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Pharmacokinetics, Safety, and Efficacy of Trastuzumab Deruxtecan with Concomitant Ritonavir or Itraconazole in Patients with HER2-Expressing Advanced Solid Tumors
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Abstract
Purpose: To evaluate drug–drug interactions between the human epidermal growth factor receptor 2 (HER2)–targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd; DS-8201a) and the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole. Patients and Methods: Patients with HER2-expressing advanced solid tumors were enrolled in this phase I, open-label, single-sequence crossover study (NCT03383692) and received i.v. T-DXd 5.4 mg/kg every 3 weeks. Patients received ritonavir (cohort 1) or itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3. Primary endpoints were maximum serum concentration (Cmax) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC17d) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment. Results: Forty patients were enrolled (cohort 1, n = 17; cohort 2, n = 23). T-DXd Cmax was similar whether combined with ritonavir [cohort 1, cycle 3/cycle 2; 90% confidence interval (CI): 1.05 (0.98–1.13)] or itraconazole [cohort 2, 1.03 (0.96–1.09)]. T-DXd AUC17d increased from cycle 2 to 3; however, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts. For DXd (cycle 3/cycle 2), Cmax ratio was 0.99 (90% CI, 0.85–1.14) for cohort 1 and 1.04 (0.92–1.18) for cohort 2; AUC17d ratio was 1.22 (1.08–1.37) and 1.18 (1.11–1.25), respectively. The safety profile of T-DXd plus ritonavir or itraconazole was consistent with previous studies of T-DXd monotherapy. T-DXd demonstrated promising antitumor activity across HER2-expressing solid-tumor types. Conclusions: T-DXd was safely combined with ritonavir or itraconazole without clinically meaningful impact on T-DXd or DXd pharmacokinetics.
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“T-DXd showed encouraging anticancer efficacy against all solid tumor types that expressed HER2.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [89]
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“ITZ or ritonavir was safely added to T-DXd without having a discernible effect on the pharmacokinetics of either drug.89”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [89]
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“T-DXd + ITZ or ritonavir had a safety profile that was in line with earlier research on TDXd monotherapy.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [89]
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References 19 · Cited by 37
Research works printed but not linked: 20
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Metadata
- Authors
- Takahashi, S., Karayama, M., Takahashi, M., Watanabe, J., Minami, H., Yamamoto, N., Kinoshita, I., Lin, C.-C., Im, Y.-H., Achiwa, I., Kamiyama, E., Okuda, Y., Lee, C., & Bang, Y.-J.
- Affiliations
- The Cancer Institute Hospital (JP)
- 2Hamamatsu University Hospital, Shizuoka, Japan.
- Sapporo National Hospital (JP)
- Shizuoka Cancer Center (JP)
- Kobe University Hospital (JP)
- National Cancer Centre Japan (JP)
- Hokkaido University Hospital (JP)
- National Taiwan University Hospital (TW)
- Samsung Medical Center (KR)
- Daiichi-Sankyo (Japan) (JP)
- Daiichi Sankyo (United States) (US)
- Seoul National University (KR)
- Corresponding author
- Takahashi, Shunji
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-08-23
- Volume
- 27
- Issue
- 21
- Pages
- 5771-5780
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC9401457
- OpenAlex
- W3195991203
- Cited by
- 37
- References
- 19
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 6
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Cancer Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Daiichi Sankyo
- AstraZeneca
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- trastuzumab deruxtecan, ritonavir, itraconazole, drug-drug interactions, HER2-positive solid tumors, antibody-drug conjugates, CYP3A inhibition, OATP1B, pharmacokinetics, deruxtecan, dose adjustment, safety, efficacy, crossover design, advanced solid tumors, HER2-targeted therapy
- MeSH terms
- Trastuzumab, Adult, Aged, Aged, 80 and over, Camptothecin, Drug Combinations, Female, Humans, Male, Middle Aged, Neoplasms, Treatment Outcome, Itraconazole, Cross-Over Studies, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Immunoconjugates, Ritonavir
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