Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers

Abstract

1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects. 2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. 3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUCt of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17-2.31) and by 51% (1.51; 1.17-2.31), respectively. Similar patterns were observed for the increase in Cmax of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. 4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.

Application of physiologically based pharmacokinetic modeling in predicting drug–drug interactions for sarpogrelate hydrochloride in humans

“…The simulation with metoprolol included only EMs for CYP2D6 to enable a direct comparison with the observed clinical data. 25 …”

“…In both instances, the clinical DDI potential associated with CYP2D6 inhibition could not be excluded for sarpogrelate hydrochloride, and clinical studies were warranted. It was reported that the area under the curve at time t (AUC t ) and C max of metoprolol, a CYP2D6 substrate, were increased by 1.53- and 1.62-fold (multiple, 1.51- and 1.67-fold), respectively, after single or multiple coadministration with sarpogrelate hydrochloride 100 mg. 25 …”

“…In addition, the predicted results of the interaction between metoprolol and sarpogrelate were compared with our previously observed clinical data. 25 …”

Bioequivalence of Sarpogrelate in Healthy Chinese Subjects Under Fasting and Fed Conditions: A 4‐Way Replicate Crossover Investigation by a Reference‐Scaled Average Bioequivalence Approach

“…Sarpogrelate is also glucuronidated directly by UDP‐glucuronosyltransferases and excreted into the urine and bile . Although sarpogrelate is reported to be a selective CYP2D6 inhibitor in vitro, increased systemic exposure of metoprolol (a CYP2D6 substrate) after coadministration with sarpogrelate did not show clinically relevant effects …”

“…20 Although sarpogrelate is reported to be a selective CYP2D6 inhibitor in vitro, increased systemic exposure of metoprolol (a CYP2D6 substrate) after coadministration with sarpogrelate did not show clinically relevant effects. 21 Before the generic sarpogrelate formulation manufactured by Tianjin Hongri Pharmaceutical Co, Ltd is commercialized, the China Food and Drug Administration (CFDA) needs to confirm that it is bioequivalent to the reference drug Anplag. However, determining the bioequivalence (BE) of sarpogrelate formulations is challenging due to its limited pharmacokinetic (PK) performance and marked within-subject variability.…”