title: Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis.
abstract: SUMMARY This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection models.
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wring
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Gaukel
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Bakela
authors.initials: B
authors.lastname: Nare
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jacobs
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Beaudet
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Tana
authors.initials: T
authors.lastname: Bowling
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Mercer
authors.affiliation: Haskins Laboratory, Pace University, New York, New York, USA.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bacchi
authors.affiliation: Haskins Laboratory, Pace University, New York, New York, USA.
authors.forename: Nigel
authors.initials: N
authors.lastname: Yarlett
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Randolph
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Parham
authors.affiliation: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Rewerts
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Platner
authors.affiliation: Drugs for Neglected Diseases Initiative, Geneva, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Don
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001681:Biological Assay; D001812:Blood-Brain Barrier / Q000187:drug effects; D001896:Boron Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014347:Trypanosoma brucei gambiense / Q000187:drug effects* / Q000254:growth & development; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D001549:Benzamides; D001896:Boron Compounds; C557508:SCYX 7158; D014344:Trypanocidal Agents