Table 4:

Four in vivo drug interaction studies discussing the involvement of BCRP (ABCG2) with the victim drug (BCRP substrate) administered intravenously.

Overall Effect	Object	Object dosing route	Precipitant	Precipitant dosing route	Percent Change AUC	Percent Change Plasma Concentration	Concentration Type	Comments	Reference
In Vivo Inhibition > 20% Effect	Copanlisiba	IV	itraconazole	Oral	57.7	3.9	Cmax	In vitro studies suggest that copanlisib is a substrate of P-gp and BCRP. According to the sponsor, the contribution of P-gp and BCRP inhibition to the increase of copanlisib exposure observed when co-administered with itraconazole is likely to be small as copanlisib was administered by IV infusion.	40
In Vivo Inhibition > 20% Effect	irinotecan	IV	regorafenib	Oral	28	22	Cmax	BCRP likely contributes to the transport of irinotecan. Regorafenib inhibits BCRP in vitro.	41
In Vivo Inhibition > 20% Effect	methotrexate	IV	proton pump inhibitors	Oral	--	103.2	Cavg	The proposed mechanisms for the interaction may involve inhibition of breast cancer resistance protein, which is also involved in mediating MTX transport.	125
In Vivo Inhibition > 20% Effect	methotrexate	IV	vindesine	IV	--	133.3	--	Membrane transport of methotrexate involves multiple transporters including the renal uptake transporters OAT1 and OAT3 in tubular cells, and a series of efflux transporters including MRP2 and BCRP. Vindesine is an inhibitor of BCRP, MRP2, OAT1, and OAT3.	42

IV – Intravenous

^a.Copanlisib is metabolized by CYP3A and transported by P-gp. Itraconazole inhibits CYP3A and P-gp.