pazopanib

Research Excerpts

Overview

Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC) It is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC)

Effects

Pazopanib has an increased propensity to cause hepatotoxicity, which may be fatal in rare cases. 600 mg was chosen for further development of pazopAnib in advanced HCCs.

Pazopanib has been approved for patients with metastatic soft tissue sarcoma, after failure of at least one line of chemotherapy. It has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients.

Actions

Pazopanib (PAZ) can inhibit tumor progression, but whether PAZ inhibits lymph node metastasis and lymphangiogenesis in colorectal cancer is still unknown. The drug did not cause significant severe toxicity aside from grade 3-4 transaminitis, hypertension, and neutropenia.

Treatment

Pazopanib is a standard treatment for metastatic renal cell carcinoma (mRCC), and 800 mg/daily is considered the optimal dose. The PALETTE study was a new treatment option for Japanese patients with metastatic non-adipocytic soft tissue sarcoma after chemotherapy.

Toxicity

There was no significant difference in the overall number of toxic events (grade 1-4) for sunitinib and pazopanib. A distinct pattern and severity of adverse events was observed in Asians when co-treated. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common.

Pharmacokinetics

The steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial. Although larger DCE-MRI parameter decreases were associated with larger C(24) and C(max) values, there was no constant relationship between tumor perfusion decreases measured by D CE-MRI and plasma pazipanib pharmacokinetic parameters.

Compound-Compound Interactions

Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosFamide turned out to be too toxic based on a variety of adverse events. TKIs such as pazop anib and cabozantinib can interact with other drugs concomitantly administered, particularly with proton-pump inhibitors (PPIs)

Bioavailability

Pazopanib (GW786034) is a novel orally bioavailable TKI that targets VEGFR1, VEG FR3, platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta and c-kit.

Dosage Studied

The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The study used a phase 1, modified 3 + 3, dose-escalation design.