Mitigating subtherapeutic cabozantinib exposure after prior mitotane therapy in adrenocortical carcinoma: Pharmacological boosting with cobicistat

Mitotane is an adrenolytic drug with cytotoxic effects, registered for the treatment of advanced adrenocortical carcinoma (ACC), a rare but aggressive tumour type with a poor prognosis despite treatment. Recently, the oral multi-kinase inhibitor cabozantinib has shown promising results as a potential second-line treatment option. Unfortunately, first-line mitotane therapy complicates subsequent treatments due to its strong and long-lasting inducing effects on drug-metabolizing enzymes resulting in persistent subtherapeutic concentrations. This is also relevant for subsequent cabozantinib treatment, and therefore only patients with mitotane concentration ≤2 mg/L were eligible to enter the cabozantinib study. However, ACC is often too aggressive to await mitotane effects to diminish. In this case report, we describe different pharmacokinetic interventions to potentiate cabozantinib efficacy in a patient with rapidly progressive ACC who had persistent subtherapeutic cabozantinib concentrations after previous mitotane treatment. First, we recommended co-administration with a high-fat meal and grapefruit juice to increase cabozantinib absorption. Second, we aimed to reduce cabozantinib clearance through co-administration of the CYP3A4 inhibitor cobicistat (150 mg once daily). Pharmacokinetic sampling revealed that cobicistat enhanced cabozantinib absorption, but had insufficient impact on metabolic enzymes and thereby failed to normalize the mitotane-induced clearance of cabozantinib. Therefore, doubling the dose is deemed necessary in order to reach therapeutic cabozantinib concentrations. Our findings suggest that an aggressive approach, combining pharmacokinetic boosting, dose escalation and frequent pharmacokinetic monitoring is required to prevent undertreatment and toxicity. By mitigating mitotane-induced subtherapeutic concentrations, this pharmacokinetic strategy may facilitate more effective use and earlier initiation of cabozantinib as second-line treatment in ACC.