Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer

• Published in: Clinical therapeutics 2024-08, Vol.46 (8), p.612-621
• Main Authors: Monk, Bradley J., Romero, Ignacio, Graybill, Whitney, Churruca, Cristina, O'Malley, David M., Knudsen, Anja Ør, Yap, Oi Wah Stephanie, Baurain, Jean-François, Rose, Peter G., Denys, Hannelore, Ghamande, Sharad, Pisano, Carmela, Fabbro, Michel, Braicu, Elena Ioana, Calvert, Paula M., Amit, Amnon, Prendergast, Emily, Taylor, Adekemi, Kheibarshekan, Leila, Zhang, Zhi-Yi, Zajic, Stefan, Jewell, Roxanne C., Gupta, Divya, González-Martín, Antonio
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anemia; Body weight; Cancer therapies; Chemotherapy; Clinical trials; Creatinine; Dosage; Dose-response effects; Dose-Response Relationship, Drug; Female; Humans; Indazoles - administration & dosage; Indazoles - adverse effects; Indazoles - pharmacokinetics; Middle Aged; Neutropenia; Niraparib; Oral administration; Ovarian cancer; Ovarian Neoplasms - drug therapy; PARP inhibitor; Patients; Pharmacokinetics; Piperidines - administration & dosage; Piperidines - adverse effects; Piperidines - pharmacokinetics; Piperidines - therapeutic use; Plasma; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects; Poly(ADP-ribose) Polymerase Inhibitors - pharmacokinetics; Population pharmacokinetics; Progression-Free Survival; Solid tumors; Statistical analysis; Thrombocytopenia; Thrombocytopenia - chemically induced; Tumors
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2024.06.001

•A niraparib population PK model was developed using pooled data from clinical trials.•PopPK/exposure-response analyses support niraparib individualized starting dose (ISD).•Use of a niraparib ISD improved the safety profile without compromising efficacy. Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW]