Abstract A134: Pharmacokinetics and metabolism of iniparib for the treatment of metastatic triple-negative breast cancer (TNBC).
Authors: Verweij Jaap , Dieras Veronique , Rockich Kevin , Su Yaming , Mery-Mignard Dominique , Pham Nga , Emmons Gary 
Published: June 2012

Abstract
Background: Iniparib (BSI-201) is an investigational anticancer agent whose mechanism of action is under study. In breast cancer cell lines and xenograft models of TNBC, iniparib has anti-proliferative activity and potentiates the cell cycle effects of some DNA damaging agents. In a randomized, open-label phase 2 study in patients with metastatic TNBC (mTNBC), iniparib combined with gemcitabine (G) and carboplatin (C) improved efficacy outcomes compared with GC alone. In a confirmatory phase 3 study, GCI failed to meet pre-specified criteria for PFS and OS; however, an exploratory subset analysis suggested a potential benefit among 2nd/3rd line patients (O'Shaughnessy et al. ASCO 2011). Here we report the pharmacokinetic and metabolism results of two clinical studies.
Methods and Results: In a Phase 1, open-label study (BEX11505; NCT01161836) following the administration of 400 mg [14C]-iniparib to 2 male and 5 female patients with solid tumors, approximately 73% of the radioactivity was excreted in urine and 16% in feces. Less than 0.5% of the dose in excreta was unchanged drug. Iniparib accounted for approximately 11% of the total radioactivity in plasma. Two metabolites, 4-iodo-3-amino-benzamide (IABM) and 4-iodo-3-amino-benzoic acid (IABA), which represent biotransformation through the nitro-reduction pathway, were only 0.4% and 1.9% of unchanged drug, respectively. The plasma t1/2 of iniparib averaged 11 minutes, while that of IABM and IABA was 0.8 h and 2.1 h, respectively. The major circulating metabolites of iniparib were products of iodine substitution with glutathione, followed by further metabolism mainly to the cysteine derivative (SAR291066) and the N-acetylated cysteine derivative (SAR289336). The sum of these three metabolites in plasma accounted for approximately 66% of the measured radioactivity. Other routes of metabolism included hydrolysis to form benzoic acid derivatives and further metabolism by glycine conjugation and nitro-reduction to IABM and IABA. The majority of the dose excreted via urine was as SAR291066 (31%) and SAR289336 (16%).
In the phase 2 randomized trial (TCD11418; NCT01045304), iniparib was administered as a 60-min IV infusion either twice weekly on days 1, 4, 8, and 11 at 5.6 mg/kg (arm A) or weekly on days 1, and 8 at 11.2 mg/kg (arm B), in combination with gemcitabine/carboplatin every 3 weeks in women with mTNBC. Pharmacokinetic parameters of iniparib and its two metabolites (IABA and IABM) were calculated based on their plasma concentrations in 69 patients (n=34 in arm A; n=35 in arm B). Iniparib, IABA, and IABM levels following a single 11.2 mg/kg dose were higher than after a 5.6 mg/kg dose, with a 2-fold increase in dose resulting in a 1.57, 2.35, and 2.04-fold increase of AUC on Day 1 in Cycle 1. The t1/2 of iniparib was short, with geometric mean values of 19 min and 25.7 min for arms A and B, respectively. The t1/2 of IABA and IABM for arms A and B were; 1.75 h and 1.78 h, and 0.793 h and 0.814 h, respectively. There was no apparent accumulation of iniparib, IABA, and IABM after repeated iniparib dosing with the present dosing regimen.
Conclusion: Iniparib is rapidly metabolized and cleared from plasma with a short t1/2 of 10–20 min and much of the drug being converted to inactive glutathione adducts. Evidence for biotransformation via nitro-reduction was seen by detection of IABM and IABA in plasma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A134.