Publications by authors named "Y Pithavala"
Landscape analysis of adverse events and dose intensity for FDA approved oncology small molecules.
Cancer Chemother Pharmacol
January 2025
As development of new oncology small molecule therapies is focused mainly on molecularly targeted agents, the dose selection paradigm has shifted from the maximum tolerated dose (MTD)-based approach traditionally utilized with cytotoxic drugs towards determining an optimal dose with long-term tolerability while maintaining efficacy. To assess overall tolerability in recently approved oncology small molecules, we surveyed 54 compounds approved by the FDA since March 2017 with respect to dose intensity, dose modifications, and treatment emergent adverse events (TEAEs). Of the 54 new molecular entities surveyed, only 15 were approved at a label dose equal to the MTD (Label Dose = MTD).
View Article and Find Full Text PDFArticle Synopsis
- The landscape of oncology drug development has improved significantly, leading to better patient outcomes and quality of life, particularly through initiatives like Project Optimus by the FDA.
- Project Optimus aims to reform how drug doses are selected in oncology, shifting the focus from maximum tolerated doses to more personalized strategies that consider disease and patient specifics.
- The Oncology Dose Optimization IQ Working Group emphasizes the need for a tailored, evidence-based approach to dose optimization, acknowledging industry's challenges and advocating for strategies that adapt to various factors in cancer treatment.
Article Synopsis
- - The study investigated how lorlatinib, a drug for lung cancer, affects certain metabolic enzymes and transporters in the body, specifically CYP2B6, CYP2C9, UGT, and P-glycoprotein (P-gp).
- - In a clinical trial with 32 patients, lorlatinib reduced the effectiveness of several probe drugs, with the most significant impact on the P-gp substrate fexofenadine, showing decreases of 67% in overall exposure and 63% in peak concentration.
- - The results indicate that lorlatinib moderately induces P-gp and slightly affects CYP2B6, CYP2C9, and UGT, suggesting that patients on lorlatinib should
Although rifampin drug-drug interaction (DDI) studies are routinely conducted, there have been instances of liver function test (LFT) elevations, warranting further evaluation. A literature review was conducted to identify studies in which combination with rifampin resulted in hepatic events and evaluate any similarities. Over 600 abstracts and manuscripts describing rifampin DDI studies were first evaluated, of which 30 clinical studies reported LFT elevations.
View Article and Find Full Text PDFLorlatinib is a third-generation, brain-penetrant anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with robust intracranial activity in patients with ALK- or ROS1-positive non-small cell lung cancer (NSCLC). Data from the ongoing open-label, single-arm, multicenter, phase-1/2 study of lorlatinib in patients with metastatic ALK- or ROS1-positive NSCLC were used to further investigate the potential brain penetration of lorlatinib. Patients received escalating lorlatinib doses (10-200 mg once daily or 35-100 mg twice daily) or the approved dosing (100 mg daily).
View Article and Find Full Text PDF