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Recently, the oral multi\u2010kinase inhibitor cabozantinib has shown promising results as a potential second\u2010line treatment option. Unfortunately, first\u2010line mitotane therapy complicates subsequent treatments due to its strong and long\u2010lasting inducing effects on drug\u2010metabolizing enzymes resulting in persistent subtherapeutic concentrations. This is also relevant for subsequent cabozantinib treatment, and therefore only patients with mitotane concentration \u22642\u2009mg\/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\u2010administration with a high\u2010fat meal and grapefruit juice to increase cabozantinib absorption. Second, we aimed to reduce cabozantinib clearance through co\u2010administration of the CYP3A4 inhibitor cobicistat (150\u2009mg once daily). Pharmacokinetic sampling revealed that cobicistat enhanced cabozantinib absorption, but had insufficient impact on metabolic enzymes and thereby failed to normalize the mitotane\u2010induced 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\u2010induced subtherapeutic concentrations, this pharmacokinetic strategy may facilitate more effective use and earlier initiation of cabozantinib as second\u2010line treatment in ACC.<\/jats:p>","DOI":"10.1002\/bcp.70404","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T22:38:27Z","timestamp":1764715107000},"page":"606-611","source":"Crossref","is-referenced-by-count":0,"title":["Mitigating subtherapeutic cabozantinib exposure after prior mitotane therapy in adrenocortical carcinoma: Pharmacological boosting with cobicistat"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7979-5149","authenticated-orcid":false,"given":"Annemieke M. 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