Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R.

PRX-105 is a plant-derived recombinant version of the human 'read-through' acetylcholinesterase splice variant (AChE-R). Its active site structure is similar to that of the synaptic variant, and it displays the same affinity towards organophosphorus (OP) compounds. As such, PRX-105 may serve as a bio-scavenger for OP pesticides and chemical warfare agents. To assess its potential use in prophylaxis and treatment of OP poisoning we conducted several preliminary tests, reported in this paper. Intravenous (IV) PRX-105 was administered to mice either before or after exposure to an OP toxin. All mice who received an IV dose of 50nmol/kg PRX-105, 2min before being exposed to 1.33×LD50 and 1.5×LD50 of toxin and 10min after exposure to 1.5×LD50 survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t½) in mice was 994 (±173) min. Additionally, a first-in-human study, to assess the safety, tolerability and pharmacokinetics of the compound, was conducted in healthy volunteers. The t½ in humans was substantially longer than in mice (average 26.7h). Despite the small number of animals and human subjects who were assessed, the fact that PRX-105 exerts a protective and therapeutic effect following exposure to lethal doses of OP, its favorable safety profile and its relatively long half-life, renders it a promising candidate for treatment and prophylaxis against OP poisoning and warrants further investigation.

Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects.

BACKGROUND AND OBJECTIVES: Macitentan is a potent, orally active, non-peptide antagonist of endothelin receptors with tissue-targeting properties, currently undergoing clinical development for the treatment of pulmonary arterial hypertension. The formation of its active metabolite, ACT-132577, as well as overall elimination of the drug, is catalyzed by the cytochrome P450 (CYP) system, predominantly CYP3A4 and to a lesser extent CYP2C19 isoenzyme. Macitentan is not a substrate of P-glycoprotein. Hepatic uptake is mostly driven by passive diffusion and is not dependent on organic anion-transporting polypeptide transport. This study aimed to investigate the magnitude of a possible effect of a potent CYP3A4 inhibitor, ketoconazole, on the pharmacokinetics of macitentan. METHODS: In a two-period, randomized, open-label, crossover study, 10 healthy subjects received each of the following treatments: Treatment A in which a single oral dose of 10 mg macitentan was administered on day 1 and Treatment B which consisted of initial daily treatment with ketoconazole 400 mg for 4 days, coadministration of macitentan and ketoconazole on the fifth day and continued administration of ketoconazole for 19 additional days. RESULTS: In the presence of ketoconazole, the exposure to macitentan expressed as area under the plasma concentration-time curve was increased by approximately a factor of 2 and to ACT-132577 was reduced by approximately 26 %. Macitentan was well-tolerated with or without ketoconazole in this study and no relevant differences in safety parameters between the treatments were observed. CONCLUSIONS: Although macitentan metabolism is indeed affected by CYP3A4 inhibition, the changes are not considered to be clinically significant and macitentan can be administered concomitantly with CYP3A4 inhibitors without need for dose adjustment.