Towards new transmission-blocking combination therapies - pharmacokinetics of 10-amino-artemisinins and 11-aza-artemisinin, and comparison with DHA and artemether
As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug and third drug with different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins and 11-aza-artemisinin, and conduct ADME profiling in vitro and PK profiling in vivo via iv and po administration to mice. The sulfamide derivative has a notably long murine microsomal half-life ( t 1/2 >150 min), low intrinsic liver clearance and total plasma clearance rates ( CL int 189.4, CL tot 32.2 mL/min/kg), and high relative bioavailability (F 59%). Kinetics are somewhat similar for 11-aza-artemisinin ( t 1/2 >150 min, CL int 576.9, CL tot 75.0 mL/min/kg), although bioavailability is lower (F 14%). In contrast, artemether is rapidly metabolized to DHA ( t 1/2 17.4 min) and eliminated ( CL int 855.0, CL tot 119.7 mL/min/kg), and has low oral bioavailability F of 2%. Whilst artemisone displays low t 1/2 of <10 min and high CL int of 302.1, it displays a low CL tot of 42.3 mL/min/kg, and moderate bioavailability F of 32%. Its active metabolite M1 displays a much improved t 1/2 of >150 min and a reduced CL int of 37.4 mL/min/kg. Artemiside has t 1/2 12.4 min and CL int 673.9 and CL tot 129.7 mL/kg/min, likely a reflection of its surprisingly rapid metabolism to artemisone, reported here for the first time. DHA is not formed from any amino-artemisinin. Overall, the efficacy and PK data strongly support the development of selected amino-artemisinins as components of new TACTs.