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 (t1/2 150min), low intrinsic liver clearance and total plasma clearance rates

(CLint 189.4, CLtot 32.2 ml/min/kg), and high relative bioavailability (F = 59%). Kinetics are

somewhat similar for 11-aza-artemisinin (t1/2 . 150 min, CLint = 576.9, CLtot = 75.0ml/min/

kg), although bioavailability is lower (F = 14%). In contrast, artemether is rapidly 

metabolized to dihydroartemisinin (DHA) (t1/2 = 17.4min) and eliminated (CLint = 855.0, CLtot =

119.7ml/min/kg) and has low oral bioavailability (F) of 2%. While artemisone displays low

t1/2 of ,10min and high CLint of 302.1, it displays a low CLtot of 42.3 ml/min/kg and moderate

bioavailability (F) of 32%. Its active metabolite M1 displays a much-improved t1/2 of

.150 min and a reduced CLint of 37.4ml/min/kg. Artemiside has t1/2 of 12.4min, CLint of

673.9, and CLtot 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.