Microdosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1), and Interaction (Grapefruit Juice) Profiles of Celiprolol Following the Oral Microdose and Therapeutic Dose

In 30 healthy volunteers matched for SLCO2B1 genotype, the effect of a genetic variant on the body's exposure to celiprolol depended on the dose. At a therapeutic dose (100 mg), people with two copies of the *3 variant had a lower average area under the concentration-time curve (AUC) of 775 ng·h/mL compared with 1097 ng·h/mL for those with one copy (*1/*3) and 1547 ng·h/mL for those with none (*1/*1). At a microdose (97.5 µg), these genotype differences disappeared. Dose-normalized AUC was much lower at the microdose, suggesting saturation of an efflux transporter at the therapeutic dose explains why the genetic effect only appears at that higher dose.

Study at a glance

Abstract

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.