133: Assessment of the Effect of P-gp Inhibition on Pharmacokinetics of the RET Inhibitor, Pralsetinib, in Healthy Subjects

Statement of Purpose: Pralsetinib (trade name GAVRETO) is a potent and selective inhibitor of rearranged during transfection (RET) kinase and oncogenic RET mutants. In the US in 2020, Pralsetinib received accelerated approval for the treatment of three indications: adult patients with RET fusion-positive, locally advanced or metastatic NSCLC, adult and pediatric patients 12 years of age and older with locally advanced or metastatic RET-mutant MTC who require systemic therapy and adult and pediatric patients 12 years of age and older with locally advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory. In vitro transporter studies suggest that pralsetinib is a P-gp substrate and therefore, co-administration of a P-gp inhibitor could increase pralsetinib exposure. A previously conducted DDI study assessed the impact of a strong CYP3A and P-gp inhibitor, itraconazole, on the PK of pralsetinib and indicated a 250% and 84% increase in pralsetinib AUC_0-inf and C_max, respectively, when co-administered with itraconazole. Based on the available information, the individual contributions of P-gp or CYP3A inhibition to the increased exposure observed when pralsetinib was co-administered with itraconazole had not been assessed. This study evaluated the effect of cyclosporine, a P-gp inhibitor, on the pharmacokinetics (PK) of pralsetinib.

Description of Methods & Materials: A Phase I, single-center, open-label, fixed-sequence study was conducted to investigate the effect of co-administration of cyclosporine, a P-gp inhibitor, on the PK of pralsetinib in 15 healthy males and females of non-childbearing potential. Subjects were administered a single 200 mg dose of pralsetinib, fasted, alone on Day 1 and in combination with a single 600 mg dose of cyclosporine, fasted, on Day 10 with a nine day washout between doses. A statistical analysis was conducted to investigate the DDI on the PK of pralsetinib by comparing pralsetinib co-administered with cyclosporine to pralsetinib alone for AUC_0-t, AUC_0-192, AUC_0-inf, and C_max. The natural log (ln)-transformed PK parameters were analyzed using a mixed model. Safety/tolerability were monitored throughout the study.

Data & Results: Of the 15 subjects enrolled in the study, 13 completed both periods. Statistical analysis of pralsetinib PK parameters AUC0-t, AUC_0-192, AUC_0-inf and C_max showed that systemic exposure to pralsetinib increased by 79%, 81%, 81% and 48%, respectively, when pralsetinib was co-administered with cyclosporine compared to pralsetinib administered alone. The half-life was similar regardless of cyclosporine administration.

Interpretation, Conclusion or Significance: Cyclosporine, an inhibitor of P-gp and a weak to moderate inhibitor of CYP3A4, was used to determine the individual contribution of P-gp inhibition on pralsetinib PK. Systemic exposure of pralsetinib increased approximately 48% to 81% when administered in combination with cyclosporine. Based on the observed changes in pralsetinib exposure when administered with cyclosporine, and the exposure-response relationships for pralsetinib, prescribing information updates were proposed to adjust the dose of pralsetinib when co-administered with a P-gp inhibitor.

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