Received: 20 September 2025
Revised: 4 November 2025
CASE REPORT
BJCP
BRITISH PHARMACOLOGICAL SOCIETY
Mitigating subtherapeutic cabozantinib exposure after prior mitotane therapy in adrenocortical carcinoma: Pharmacological boosting with cobicistat
Annemieke M. Peters van Ton 1,2 İD
|
Nielka P. van Erp2 2 İD
|
Annenienke C. van de Ven 3
İD
İD | Janneke E. W. Walraven 1 Loek A. W. de Jong2 İD |
1Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands 2Department of Pharmacy, Pharmacology and Toxicology, Radboudumc, Nijmegen, The Netherlands
3Department of Internal Medicine, Division of Endocrinology, Radboudumc, Nijmegen, The Netherlands
Correspondence
Loek A. W. de Jong, Department of Pharmacy, Pharmacology and Toxicology, Radboudumc, Nijmegen, The Netherlands.
Email: loek.dejong@radboudumc.nl
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 cabozan- tinib has shown promising results as a potential second-line treatment option. Unfor- tunately, 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 cabo- zantinib 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 phar- macokinetic 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 cobi- cistat enhanced cabozantinib absorption, but had insufficient impact on metabolic enzymes and thereby failed to normalize the mitotane-induced clearance of cabozan- tinib. Therefore, doubling the dose is deemed necessary in order to reach therapeutic cabozantinib concentrations. Our findings suggest that an aggressive approach, com- bining 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 treat- ment in ACC.
KEYWORDS
adrenocortical carcinoma, cabozantinib, cobicistat, mitotane, pharmacokinetic boosting, pharmacokinetic enhancement
@ 2025 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
BJCP
BRITISH PHARMACOLOGICAL SOCIETY
1 INTRODUCTION |
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, which annually affects 1-2 people per million worldwide.1,2 ACCs are often aggressive tumours with a poor prognosis and disappointing response to currently available systemic treatments. The approved first line systemic therapy for ACC is mitotane,3 a cell-specific adrenolytic, which in some cases of advanced disease is combined with etoposide, doxorubicin and cisplatin chemotherapy. This current standard treatment for advanced ACC results in an objective response rate of 23%, a median progression- free survival (PFS) of only 5.6 months (95% CI 3.6-7.4) and a median overall survival of 14.8 months (95% CI 11.3-17.1).4 In second-line set- ting, treatment options are limited, and therefore treatment within a trial setting is preferred. If this is not available, streptozocin4 or capecitabine- gemcitabine5,6 can be considered, taking into account the low response rates.7 Recently, the oral multi-kinase inhibitor cabozantinib has shown promising results as a potential second-line treatment option,8,9 demon- strating a median progression-free survival of 6 months (95% CI 4.3 - not reached).9 However, first-line mitotane therapy presents challenges to the effectiveness of subsequent treatments due to its strong and long-lasting inducing effect on the activity of drug-metabolizing enzymes and drug-transporters in both the liver and intestines, resulting in poten- tial clinically relevant drug-drug interactions.10 This effect also extends to cabozantinib, which is predominantly metabolized by cytochrome P450 (CYP)3A4 into inactive metabolites. Mitotane is expected to increase both intestinal and hepatic clearance of cabozantinib, causing low and possible subtherapeutic cabozantinib plasma concentrations. Mitotane’s long and highly variable plasma elimination half-life of 18- 159 days11 significantly complicates the timely initiation of cabozantinib as second-line treatment options in patients with ACC. The referenced single-arm phase 2 trial demonstrating promising efficacy of cabozanti- nib9 was conducted in a highly selected patient population, including only patients with low mitotane concentrations (≤2 mg/L). In some cases, it may take several months for mitotane plasma levels to decline below this threshold after discontinuation. Consequently, patients in this trial who could await mitotane levels to diminish without experiencing further clin- ical deterioration, likely had a more favourable prognosis. Patients with a less favourable prognosis may particularly benefit from strategies that enable earlier initiation of cabozantinib therapy. Pharmacological boost- ing represents an elegant strategy to overcome the CYP3A4-inducing effects of mitotane, enabling early initiation of cabozantinib as second- line treatment in ACC. Here, we present a 61-year-old man with rapidly progressive adrenocortical carcinoma treated with surgery, mitotane combined with chemotherapy and ultimately cabozantinib, who was cotreated with the pharmacokinetic enhancer cobicistat with the aim of irreversibly inhibiting CYP3A4 metabolism, thereby boosting cabozanti- nib concentrations and its efficacy against ACC.
