Plasma levels of SN-38 after co-administration of gefitinib and oral irinotecan in young and old mice

Abstract

2062 Background: Preclinical studies demonstrate that irinotecan, approved for I.V. administration, is most effective when administered at frequent, low doses. This administration schedule would be most practical if irinotecan were administered orally. However, the oral availability of irinotecan is limited. Gefitinib can alter the oral bioavailability of irinotecan through inhibition of gut transporters (ABCG2) that prevent intestinal absorption. Thus, we evaluated a potential method for giving irinotecan at low doses on a protracted schedule by administering orally with gefitinib. Additionally, we hypothesized that the pharmacokinetics of irinotecan may differ in older versus younger adult mice. Plasma levels of SN-38 were measured and compared in old and young Balb/c mice given oral irinotecan alone or with gefitinib. Methods: Adult (2 months old) and older, retired breeder (10 months old) Balb/c mice were orally administered irinotecan at 10 mg/kg, 20 mg/kg or 40 mg/kg either alone (control) or with 30 mg/kg PO gefitinib daily for 5 days. On the fifth day, the mice were sacrificed approximately 4–6 hours after administering drugs. Plasma was collected and SN-38 levels determined by HPLC. Results: Nearly all mice receiving irinotecan with gefitinib had a 3 fold or more increase in the level of SN-38 in the plasma as compared to the mice receiving irinotecan alone. The older mice had a more dramatic increase. Conclusions: The plasma levels of SN-38 were consistently elevated in mice treated with oral gefitinib and irinotecan when compared to mice treated with irinotecan only. The more pronounced increase in SN-38 levels seen in the older mice may be due to changes in drug elimination with aging. The results indicate that oral irinotecan can be given in the presence of gefitinib resulting in higher levels of SN-38 in the plasma of young and older mice. Combination treatment allows easier titration of irinotecan in protracted dosing protocols evaluating efficacy and toxicity in older mice, and ultimately, humans. [Table: see text] No significant financial relationships to disclose.