Pazopanib for the Treatment of Metastatic Renal Cell Carcinoma - Corrected Proof

Amy M. Pick, Kelly K. Nystrom — 2012-02-20

Background: Renal cell carcinoma (RCC) is the most common cancer in the kidneys. Until 2005, treatment options were limited to immunotherapy. Since that time, there have been numerous targeted therapy agents approved with improved efficacy toward RCC. Pazopanib is a multi–tyrosine kinase inhibitor that was approved by the US Food and Drug Administration in October 2009 and by the European Medicines Agency in June 2010 for the treatment of metastatic RCC. Objective: The objective of this report was to review pazopanib's mechanism of action; pharmacologic, pharmacokinetic, and dynamic properties; potential drug interactions; and the results of clinical trials evaluating efficacy and tolerability associated with pazopanib for the treatment of RCC. Methods: MEDLINE, International Pharmaceutical Abstracts, and Web of Science were searched for English-only clinical trials and therapeutic reviews (publication dates: 2000–January 1, 2012). Abstracts from the 2000 to 2011 meetings of the American Society of Clinical Oncology were searched for an updated safety profile and tolerability data of pazopanib in RCC. References from relevant articles were reviewed. Key search terms included pazopanib, Votrient, GW786034, renal cell carcinoma, adverse events, pharmacology, pharmacokinetic, and clinical trial. Results: Two clinical trials met the inclusion criteria for the use of pazopanib in RCC (a Phase II and a Phase III trial). Pazopanib is an inhibitor of numerous tyrosine kinases, including vascular endothelial growth factor receptor and platelet-derived growth factor receptors. It is involved in inhibiting signaling pathways, angiogenesis, and cell proliferation. Pazopanib was approved by the US Food and Drug Administration and the European Medicines Agency at the dose of 800 mg daily. Peak concentrations are achieved within 2 to 4 hours of this dose with a mean t½ of 35 hours. The pharmacokinetic properties of pazopanib are affected by food as well as by crushing the tablet. A 2-fold increase in AUC was seen when pazopanib was administered with a high-fat meal as well as when crushing the tablet. Thus, pazopanib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Pazopanib is primarily metabolized by cytochrome P-450 3A4, and caution should be used with concomitant administration of cytochrome P-450 inducers and/or inhibitors. In a Phase III trial of pazopanib in metastatic RCC, pazopanib reportedly improved progression-free survival from a median of 4.2 to 9.2 months compared with placebo (P < 0.0001). The most common adverse effects of pazopanib were hypertension, hair depigmentation, diarrhea, nausea, anorexia, and vomiting. Many of the grade 3/4 toxicities were hepatic in nature, with elevations occurring in aspartate aminotransferase, alanine aminotransferase, and bilirubin. Conclusions: Pazopanib is reportedly effective in the treatment of metastatic RCC. Although there are currently no direct comparisons between pazopanib and other tyrosine kinase inhibitors, the data suggest that pazopanib may be a first-line option in the treatment of RCC. The only Phase III trial of pazopanib suggests improvement of progression-free survival in RCC as well as tolerability in the selected population.

A Randomized, Open-Label, 5-Period, Balanced Crossover Study to Evaluate the Relative Bioavailability of Eltrombopag Powder for Oral Suspension (PfOS) and Tablet Formulations and the Effect of a High-Calcium Meal on Eltrombopag Pharmacokinetics When Administered With or 2 Before or After PfOS - Corrected Proof

2012-02-16

Background: Bioavailability of the tablet formulation of eltrombopag, an oral thrombopoietin receptor agonist indicated for the treatment of chronic immune thrombocytopenia, is reduced by chelation of polyvalent cations (eg, calcium). A powder for oral suspension (PfOS) formulation has been developed for use in pediatrics. Objective: We aimed to assess the bioavailability of eltrombopag PfOS relative to the tablet formulation and the effect of a high-calcium meal on PfOS bioavailability. Methods: In this single-dose, open-label, randomized-sequence, crossover study, healthy subjects received 25 mg eltrombopag orally as a tablet fasted and as PfOS fasted or with, 2 hours before, or 2 hours after a high-calcium meal. Noncompartmental pharmacokinetic parameters were estimated from plasma concentration-time data collected over 72 hours post-dose. Tolerability was assessed by laboratory tests, physical examinations, and adverse events (AEs). Results: The 40 enrolled subjects included 22 males and 18 females of white/European (60%) or African-American/African (40%) heritage with mean (SD) (mininum, maximum) age of 34 (12) (19, 62) years, weight of 75 (12) (54, 101) kg, and body mass index of 25.8 (2.9) (19.7, 30) kg/m2. Plasma eltrombopag AUC0–∞ was higher for the PfOS than the tablet (geometric least-squares mean ratio [GMR]: 1.22; 90% CI: 1.08–1.38). Plasma eltrombopag AUC0-infinity was reduced when the PfOS was administered with a high-calcium meal (GMR: 0.25; 90% CI: 0.224–0.287) or 2 hours after a meal (GMR: 0.53; 90% CI: 0.470–0.601), and, to a lesser extent, when administered 2 hours before a meal (GMR: 0.80; 90% CI: 0.711–0.908). The absorption lag time and t½ did not differ between treatments; Tmax was delayed 1 hour when the PfOS was dosed with a high-calcium meal. AEs were not serious and mild or moderate in intensity. AEs reported in >1 subject included headache (11 subjects; 27.5%), presyncope (3 subjects, 7.5%), and vomiting (2 subjects, 5%). No clinically significant trends in laboratory tests or vital signs were observed. Conclusions: In a healthy adult volunteer population, bioavailability of eltrombopag PfOS was greater than the tablet and was reduced when administered with or 2 hours before or after a high-calcium meal; this effect was attenuated with PfOS dosing 2 hours before the meal. Eltrombopag was generally well tolerated. Clinicaltrials.gov Identifier: NCT01072162.

Clinical Therapeutics - Articles in Press

Pazopanib for the Treatment of Metastatic Renal Cell Carcinoma - Corrected Proof