Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study

Mar Drugs. 2024 Apr 16;22(4):178. doi: 10.3390/md22040178.

Abstract

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Keywords: cancer; cytochrome P450; drug interactions; pharmacokinetics.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Area Under Curve
  • Carbolines* / administration & dosage
  • Carbolines* / adverse effects
  • Carbolines* / pharmacokinetics
  • Cytochrome P-450 CYP3A Inhibitors* / administration & dosage
  • Cytochrome P-450 CYP3A Inhibitors* / pharmacokinetics
  • Cytochrome P-450 CYP3A Inhibitors* / pharmacology
  • Drug Interactions*
  • Female
  • Heterocyclic Compounds, 3-Ring / administration & dosage
  • Heterocyclic Compounds, 3-Ring / adverse effects
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics
  • Heterocyclic Compounds, 4 or More Rings* / administration & dosage
  • Heterocyclic Compounds, 4 or More Rings* / adverse effects
  • Heterocyclic Compounds, 4 or More Rings* / pharmacokinetics
  • Humans
  • Itraconazole* / administration & dosage
  • Itraconazole* / adverse effects
  • Itraconazole* / pharmacokinetics
  • Male
  • Middle Aged
  • Neoplasms* / drug therapy

Substances

  • Itraconazole
  • Heterocyclic Compounds, 4 or More Rings
  • Cytochrome P-450 CYP3A Inhibitors
  • Carbolines
  • PM 01183
  • Heterocyclic Compounds, 3-Ring
  • Antineoplastic Agents