2 CASE REPORT
|
The patient was referred to our institute with clinical features consistent with Cushing’s syndrome and a 9 cm cortisol- and
androgen-producing tumour in his left adrenal gland. An adrenalec- tomy was performed, and the pathologist diagnosed a T4N0M0 adrenocortical carcinoma with high proliferative activity (MIB-1 index 40%) and a R1 resection (with focal vaso-invasive growth). Given the high risk of recurrent disease, adjuvant mitotane in a slow build-up schedule to limit mitotane toxicity was started 6 weeks postoperatively. A CT-scan performed almost 7 weeks after his sur- gery already showed locally recurrent disease with progression along the pancreatic tail together with lesions suspicious for metastases in parailiacal lymph nodes and the liver. The endocrinologist acceler- ated the dose-escalation of mitotane and referred the patient to the oncologist for treatment with systemic chemotherapy. The patient received 6 cycles of etoposide, doxorubicin and cisplatin together with mitotane, which he tolerated well. Evaluation by CT and MRI after 6 cycles showed prominent and progressive liver metastases and new sclerotic osseous lesions. First-line palliative treatment failed, and the patient inquired about the possibility of off-label cabozantinib therapy based on the recent promising finding in the phase II trial.9 The mitotane plasma trough concentration was 16 mg/L when mitotane treatment was ended. Sixteen days later, the mitotane plasma concentration dropped to 12 mg/L. The esti- mated mitotane half-life for this patient was ~39 days. Therefore it would take over 3 months to achieve a mitotane concentration <2 mg/L, assuming linear kinetics,12,13 dictated as the start criteria for cabozantinib in the earlier clinical trial.9 In the meantime evalua- tion by CT and MRI showed progression of liver metastases within 6 weeks after completion of chemotherapy. Despite the anticipated clinically relevant drug-drug interaction with mitotane, cabozantinib treatment was initiated at a dose of 60 mg once daily, administered not on an empty stomach as recommended by the label but with a high-fat breakfast to improve absorption, which increases Cmax and AUC by 41% and 57%, respectively, compared to fasted condi- tions.14 Plasma concentrations of both mitotane and cabozantinib were monitored to optimize treatment. Based on earlier research in patients with renal cell cancer and salivary gland cancer, a target cabozantinib trough concentration of approximately 600 µg/L was aimed for.15,16 Figure 1 displays the drug concentrations of both drugs over time. Cabozantinib trough concentrations were consid- ered subtherapeutic after 2 and 4 weeks of treatment (102 and 153 µg/L, respectively). The patient was subsequently instructed to take cabozantinib with a glass of grapefruit juice in order to inhibit intestinal CYP3A4 enzyme activity, thereby improving the absorp- tion and bioavailability of cabozantinib, as previously described.17,18 However, this strategy did not result in significant improvement in cabozantinib plasma concentrations, with only a modest increase to 252 µg/L after one month of co-administration with grapefruit juice, still well below the proposed target concentration. The low cabo- zantinib concentrations in this patient were likely explained by reduced absorption (by enhanced intestinal metabolism) and high cabozantinib clearance due to the persistent cytochrome P450-inducing effects of mitotane. As mitotane levels remained ele- vated (7 mg/L), we initiated treatment with the strong CYP3A4 inhibitor cobicistat (150 mg once daily) to counteract mitotane-
BJCP
BRITISH PHARMACOLOGICAL SOCIETY
Mitotane and Cabozantinib Cmin
Grapefruit
Cobicistat
Mitotane
150mg QD
Cabozantinib
20
EDP chemotherapy
60mg QD
60mg BID
1200
18-
16
1000
Mitotane (mg/L)
Mitotane Cmin (mg/L)
Cabozantinib Cmin (µg/L)
Cabozantinib (ug/L)
14
800
12-
10.
