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Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer
Stephen I Shibata1, Vincent Chung, Timothy W Synold
1City of Hope, Duarte, CA 91010, USA.
Purpose:
Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction.
Experimental Design:
Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used.
Results:
Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites.
Conclusions:
In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.
Insights
Pazopanib is well tolerated at 800 mg daily for mild liver dysfunction. Patients with moderate to severe hepatic impairment tolerated a reduced dose of 200 mg daily, with less than dose-proportional exposure.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Pazopanib is a multitargeted receptor tyrosine kinase inhibitor.
- Limited data exist on how liver function affects pazopanib metabolism and pharmacokinetics.
Purpose of the Study:
- To determine the maximum-tolerated dose (MTD) of pazopanib in patients with varying hepatic dysfunction.
- To characterize the pharmacokinetic profile of pazopanib in these patient groups.
Main Methods:
- Patients with solid tumors or lymphoma were stratified into four groups based on hepatic dysfunction severity (NCI-ODWG criteria).
- Pazopanib was administered orally once daily in a 21-day cycle using a modified 3+3 dose-escalation design.
Main Results:
- Ninety-eight patients were enrolled. Mild hepatic dysfunction group tolerated 800 mg/day; moderate and severe groups tolerated 200 mg/day.
- Pharmacokinetics in the mild group were similar to normal controls. Moderate/severe groups showed less than dose-proportional exposure at 200 mg compared to 800 mg in mild/normal groups.
- Reduced MTD in moderate/severe groups is not attributed to decreased drug clearance or altered metabolite proportions.
Conclusions:
- Pazopanib is well tolerated at the FDA-approved 800 mg dose in patients with mild liver dysfunction.
- Patients with moderate to severe hepatic impairment tolerated a reduced dose of 200 mg daily.
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