Optimization of irinotecan chronotherapy with P-glycoprotein inhibition

The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F(1) mice. A three-fold 24 h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p < 0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GOS), a mouse tumor cell line moderately sensitive to irinotecan. Non-tumor-bearing mice received irinotecan (50 mg/kg/day i.v. x 4 days) as a single agent or combined with P-gp inhibitor PSC833 (6.25 mg/kg/day i.p. x 4 days) at ZT3 or ZT15, respectively corresponding to the worst or the best irinotecan tolerability. Endpoints involved survival, body weight change and hematologic toxicity. Antitumor efficacy was studied in GOS-bearing mice receiving irinotecan (25, 30 or 40 mg/kg/day x 4 days) and +/- PSC833 at ZT3 or ZT15, with survival, body weight change, and tumor growth inhibition as endpoints. Non-tumor bearing mice lost an average of 17% or 9% of their body weight according to irinotecan administration at ZT3 or ZT15 respectively (p < 0.001). Dosing at ZT15 rather than ZT3 reduced mean leucopenia (9% vs 53%; p < 0.001). PSC833 aggravated irinotecan lethal toxicity from 4 to similar to 60%. In tumor-bearing mice, body weight loss was similar to halved in the mice on irinotecan or irinotecan-PSC833 combination at ZT15 as compared to ZT3 (p < 0.001). PSC833-irinotecan at ZT15 increased tumor inhibition by similar to 40% as compared to irinotecan only at ZT15. In conclusion, P-gp was an important determinant of the circadian balance between toxicity and efficacy of irinotecan. (C) 2013 Elsevier Inc. All rights reserved.