600
8
6
400
4.
200
2
0
0
0
10
20
30
40
50
60
70
Time (weeks since diagnosis)
induced enhancement of cabozantinib metabolism in order to increase cabozantinib plasma concentrations and thereby efficacy. Cabozantinib and cobicistat were co-administered in the morning under fed conditions. Pharmacokinetic sampling of cabozantinib before and 3.5 weeks after initiation of cobicistat (Figure 2) demon- strated increased cabozantinib exposure and peak concentration (Cmax) following cobicistat co-administration, suggesting enhanced absorption of cabozantinib. Nevertheless, cabozantinib clearance remained high, resulting in persistently subtherapeutic trough con- centrations. Since pharmacokinetic enhancement alone proved insuf- ficient and no clinical toxicity was observed, dose escalation to 60 mg twice daily in combination with cobicistat boosting was con- sidered safe. This approach resulted in an adequate cabozantinib trough concentration (648 ug/L) after 10 days, while mitotane levels remained elevated (4 mg/L). Five weeks later, the patient presented with recurrent Cushing’s syndrome, suggestive of tumour progres- sion after cessation of mitotane. The following day, the patient was admitted with pneumosepsis, abdominal pain secondary to liver metastases, a lumbar compression fracture and radiological signs of bone marrow infiltration. Given this extensive disease progression and the patient’s deteriorating condition, cabozantinib and cobicistat treatments were terminated, and the treatment goal was shifted to best supportive care. The patient was treated for Cushing’s syn- drome with osilodrostat (a cortisol synthesis inhibitor, which has no known drug-drug interaction with mitotane) and received palliative radiotherapy to the L2 vertebra. Two months later, the patient died of metastatic adrenocortical carcinoma.
3 DISCUSSION |
This case report highlights the clinical challenges encountered in the treatment of ACC and presents a potential strategy of utilizing phar- macokinetic boosting and dosing strategies to address these chal- lenges. The strong and long-lasting inducing effect of mitotane on cytochrome P450 activity will last for months after mitotane therapy cessation,10 significantly limiting subsequent anti-cancer treatments. Especially patients with an aggressive tumour type may not have suf- ficient time to await mitotane concentrations to drop below 2 mg/L.
To potentiate cabozantinib efficacy, we recommended co- administration with a high-fat meal14 and grapefruit juice17,18 to increase cabozantinib absorption. Additionally, cabozantinib clearance can be reduced through co-administration of the irreversible CYP3A4 inhibitor cobicistat. This boosting strategy is well-established in the treatment of HIV and hepatitis C with protease inhibitors.20,21 A human hepatocyte-based in vitro model showed that coincubation of both cobicistat and ritonavir reduced clearance of a CYP3A4 sub- strate in the presence of the strong CYP3A4 inducer rifampicin in a concentration-dependent manner.22 The irreversible CYP3A4 inhibi- tor ritonavir was even more effective than cobicistat in attenuating the rifampicin-induced clearance. Nevertheless, we chose cobicistat over ritonavir as a pharmacokinetic enhancer in this patient because it lacks off-target effects, has a favourable safety profile, and we had previous experience with cobicistat in an oncological setting. 18,23 Concomitant use of cobicistat as a pharmacokinetic enhancer has been described in the treatment of lung cancer24,25 and renal
BJCP
BRITISH PHARMACOLOGICAL SOCIETY
(A) Cabozantinib 60mg QD
1400
Cabozantinib (µg/L)
1200
AUC0-24: 7315 µg/L
Cmax: 468 µg/L
1000
Co: 252 µg/L
800
600
400
200
0
TO
T2
T4
T6
Hours before (TO) and after cabozantinib administration
(B) Cabozantinib 60mg QD + cobicistat 150mg QD
1400
Cabozantinib (µg/L)
AUC0-24: 11029 µg/L
1200
Cmax: 769 µg/L
1000
Co: 217 µg/L
800
600
400
200
0
TO
T2
T4
T6
Hours before (TO) and after cabozantinib administration
(C) Cabozantinib 60mg BID + cobicistat 150mg QD
(D) Cabozantinib AUC0-24
1400
50000
Cabozantinib (µg/L)
1200
1000
AUC0-24 (µg/L/h)
Mean population exposure (SD)
40000
A. Cabozantinib 60mg QD
800
30000
B. Cabozantinib 60mg QD
600
AUC0-24: 22056 µg/L
20000
+ Cobicistat 150mg QD
400
C, Cabozantinib 60mg BID
Cmax: 1206 µg/L
10000
+ Cobicistat 150mg QD
200
Co: 648 µg/L
0
0
TO
T2
T4
T6
A
B
C
Hours before (TO) and after cabozantinib administration
cancer,18 and is currently being studied in ovarian cancer23 and pan- creatic cancer.26 Pharmacokinetic boosting in patients previously trea- ted with mitotane has not been studied, and its use was off-label.
