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-artemisinin and conduct absorption, distribution, and metabolism and excretion (ADME) profiling and pharmacokinetic (PK) profiling via intravenous (i.v.) and oral (p.o.) administration to mice. The sulfamide derivative has a notably long murine microsomal half-life ( > 150 min), low intrinsic liver clearance and total plasma clearance rates (CL 189.4, CL 32.2 ml/min/kg), and high relative bioavailability ( = 59%). Kinetics are somewhat similar for 11-aza-artemisinin ( > 150 min, CL = 576.9, CL = 75.0 ml/min/kg), although bioavailability is lower ( = 14%). In contrast, artemether is rapidly metabolized to dihydroartemisinin (DHA) ( = 17.4 min) and eliminated (CL = 855.0, CL = 119.7 ml/min/kg) and has low oral bioavailability () of 2%. While artemisone displays low of <10 min and high CL of 302.1, it displays a low CL of 42.3 ml/min/kg and moderate bioavailability () of 32%. Its active metabolite M1 displays a much-improved of >150 min and a reduced CL of 37.4 ml/min/kg. Artemiside has of 12.4 min, CL of 673.9, and CL of 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.