# 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

## TL;DR

A patient taking apalutamide for prostate cancer experienced a drug interaction with cyclosporine due to CYP3A4 enzyme induction.

## Contribution

This case report provides evidence that apalutamide activates PXR and induces CYP3A4, causing sustained drug interactions.

## Key findings

- Apa caused subtherapeutic cyclosporine levels until Apa was discontinued.
- In vitro tests confirmed Apa strongly activates PXR and induces CYP3A4.
- Cyclosporine levels normalized after stopping apalutamide.

## Abstract

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.

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.

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.

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.