This case report emphasizes the importance of monitoring plasma concentrations to enable personalized therapy, not only to reach ther- apeutic concentrations of a CYP3A4 substrate but also to prevent toxicity once the inducing effects of mitotane slowly diminish, leading to increased exposure of CYP3A4 substrates. It is important to realize that mitotane induces multiple drug-metabolising enzymes and drug transporters which affect the metabolism of many co-medications.27 Even two compounds of the chemotherapeutic regime often co- administered with mitotane (etoposide and doxorubicin) are likely affected by mitotane-induced effects on cytochrome P450 enzymes and P-glycoprotein.28,29 Due to its long half-life, interactions with mitotane should still be taken into account, even months after mito- tane discontinuation.
The elaborative PK sampling in this case further enabled us to study the effects of cobicistat on both the absorption and the elimina- tion of cabozantinib. It showed large intra-patient variability in the
time to reach maximum cabozantinib plasma concentrations (Tmax), which could be caused by differences in the type and amount of co- administered food and the level of gastric acidity, which both affect cabozantinib absorption.14 In this case, patient’s cabozantinib concen- trations did not reach the predefined target level despite a dosage of 60 mg once daily co-administered with a high-fat meal and cobicistat 150 mg once daily. Although cobicistat enhanced cabozantinib Cmax, suggesting a successful local inhibitory effect on intestinal CYP3A4 leading to increased bioavailability, it had insufficient impact on cabo- zantinib clearance, failing to normalize the increased systemic clear- ance. Doubling the cabozantinib dose was deemed necessary to achieve plasma target levels of ~600 µg/L, which can be considered as best-tolerated cabozantinib exposure levels based on earlier find- ings of our group in patients treated with cabozantinib for salivary gland cancer and renal cell carcinoma.15,16 Unfortunately, rapid dis- ease progression occurred, and the patient passed away. Despite our efforts, therapeutic cabozantinib concentrations were only reached after 2.5 months and might therefore have been too late to make a difference for this patient with an aggressive tumour. In retrospect,
BJCP
BRITISH PHARMACOLOGICAL SOCIETY
considering our patient’s outcome, we might have preferred a more aggressive instead of a stepwise strategy. A stronger pharmacological enhancement may have been achieved by administering cobicistat twice daily, considering its short plasma half-life of 3-4 h. Alterna- tively, the potent CYP3A4 inhibitor ritonavir could be used instead of cobicistat. This case report is limited by its description of only one patient. Given the considerable interpatient variability in pharmacoki- netics, the effect of boosting may vary in other patients. In future cases where cabozantinib therapy is initiated after recent discontinua- tion of mitotane, it is advisable to combine multiple interventions including administration with a high-fat meal and grapefruit juice, a doubled cabozantinib dose and pharmacological enhancement with either cobicistat twice-daily or ritonavir. We encourage other researchers to investigate PK boosting strategies for anticancer drugs to enhance treatment options for cancer patients. It is essential that such approaches are always combined with monitoring of plasma drug concentrations to evaluate the effect.
4 CONCLUSIONS
|
If cabozantinib is considered as second-line treatment following mito- tane in advanced ACC, we recommend an early start with a doubled cabozantinib dose, combined with pharmacokinetic boosting and fre- quent pharmacokinetic monitoring to prevent undertreatment and toxicity. This strategy facilitates earlier initiation of cabozantinib as second-line treatment in adrenocortical carcinoma and prevents potentially harmful treatment delay.
