Sustained Drug-Drug Interaction Between Cyclosporine and Apalutamide in a Patient With Metastatic Hormone-Sensitive Prostate Cancer: A Case Report and Evaluation of CYP3A4 Induction via Pregnane X Receptor Activation by Apalutamide.

Abstract

Background: Apalutamide (Apa) is a key therapeutic agent for prostate cancer. Despite its efficacy, Apa is known to induce several drug-metabolizing enzymes including cytochrome P450 3A4 (CYP3A4), raising concerns about drug-drug interactions (DDIs). This study reports a rare case of a sustained DDI between Apa and cyclosporine (CsA)-a CYP3A4 substrate-in a patient with metastatic hormone-sensitive prostate cancer (mHSPC) and primary pure red cell aplasia (PRCA). We further investigated whether Apa could activate pregnane X receptor (PXR), a key nuclear receptor that regulates CYP3A4 expression.

Methods: With informed consent, residual blood samples were used to measure serum Apa concentration. To assess the potential of Apa in activating PXR, a reporter gene assay and a CYP3A4 mRNA induction test were performed.

Case presentation: A 75-year-old man with mHSPC was treated with Apa and leuprorelin. He developed PRCA and was administered CsA (5 mg/kg/day) on Day 1. Despite a target trough concentration (C _trough) of 150-200 ng/mL, the C _trough of CsA remained subtherapeutic (34 ng/mL on Day 5), even after dose escalation to 10 mg/kg/day (C _trough: 66 ng/mL on Day 7), suspecting a DDI with Apa. On Day 8, Apa was discontinued and the CsA dosage was reduced to 5 mg/kg/day. The Apa concentrations measured on Days 13, 26, and 34 were 1.1, 0.15, and 0.07 μg/mL, respectively, and the C _trough of CsA increased to 45, 82, and 134 ng/mL, respectively. In vitro experiments demonstrated that Apa was a strong activator of PXR and capable of inducing CYP3A4.

Conclusion: Apa induced CYP3A4 via the PXR pathway, leading to a sustained DDI with CsA. Careful monitoring is necessary when Apa is coadministered with CYP3A4 substrates.