Journal
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
Volume 21, Issue -, Pages 65-73Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2023.01.003
Keywords
Oxamniquine; Schistosome; Schistosomiasis; Parasitic worm; PK; PD relationship
Categories
Ask authors/readers for more resources
The antischistosomal drug OXA requires activation by a sulfotransferase within the parasitic worm for killing. However, its clinical plasma concentrations are much lower than the in vitro efficacious concentration for schistosomal killing. By modeling the pharmacokinetic data, it was determined that the parasite resides in the vasculature between the intestine and the liver, which explains the required human dose. In silico models and follow-up PK studies in mice confirmed the dose needed to recapitulate human conditions.
The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for in vitro schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with in vitro studies and explains the required human dose. In silico models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50-100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20-40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of in vitro efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill S. mansoni, S. haematobium, and S. japonicum, whereas OXA is only effective against S. mansoni. Second-generation OXA analogs should optimize both in vitro killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available