AUTHOR CONTRIBUTIONS
Annemieke M. Peters van Ton: Investigation; visualization; writing- original draft. Nielka P. van Erp: Conceptualization; investigation; writing-review and editing. Annenienke C. van de Ven: Investigation; writing-review and editing. Janneke E. W. Walraven: Investigation; writing-review and editing. Loek A. W. de Jong: Conceptualization; investigation; writing-review and editing.
CONFLICT OF INTEREST STATEMENT
Nielka P. van Erp has received research funding from Astellas and Ipsen (all paid to the institute). Annemieke M. Peters van Ton, Annenienke C. van de Ven, Janneke E.W. Walraven and Loek A.W. de Jong declare no potential conflicts of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
ORCID
Annemieke M. Peters van Ton (D https://orcid.org/0000-0001-7979- 5149
Nielka P. van Erp DD https://orcid.org/0000-0003-1553-178X
Annenienke C. van de Ven ID https://orcid.org/0009-0009-0977-5690
Janneke E. W. Walraven D https://orcid.org/0000-0001-7161-5369 Loek A. W. de Jong D https://orcid.org/0000-0002-3989-8386
REFERENCES
1. Kerkhofs TM, Verhoeven R, van J, et al. Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur J Cancer. 2013;49(11):2579-2586. doi:10.1016/j.ejca. 2013.02.034
2. Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg. 2006;30(5):872-878. doi:10.1007/ s00268-005-0329-x
3. Corso CR, Acco A, Bach C, Bonatto SJR, de Figueiredo BC, de Souza LM. Pharmacological profile and effects of mitotane in adreno- cortical carcinoma. Br J Clin Pharmacol. 2021;87(7):2698-2710. doi: 10.1111/bcp.14721
4. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23): 2189-2197. doi:10.1056/NEJMoa1200966
5. Sperone P, Ferrero A, Daffara F, et al. Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer. 2010;17(2):445-453. doi:10.1677/ERC- 09-0281
6. Henning JEK, Deutschbein T, Altieri B, et al. Gemcitabine-based chemotherapy in adrenocortical carcinoma: a multicenter study of efficacy and predictive factors. J Clin Endocrinol Metabol. 2017; 102(11):4323-4332. doi:10.1210/jc.2017-01624
7. Fassnacht M, Assie G, Baudin E, et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020; 31(11):1476-1490. doi:10.1016/j.annonc.2020.08.2099
8. Kroiss M, Megerle F, Kurlbaum M, et al. Objective response and pro- longed disease control of advanced adrenocortical carcinoma with Cabozantinib. J Clin Endocrinol Metab. 2020;105(5):1461-1468. doi: 10.1210/clinem/dgz318
9. Campbell MT, Balderrama-Brondani V, Jimenez C, et al. Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial. Lancet Oncol. 2024;25(5):649-657. doi:10.1016/S1470- 2045(24)00095-0
10. van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol. 2011;164(4):621-626. doi:10. 1530/EJE-10-0956
11. Moolenaar AJ, van Slooten H, van Seters AP, Smeenk D. Blood levels of o,p’-DDD following administration in various vehicles after a single dose and during long-term treatment. Cancer Chemother Pharmacol. 1981;7(1):51-54. doi:10.1007/BF00258213
12. Arshad U, Taubert M, Kurlbaum M, et al. Enzyme autoinduction by mitotane supported by population pharmacokinetic modelling in a large cohort of adrenocortical carcinoma patients. Eur J Endocrinol. 2018;179(5):287-297. doi:10.1530/EJE-18-0342
13. Cazaubon Y, Talineau Y, Feliu C, et al. Population pharmacokinetics modelling and simulation of Mitotane in patients with adrenocortical carcinoma: an individualized dose regimen to target all patients at three months? Pharmaceutics. 2019;11(11):566. doi:10.3390/ pharmaceutics 11110566
