Analysis of the Disposition of a Novel p38 MAPK Inhibitor, AKP-001, and Its Metabolites in Rats with a Simple Physiologically Based Pharmacokinetic Model

Abstract

5-[(2-Chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001) is a potent p38 mitogen-activated protein kinase inhibitor that is being developed to specifically target the intestines for the treatment of inflammatory bowel disease. According to the ante-drug concept, AKP-001 was designed to be metabolized to inactive forms via the first-pass metabolism to avoid undesirable systemic exposure. The purpose of this study is to investigate the pharmacokinetic characteristics of AKP-001 and its metabolites (M1 and M2) in rats, utilizing a simple physiologically based pharmacokinetic (PBPK) model. In vitro metabolic activity of AKP-001 in the S9 fraction of rat liver was examined, and plasma concentration-time profiles were developed following intravenous and/or oral administration of AKP-001 and its metabolites. AKP-001 was primarily metabolized to M1; however, M2 was not detected in liver S9 fractions. In accordance with this observation in vitro, M2 was detected in plasma after oral dosing of AKP-001 with a lag time of 1.5 hours, but not after intravenous dosing. To analyze pharmacokinetics in rats in vivo, a simple PBPK model was developed by simultaneous fitting of the plasma concentrations after treatment with AKP-001 and its metabolites. The observed plasma concentration-time profiles of AKP-001 and metabolites were described by the model adequately. Intestinal and systemic exposures of AKP-001 were simulated using the model to assess the relationship between pharmacokinetics and efficacy/safety. Model analysis suggested that oral bioavailability of intestinetargeting ante-drugs should be low to avoid systemic side effects. The pharmacokinetic properties of AKP-001 meet this criterion owing to extensive first-pass metabolism.

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

“…Recent efforts have focused on the development of drugs that exhibit reduced severe side effects as well as mechanisms that provide potent non-toxic targeted treatment of a specific tissue [117,120,121]. These studies involved the identification of p38α/βMAPK “inhibitors that show prodrug or antedrug properties; The prodrug properties involve an inactive compound that undergoes metabolic transformation-activation in vivo to provide an active drug to a specific targeted tissue.…”

“…This study has analyzed the in vivo disposition of a novel p38 MAPK inhibitor, AKP-001, and its metabolites in rats with a simple physiologically based pharmacokinetic mode [121]. AKP-001 (Figure 9) is a novel and potent p38α/β inhibitor designed for its tissue-specific targeting that inhibits the phosphorylation of downstream protein targets.…”

“…[IC α 50 = 10.9 nM; IC β 50 =326 nM. AKP-001] [121]. It was synthesized for the treatment of inflammatory bowel disease (IBD), a disease of severe inflammation and oxidative stress, following the principles of ante/soft drug design [121].…”

“…AKP-001] [121]. It was synthesized for the treatment of inflammatory bowel disease (IBD), a disease of severe inflammation and oxidative stress, following the principles of ante/soft drug design [121]. The active antedrug is easily administered (orally) to the gut and is rapidly inactivated systemically.…”

“…AKP-001 is also hydrolyzed to M1 in rat plasma. This hydrolytic clearance (of AKT-001) in rat extracellular fluid is quite low compared with the total clearance; thus the hydrolytic clearance of AKP-001 and the contribution of plasma hydrolysis is minimal [Figure 10][121]. ” “In vitro inhibition studies indicate that M1 formation in rat liver S9 fractions is mediated by carboxylesterase, which, in fact was observed in various rat tissues [127].…”