Background And Objectives: Veliparib is an orally active potent poly(ADP-ribose) polymerase (PARP) inhibitor currently in phase III clinical trials in solid tumors. This phase I study evaluated the pharmacokinetics and mass balance of veliparib administered alone and in combination with temozolomide, and assessed any potential pharmacokinetic drug-drug interaction between veliparib and temozolomide.
Methods: This was an open-label, dose-escalation study of veliparib in combination with temozolomide in 42 subjects with nonhematologic malignancies. Veliparib was administered orally at doses ranging from 10 to 80 mg twice daily on days 1-7, and temozolomide was administered orally at 150-200 mg/m once daily on days 1-5 of each 28-day cycle. The pharmacokinetics of veliparib, its M8 metabolite, and temozolomide, as well as urinary excretion of unchanged veliparib and its M8 metabolite, were determined.
Results: Mean veliparib maximum observed plasma concentration (C ) and area under the plasma concentration-time curve for the first 6 h postdose (AUC) values increased dose proportionally in the veliparib 10-80 mg twice-daily dose range. The urinary recovery of veliparib dose as the unchanged parent compound alone and together with the M8 metabolite was 73 ± 18 and 90 ± 22%, respectively, over a 12-h dosing interval on day 6 of Cycle 1. Veliparib and temozolomide pharmacokinetic exposures were not affected when administered together.
Conclusions: Veliparib is a Biopharmaceutical Classification System (BCS) Class 1 compound, with no less than 90% of the dose absorbed and an oral bioavailability of at least 73%. Veliparib is primarily eliminated by renal excretion. Veliparib exhibited linear pharmacokinetics in the 10-80 mg twice-daily dose range. No pharmacokinetic interaction was observed when veliparib and temozolomide were administered together.
Clinical Trial Registration Number: NCT00526617.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s40262-017-0547-z | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Responsive boronate ester lipid nanoparticles for enhanced delivery of veliparib and platinum (IV) prodrug in chemotherapy.
J Colloid Interface Sci
December 2024
Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), Wuhan 430074, China.
The chemotherapeutic effectiveness of breast cancer treatment is currently unsatisfactory due to inadequate drug delivery, suboptimal drug release, and drug inactivation. Herein, we present an innovative boronate ester lipid nanoformulation to improve the delivery of a platinum (IV) prodrug (Pt-C12) and veliparib (Veli), aiming to increase their therapeutic efficacy through a synergistic effect. We identify the optimal ratio of Pt-C12 to Veli for achieving synergy in vitro, followed by the encapsulation of Pt-C12 and Veli in lipid nanoparticles (NPs) incorporating responsive boronate ester lipids (LPC-PPE) to produce responsive lipid NPs (LPV NPs).
View Article and Find Full Text PDFprotein kinase inhibitors as Targeted therapy for glioblastoma: A meta-analysis of randomized controlled clinical trials.
Pharmacol Res
December 2024
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Glioblastoma (GBM) is the most common and lethal primary brain tumor. The standard treatment for newly diagnosed GBM includes surgical resection, when feasible, followed by radiotherapy and temozolomide-based chemotherapy. Upon disease progression, the anti-vascular endothelial growth factor-A (VEGF-A) monoclonal antibody bevacizumab, can be considered.
View Article and Find Full Text PDFDual Targeting of CXCR1 and PARP in Models of High-Grade Serous Ovarian Carcinoma.
Cancers (Basel)
November 2024
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Illinois at Chicago, 833 S Wood Str., Chicago, IL 60612, USA.
Background/objectives: Clinical use of poly(ADP-ribose) polymerase inhibitors (PARPis) against metastatic high-grade serous ovarian carcinoma (HGSOC) is limited to cases with deficient a homologous recombination (HR). Our objective was to determine whether the impairment of the fractalkine receptor (CXCR1) could sensitize HR-proficient cases to PARPis.
Methods: The efficacy of a dual drug combination, including AZD8797, an inhibitor of CXCR1, and several PARPis was examined using cell lines and xenograft models.
Poly (ADP-Ribose) Polymerase Inhibitor Olaparib-Resistant -Mutant Ovarian Cancer Cells Demonstrate Differential Sensitivity to PARP Inhibitor Rechallenge.
Cells
November 2024
Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Poly (ADP-ribose) polymerase inhibitors (PARPis) show cytotoxicity in homologous recombination deficiency (HRD) seen in -mutant ovarian cancer (OvCa). Despite initial responses, resistance often develops. The reintroduction of different PARPis, such as niraparib or rucaparib, has shown some clinical activity in mutation-associated OvCa patients with prior olaparib treatment, yet the underlying mechanisms remain unclear.
View Article and Find Full Text PDFBackground: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.
Methods: We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!