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 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) > 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 dihydroartemisinin (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%. While 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) of 12.4 min, CL(int) of 673.9, and CL(tot) 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.