Toward New Transmission-Blocking Combination Therapies: Pharmacokinetics of 10-Amino-Artemisinins and 11-Aza-Artemisinin and Comparison with Dihydroartemisinin and Artemether

Abstract

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.

Keywords: amino-artemisinins; antimalarial agents; combination therapies; pharmacokinetics; transmission-blocking.

FIG 1

Artemisinin 1 and clinical derivatives DHA 2, artemether 3, and artesunate 4. The latter two are rapidly converted into DHA in vivo via metabolism or facile hydrolysis, respectively. As a hemiacetal, DHA rearranges irreversibly under physiological conditions into an active peroxyhemiacetal that in turn rearranges to the inert deoxyartemisinin (see references 41–44).

FIG 2

The amino-artemisinins 5 to 10 in which the exocyclic oxygen atom at C-10 of the clinical artemisinins (Fig. 1) is replaced by a nitrogen atom and 11-aza-artemisinin 11 in which an –NH group replaces O-11. As discussed below, artemiside 5 is rapidly metabolized to artemisone 6, which must proceed via artemisox 13, and then to M1 12, the primary metabolite of artemisone. Calculated log P data are given, and efficacy data for 1 to 12 appear in references , , and and are summarized in Tables S1 to S7.

FIG 3

Plasma concentration-time curves for artemether 3 (solid line) and its metabolite DHA 2 formed following (a) intravenous dosing (i.v.) and (b) oral dosing (p.o.). All results are presented as the mean ± standard deviation.

FIG 4

Plasma concentration-time curves for artemiside 5 (solid line) and its metabolites artemisone 6 (dashed line) and M1 12 (solid gray line) formed following (a) intravenous dosing (i.v.) and (b) oral dosing (p.o.). All results are presented as the mean ± standard deviation.

FIG 5

Plasma concentration-time curves for artemisone 6 (solid line) and its metabolite M1 12 (dashed line) formed following (a) intravenous (i.v.) and (b) oral (p.o.) dosing. All results are presented as the mean ± standard deviation.

FIG 6

Plasma concentration-time curves for (a) sulfamide 7 and (b) 11-aza-artemisinin 11 following intravenous (i.v., blue line) and oral (p.o., red line) dosing. All results are presented as the mean ± standard deviation.

FIG 7

Plasma concentration-time curves for (a) the phenylurea 9 and (b) the arylurea 10 following intravenous (i.v., blue line) and oral (p.o., red line) dosing. All results are presented as the mean ± standard deviation.