Effects of Ketoconazole and Quinidine on Pharmacokinetics of Pactimibe and Its Plasma Metabolite, R-125528, in Humans

Abstract

ABSTRACT:Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is cleared solely by CYP2D6 despite its acidity. To evaluate contributions of the cytochrome P450 enzymes on the pharmacokinetics of pactimibe and R-125528 in humans, drug-drug interaction studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were given a single dose of pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, the area under the plasma concentrationtime curve (AUC 0-inf ) of pactimibe modestly increased 1.7-fold and AUC 0-tz of R-125528 decreased by 55%. In addition, 17 healthy male subjects were given a single dose of pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, the AUC 0-inf for pactimibe modestly increased 1.7-fold. On the other hand, the AUC 0-tz of R-125528 was markedly elevated 5.0-fold, although the AUC 0-inf could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 h. As the f m CYP3A4 and f m CYP2D6 values of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, the f m CYP2D6 of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed with the quinidine treatment.Pactimibe sulfate [7-(2, 2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl] acetic acid hemisulfate (formerly named CS-505) (Fig. 1A) is a novel lipophilic acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases (Kitayama et al., 2006a,b,c;Nissen et al., 2006). A number of acyl coenzyme A:cholesterol acyltransferase inhibitors have been synthesized, and their pharmacological profiles were evaluated in animals and humans. However, several adverse effects such as adrenal toxicity (Vernetti et al., 1993;Reindel et al., 1994;Matsuo et al., 1996), diarrhea (Kashiwa et al., 1997), and hepatotoxicity (Ishi et al., 1994;Nakaya et al., 1994) and various elusive efficacies in humans (Harris et al., 1990;Hainer et al., 1994;Tardif et al., 2004) have been revealed, and none of these compounds has so far succeeded in clinical development. Pactimibe sulfate was selected as a clinical development candidate showing good oral absorbability and potent pharmacological effects in apolipoprotein Edeficient mice (Terasaka et al., 2007) and Watanabe heritable hyperlipidemic rabbits (Kitayama et al., 2006b) without showing significant adrenal toxicity even in dogs, the most sensitive animal species.In vivo biotransformatio...

Ketoconazole‐Associated Liver Injury in Drug‐Drug Interaction Studies in Healthy Volunteers

“…The selected study set consisted of 53 separate DDI studies taken from 46 publications between 2005 and 2015, which included 971 subjects with systemic ketoconazole exposure (Table ). A majority of the studies were conducted at study centers in the United States and Germany (Table ).…”

“…Kotsuma et al reported 2 treatment‐emergent adverse effects and an increase in serum ALT levels in subject B, although exact ALT levels were not provided. This study evaluated the possible DDI of ketoconazole with pactimibe, an ACAT‐1 inhibitor that failed to reach the market.…”

ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo

“…However, many potent ACAT inhibitors, including avasimibe (CI-1011), eflucimibe (F 12511), and pactimibe sulfate (CS-505) do not have detectable adrenalytic activity (Junquero, et al 2001; Kotsuma, et al 2008; Robertson, et al 2001). Targeted deletion of the mouse gene that encodes the adrenocortial ACAT1 enzyme ( Acact ) depletes cholesterol esters in adrenals, but it does not cause corticosteroid insufficiency (Meiner, et al 1996).…”

Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

“…Recently, we found novel substrates for CYP2D6, pactimibe sulfate and its indole metabolite, R-125528, that are acidic compounds with a carboxyl group and no basic nitrogen in their structures (Kotsuma et al, 2008b). In human clinical drug-drug interaction study, the AUC 0 -72 h of pactimibe and R-125528 were increased 1.7-and 5.0-fold, respectively, by cotreatment with quinidine (Kotsuma et al, 2008a). Interestingly, their sites of metabolism are relatively far from the aromatic moiety (the -1 position of the N-octyl chain in Fig.…”