Effects of T. Brucei infection on the pharmacokinetics of DB868 and DB829

Claudia is currently working with the compound DB868, a prodrug that is a lead candidate for the treatment of the CNS stage of Human African Sleeping Sickness.  Her research includes elucidating the pathway of biotransformation of DB868 into its active compound (DB829) and the enzymes that are involved in this pathway.  Additionally, she will assess the changes in activity and expression of these enzymes during infection with the parasite Trypanosoma brucei and will ultimately look at the overall changes in disposition of DB829 in an in vivo rat model of the infection.

Infection related changes in drug pharmacokinetics remain a concern in medicine, as evidenced by reports of altered drug clearance during episodes of infection (e.g., clozapine and theophylline).  It has been demonstrated in vitro that cytokines mediate the downregulation of members of drug metabolizing enzymes (DMEs), such as the cytochrome P450 enzyme superfamily, and key drug transporters.  The consequences of DME and transporter downregulation are often manifested as reduced drug clearance or exposure, which in many cases has the potential of toxic side effects or suboptimal levels of drug. DB75 is a potent antiparasitic drug that was in development for the treatment of Human African Trypanosomiasis (HAT).   Generation of DB75 from its prodrug (DB289) is dependent on the hepatic biotransformation of the prodrug, and its major route of elimination is through biliary excretion.  We are investigating if trypanosomiasis will alter the pharmacokinetics and disposition of DB75 and its prodrug in the rat experimental model of the disease.  Initial results show that the trypanosomal infection alters the disposition of both the prodrug and DB75 resulting in increased exposure.