A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie.
Quinacrine was reported to have a marked in vitro antiprion action in mouse neuroblastoma cells. On compassionate grounds, quinacrine was administered to Creutzfeldt-Jakob disease patients, despite the absence of preclinical in vivo studies to evaluate efficacy. Quinacrine failed to provide therapeutic benefit. The aim of the study was to investigate possible pharmacokinetic and/or pharmacodynamic explanations for the discrepancy between the proven action of quinacrine in vitro and its lack of clinical efficacy. We conducted in vitro experiments reproducing the culture conditions in which antiprion effects had been previously observed and recalculated the EC(50) by determining the actual extracellular (120 nM) and intracellular (6713 nM) quinacrine neuroblastoma concentrations with the reported quinacrine EC(50) (300 nM). A randomized clinical trial in scrapie-affected ewes confirmed the absence of therapeutic benefit of quinacrine. The in vivo quinacrine exposure was evaluated in a pharmacokinetic investigation in healthy ewes. Cerebrospinal fluid concentrations (<10.6 and 55 nM after administration of therapeutic and toxic quinacrine doses, respectively) were much lower than the quinacrine extracellular neuroblastoma concentrations corresponding to the reported EC(50). The total brain tissue concentrations (3556 nM) obtained after a repeated therapeutic dosage regimen were within the range of the intracellular neuroblastoma quinacrine concentrations. In conclusion, in order to avoid in vivo trials for which failure can be predicted, the measurement in vitro of the antiprion EC(50) in both intra- and extracellular biophases should be determined. It can then be established if these in vitro antiprion concentrations are achievable in vivo.
Gayrard
Véronique
V
UMR 181 de Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France.
Picard-Hagen
Nicole
N
Viguié
Catherine
C
Laroute
Valerie
V
Andréoletti
Olivier
O
Toutain
Pierre-Louis
PL
D000465:Algorithms; D000818:Animals; D045744:Cell Line, Tumor; D003470:Culture Media; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D007273:Injections, Intramuscular; D017096:Prion Diseases / Q000188:drug therapy* / Q000662:veterinary*; D011796:Quinacrine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012608:Scrapie / Q000188:drug therapy*; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy*; D016019:Survival Analysis; D017211:Treatment Failure
D003470:Culture Media; D011796:Quinacrine