Capivasertib, in conjunction with the administration of fulvestrant, was approved by the FDA on November 16, 2023, for hormone receptor (HR)–positive, human epidermal growth factor receptor 2–negative locally advanced or metastatic breast cancer (BC) in patients with >1 PIK3CA/AKT1/PTEN–alterations (as determined by a FDA-approved companion test) following progression on at least one endocrine-based regimen in patients with metastatic disease or recurrence who are on or are within 12 months of completing adjuvant therapy.

The phosphatidylinositol-3-kinase/protein kinase B (PI3K/PKB [also known as AKT]) signaling pathway is dysregulated in BC, with about 40% of HR+ BCs having a PIK3CA mutation. Overall, in BC about 73% of tumors have at least one alteration in the PIK3CA-AKT1-PTEN pathway, with 30% harboring a PIK3CA mutation, 4% having an AKT1 mutation, 55% having PTEN alterations, 2% having a PIK3R1 mutation, and about 1% harboring a PIK3R2 mutation, according to research published in Frontiers in Oncology.

Capivasertib, an AKT serine/threonine protein kinase inhibitor, inhibits all three isoforms of AKT (AKT1, AKT2, and AKT3). AKT plays a role in the development of resistant to BC therapies including hormonal drugs (e.g., aromatase inhibitors) and chemotherapy. Its approval represents a first-in-class that was approved under the FDA’s Priority Review program in collaboration with researchers from Australia, Brazil, Canada, Israel, Singapore, Switzerland, and the United Kingdom.

Capivasertib is metabolized by cytochrome P450 3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase-2B7 (UGT2B7). Drug metabolized by CYP3A4 are subject to numerous drug-drug interactions. To explore this issue further, researchers conducted a phase I, single-center, open-label, fixed sequence drug-drug interaction study to determine the effects of itraconazole on the pharmacokinetics of capivasertib and its major metabolite, AZ14102143, and the frequency and severity of adverse events.

The study enrolled 11 healthy nonpregnant, nonlactating females (mean age: 54 years) who were nonsmokers. Exclusion criteria included a history or presence of a condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs; any clinically significant hematological, laboratory or cardiac abnormalities (based on blood pressure and EKG); or use of medications (e.g., analgesics, hormonal agents, herbal supplements, vitamin megadoses, and minerals) within 2 weeks (or 3 weeks of capivasertib administration depending on the enzyme-inducing effects of the drug or within 5 half-lives, whichever was longer prior to the single dose of 80-mg oral capivasertib). Foods that were known to interact with CYP3A4 (e.g., grapefruit, Seville oranges) or quinine could not be used within 7 days of capivasertib administration.

Study participants received capivasertib 80 mg orally as a tablet along with itraconazole orally as two hard capsules, each containing itraconazole 100 mg on a lead-in schedule with capivasertib administered on Day 1, itraconazole introduced on Day 3 followed 12 hours later by a second dose, and then additional doses of itraconazole 200 mg on Days 4 and 5. On Day 6, both drugs were administered concomitantly, followed by a final dose of itraconazole on Day 7. A predose blood sample was obtained, and additional samples were taken at 16 time points following drug administration. Samples were analyzed using cation exchange–based solid-phase extraction and reversed-phase high-performance liquid chromatography with tandem mass spectrometry.

Some key takeaways from this study were:

• Coadministration of capivasertib and itraconazole did not affect median tmax
• The mean t1/2 of capivasertib was longer when coadministered with itraconazole and increased from 7.4 hours to 10.3 hours
• The time to obtain the last quantifiable capivasertib measurement doubled when co-administered with itraconazole from 24.1 hours to 48 hours
• Capivasertib’s major metabolite, AZ14102143, is inactive as an AKT inhibitor
• There were no Grade 3 adverse events (AEs), with the most common AEs being cough, dyssomnia, back pain, and acne
• Coadministration of itraconazole only increased the area under the concentration–time curve (AUC)inf 1.95-fold, which is equivalent to increasing the dose of capivasertib 2-fold. This demonstrated less potent CYP3A4 inhibition compared with itraconazole’s interaction with midazolam, in which the benzodiazepine’s AUCinf is increased 10-fold
• It is postulated that CYP3A4-mediated metabolism is not the predominant route of elimination of capivasertib, and the risk of CYP3A4-mediated drug interactions is “not very high,” although clinically relevant interactions cannot be ruled out
• It is important to keep in mind that this study used a one-time capivasertib dose of 80 mg orally. The recommended dosage is 400 mg orally twice daily, with or without food, for 4 days followed by 3 days off.

The prescribing information for capivasertib recommends avoiding concomitant use of strong CYP3A4-inhibitors and/or strong and moderate CYP3A-inducers and to reduce the dose of capivasertib in the presence of moderate CYP3A4 inhibitors.

As drug experts, pharmacists should be aware of the potential drug-drug interactions involved in the use of this first-in-class medication for BC.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.