A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors

Abstract

Because cancer patients may have difficulty swallowing whole tablets, crushing tablets or ingesting an oral suspension is a practical alternative. This open-label, 2-part, randomized crossover, phase I study evaluated the pharmacokinetics and tolerability of pazopanib administered as a crushed tablet or an oral suspension relative to whole tablet in patients with advanced cancer (Part 1). Patients completing Part 1 were eligible for continuous daily pazopanib 800 mg (Part 2). Administration of a single pazopanib 400 mg crushed tablet increased the area under the curve from 0 to 72 h (AUC((0-72)); 46%) and maximum observed plasma concentration (C(max); ~2-fold), and decreased time to achieve maximum plasma concentration (T(max); ~2 h), indicating increased rate and extent of oral absorption relative to whole-tablet administration. Similarly, a single dose of pazopanib 400 mg suspension increased AUC((0-72)) (33%) and C(max) (29%), and decreased T(max) (1 h). These changes in pharmacokinetic parameters were not associated with increases in the magnitude or duration of short-term (ie, up to 72 h) blood pressure elevation compared with whole-tablet administration.

Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

“…The most likely explanation for pazopanib’s non-linear PK behaviour is saturable oral absorption. Interestingly, recent studies have shown that by either taking pazopanib with food(9) or crushing the tablet(10), one can increase the oral bioavailability by as much as 2-fold. On the current trial, patients were instructed to take pazopanib on an empty stomach in accordance with the current FDA recommendations and to minimize the variable effect of food.…”

Tyrosine Kinase Inhibitors in the Treatment of Advanced Renal Cell Carcinoma: Focus on Pazopanib

“…Crushing tablets or taking oral suspension increases plasma concentration approximately 100% and 29% respectively, and decreased time to achieve maximum plasma concentration (by approximately 2 h and 1 h respectively), indicating increased rate and extent of oral absorption relative to whole-tablet administration 22. A similar effect is observed following administration of pazopanib with low- and high-fat meals, such that the drug should ideally be taken at least one before or two hours after a meal 21,23…”

Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors

“…208 A higher C min (comparing the lowest quartile with the remainder) has been found to be important in maximizing the efficacy of nilotinib in imatinib-resistant or -intolerant CML. 107,237 The presence of hypertension has also been linked to improved recovery, 238 hence it has been suggested that this may act as a surrogate marker for pazopanib exposure. 236 Pazopanib Clinical trials have shown improvement in PFS when plasma pazopanib concentrations were maintained above 20 mg/L.…”

“…208 However, a separate paper concluded that "blood level testing" was unlikely to play a major role in patient management because they found no significant difference in response at 12 months between the lowest quartile C min and the remaining patients. 238 107,237 The presence of hypertension has also been linked to improved recovery, 238 hence it has been suggested that this may act as a surrogate marker for pazopanib exposure.…”