Toward new transmission-blocking combination therapies: Pharmacokinetics of 10-amino-artemisinins and 11-aza-artemisinin and comparison with dihydroartemisinin 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 a third drug with a different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins, and 11-aza-arte-misinin and conduct absorption, distribution, and metabolism and excretion (ADME) profiling in vitro and pharmacokinetic (PK) profiling in vivo via intravenous (i.v.) and oral (p.o.) administration to mice. The sulfamide derivative has a notably long murine microsomal half-life (t_1/2 . 150min), low intrinsic liver clearance and total plasma clearance rates (CL_int 189.4, CL_tot 32.2ml/min/kg), and high relative bioavailability (F = 59%). Kinetics are somewhat similar for 11-aza-artemisinin (t_1/2 . 150min, CL_int = 576.9, CL_tot = 75.0ml/min/ kg), although bioavailability is lower (F = 14%). In contrast, artemether is rapidly metabolized to dihydroartemisinin (DHA) (t_1/2 = 17.4min) and eliminated (CL_int = 855.0, CL_tot = 119.7ml/min/kg) and has low oral bioavailability (F) of 2%. While artemisone displays low t_1/2 of,10min and high CL_int of 302.1, it displays a low CL_tot of 42.3ml/min/kg and moderate bioavailability (F) of 32%. Its active metabolite M1 displays a much-improved t_1/2 of .150min and a reduced CL_int of 37.4ml/min/kg. Artemiside has t_1/2 of 12.4min, CL_int of 673.9, and CL_tot of 129.7ml/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.