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

• Published in: Clinical therapeutics Vol. 46; no. 8; pp. 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: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2024; Elsevier Limited
• 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; Internal Medicine; 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; United States > US; Europe; Q1; Population pharmacokinetics; Q2; PR; PS; PRED; ALP; ALT; Ovarian cancer; BSA; QD; AUCss; FSD; Vp1; Tlag; Vp2; PFS; Q2/F; Vp1/F; BSV; RSE; PARP inhibitor; HRp; Vc/F; pcVPC; Cave; Frel; IIV; CL/F; IPRED; BLQ; VPC; prand; Vc; LOESS; Q1/F; CWRES; OC; BW; ECOG; PLT; ISD; Vp2/F; HRnd; OBS; AST; GI; nCrCl; Niraparib; CL; D1; CR; CV; Ka; CrCl; HRD; Eastern Cooperative Oncology Group; alanine aminotransferase; homologous recombination–proficient; homologous recombinant deficiency; conditional weighted residual; alkaline phosphatase; apparent central volume of distribution; relative bioavailability; AUC ss; second intercompartmental clearance; apparent clearance; prandial; F rel; clearance; fixed starting dose; individual predicted concentration; T lag; lag time; relative standard error; apparent first intercompartmental clearance; between-subject variability; coefficient of variation; apparent second intercompartmental clearance; interindividual variability; body weight; visual predictive check; apparent first peripheral volume of distribution; locally weighted scatterplot smoothing; performance status; homologous recombination not determined; first intercompartmental clearance; creatinine clearance; gastrointestinal; first peripheral volume of distribution; second peripheral volume of distribution; C ave; body surface area normalized creatinine clearance; steady-state area under the concentration-time curve based on starting dose; baseline platelet count; once daily; first-order absorption rate constant; K a; prediction-corrected visual predictive check; observations; apparent second peripheral volume of distribution; central volume of distribution; population-predicted concentration; partial response; below the limit of quantification; progression-free survival; complete response; aspartate aminotransferase; duration of zero-order drug release; individualized starting dose; model-predicted average concentration up to the time of disease progression/death or censoring; homologous recombination–deficient; body surface area
• 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] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www.clinicaltrials.gov.