14. Nguyen L, Holland J, Mamelok R, et al. Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozan- tinib in healthy adult subjects. J Clin Pharmacol. 2015;55(11):1293- 1302. doi:10.1002/jcph.526
15. Krens SD, van Erp NP, Groenland SL, et al. Exposure-response analyses of cabozantinib in patients with metastatic renal cell cancer. BMC Cancer. 2022;22(1):228. doi:10.1186/s12885-022-09338-1
BJCP
BRITISH PHARMACOLOGICAL SOCIETY
16. Krens SD, van Boxtel W, Uijen MJM, et al. Exposure-toxicity relation- ship of cabozantinib in patients with renal cell cancer and salivary gland cancer. Int J Cancer. 2022;150(2):308-316. doi:10.1002/ijc. 33797
17. Kupferschmidt HH, Ha H, Ziegler W, Meier P, Krähenbühl S. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther. 1995;58(1):20-28. doi:10.1016/0009-9236(95) 90068-3
18. Lubberman FJE, van Erp NP, ter Heine R, van Herpen CML. Boosting axitinib exposure with a CYP3A4 inhibitor, making axitinib treatment personal. Acta Oncol. 2017;56(9):1238-1240. doi:10.1080/0284186 X.2017.1311024
19. Pharma, I., Cabometyx - Summary of product characteristics (SPC). https://www.ema.europa.eu/en/medicines/human/EPAR/cabometyx
20. Renjifo, B.et al., Pharmacokinetic enhancement in HIV antiretroviral therapy: a comparison of ritonavir and cobicistat. AIDS Rev, 2015. 17(1): p. 37-46.
21. Larson KB, Wang K, Delille C, Otofokun I, Acosta EP. Pharmacoki- netic enhancers in HIV therapeutics. Clin Pharmacokinet. 2014;53(10): 865-872. doi:10.1007/s40262-014-0167-9
22. Roberts O, Khoo S, Owen A, Siccardi M. Interaction of rifampin and Darunavir-ritonavir or Darunavir-Cobicistat in vitro. Antimicrob Agents Chemother. 2017;61(5). doi:10.1128/AAC.01776-16
23. Overbeek JK, Guchelaar NAD, Mohmaed Ali MI, et al. Pharmacoki- netic boosting of olaparib: study protocol of a multicentre, open-label, randomised, non-inferiority trial (PROACTIVE-B). Contemp Clin Trials Commun. 2025;45:101477. doi:10.1016/j.conctc.2025.101477
24. Hohmann N, Bozorgmehr F, Christopoulos P, et al. Pharmacoen- hancement of low Crizotinib plasma concentrations in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer using the CYP3A inhibitor Cobicistat. Clin Transl Sci. 2021;14(2):487-491. doi:10.1111/cts.12921
25. van Veelen A, Gulikers J, Hendriks LEL, et al. Pharmacokinetic boost- ing of osimertinib with cobicistat in patients with non-small cell lung cancer: the OSIBOOST trial. Lung Cancer. 2022;171:97-102. doi:10. 1016/j.lungcan.2022.07.012
26. Hohmann N, Sprick MR, Pohl M, et al. Protocol of the IntenSify-trial: an open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination’s pharmacokinetics, safety, and efficacy. Clin Transl Sci. 2023;16(12):2483-2493. doi:10.1111/cts.13661
27. Theile D, Haefeli WE, Weiss J. Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro. Endocrine. 2015;49(3): 842-853. doi:10.1007/s12020-014-0517-2
28. Jouinot A, Royer B, Chatelut E, et al. Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study. Endocr Connect. 2018;7(12):1409-1414. doi:10.1530/EC-18-0428
29. Gagliano T, Gentilin E, Benfini K, et al. Mitotane enhances doxorubi- cin cytotoxic activity by inhibiting P-gp in human adrenocortical carci- noma cells. Endocrine. 2014;47(3):943-951. doi:10.1007/s12020- 014-0374-z
How to cite this article: van Ton AMP, van Erp NP, van de Ven AC, Walraven JEW, de Jong LAW. Mitigating subtherapeutic cabozantinib exposure after prior mitotane therapy in adrenocortical carcinoma: Pharmacological boosting with cobicistat. Br J Clin Pharmacol. 2026;92(2):606-611. doi:10.1002/bcp.70404