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

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.

Comparison of Inhibitory Duration of Grapefruit Juice on Organic Anion-Transporting Polypeptide and Cytochrome P450 3A4

“…11,16) The decrease AUC 0-8 of celiprolol in the previous two studies was higher than that observed in our study. These differences between studies may be attributable to the volume of grapefruit juice ingested.…”

“…Grapefruit juice interactions with OATPs expressed in the intestine may be mediated through inhibition of transporter activity rather than through a reduction in protein expression. 16) Regarding the duration of the inhibitory effect of grapefruit juice on OATPs, only one previous study has reported no effect of grapefruit juice ingestion 4 h before fexofenadine administration. 21) Our results indicate that the inhibitory effect of grapefruit juice on OATP dissipates faster than its effect on CYP3A4 activity, which is sustained for at least 48 h. Very recently, Shirasaka et al reported the effects of pre-incubation with fruit juices on OATP2B1-mediated transport of specific substrates in vitro.…”

“…11,15,16) In clinical settings, it is important to know how long OATP inhibition will be sustained after the intake of grapefruit juice, so that practitioners can administer drugs without the concern of interactions. Several reports have been published about the duration of CYP3A4 inhibition.…”

“…10) Furthermore, celiprolol, a β-adrenoceptor blocking agent, has been reported to be a substrate of uptake transporters such as OATP1A2 and OATP2B1, and markedly reduced drug absorption when co-administered with grapefruit juice. 11,15,16) In clinical settings, it is important to know how long OATP inhibition will be sustained after the intake of grapefruit juice, so that practitioners can administer drugs without the concern of interactions. Several reports have been published about the duration of CYP3A4 inhibition.…”

Human Micro Dosing Studies (Phase 0): A Novel Approach in Clinical Research

“…Although the emphasis has been on pharmacokinetic prediction there are other applications of micro dosing that are emerging. Micro dosing helps in predicting drug-drug interactions 18 and food-drug interaction before the drug enters Phase 1 clinical trials 19 . It can also assess polymorphisms associated with drug transporters 20 , especially in genetically diverse populations.…”