HIV-1 infected patients with increased cardiovascular disease and chronic kidney disease risk associated with aging. In addition, ATV/c is a new opportunity to expand the strategy of switch to a dual therapy to lower the risk of long-term toxicities as well as the advantage of its cost-benefit.