CAS 1189661-02-6 Carebastine-[d5] (2024)

1. Pharmaco*kinetics and safety of ebastine in healthy subjects and patients with renal impairment

Robert J Noveck, Suzanne K Swan, Richard A Preston Clin Pharmaco*kinet . 2007;46(6):525-34. doi: 10.2165/00003088-200746060-00006.

Objective:To assess the differences in the pharmaco*kinetics and cardiac safety of ebastine and its active metabolite, carebastine, in patients with normal and impaired renal function.Methods:Twenty-four patients with varying degrees of renal impairment (mild, moderate or severe: n = 8 per group) and 12 healthy subjects participated in an open-label, parallel-group, multicentre study. Ebastine 20mg was administered orally once daily for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours on day 1 and for 72 hours on day 5 by using a validated sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 ng/mL for ebastine and 1.00 ng/mL for carebastine. Renal function was assessed by measuring 24-hour creatinine clearance (CL(CR)) at baseline. Cardiac and general safety parameters were also monitored.Results:The pharmaco*kinetics of ebastine were not modified by renal impairment. No correlation between ebastine pharmaco*kinetics and renal function, as expressed by CL(CR) assessed 2 days prior to dosing, was observed. Comparison of the plasma exposure and the elimination half-life of ebastine and carebastine between groups showed no significant differences. Therefore, no apparent accumulation of ebastine and carebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmaco*kinetics for both healthy subjects and patients with renal impairment, even though the variability between the groups was large. In addition, no differences were observed in the safety of ebastine between patients with renal impairment and healthy subjects when assessing adverse events, vital signs, laboratory parameters or ECGs.Conclusion:Ebastine was generally well tolerated in subjects with impaired renal function. No clinically important pharmaco*kinetic or safety differences were observed between patients with renal impairment and healthy subjects with normal renal function.

2. Characterization of ebastine, hydroxyebastine, and carebastine metabolism by human liver microsomes and expressed cytochrome P450 enzymes: major roles for CYP2J2 and CYP3A

Jae-Gook Shin, Dong-Jun Lee, Zeuresenay Desta, Kwang-Hyeon Liu, Ji-Hong Shon, Yune-Jung Yoon, Chang Soo Choi, Mi-Gyung Kim, Min-Jung Kim, Young Kil Choi Drug Metab Dispos . 2006 Nov;34(11):1793-7. doi: 10.1124/dmd.106.010488.

Ebastine undergoes extensive metabolism to form desalkylebastine and hydroxyebastine. Hydroxyebastine is subsequently metabolized to carebastine. Although CYP3A4 and CYP2J2 have been implicated in ebastine N-dealkylation and hydroxylation, the enzyme catalyzing the subsequent metabolic steps (conversion of hydroxyebastine to desalkylebastine and carebastine) have not been identified. Therefore, we used human liver microsomes (HLMs) and expressed cytochromes P450 (P450s) to characterize the metabolism of ebastine and that of its metabolites, hydroxyebastine and carebastine. In HLMs, ebastine was metabolized to desalkyl-, hydroxy-, and carebastine; hydroxyebastine to desalkyl- and carebastine; and carebastine to desalkylebastine. Of the 11 cDNA-expressed P450s, CYP3A4 was the main enzyme catalyzing the N-dealkylation of ebastine, hydroxyebastine, and carebastine to desalkylebastine [intrinsic clearance (CL(int)) = 0.44, 1.05, and 0.16 microl/min/pmol P450, respectively]. Ebastine and hydroxyebastine were also dealkylated to desalkylebastine to some extent by CYP3A5. Ebastine hydroxylation to hydroxyebastine is mainly mediated by CYP2J2 (0.45 microl/min/pmol P450; 22.5- and 7.5-fold higher than that for CYP3A4 and CYP3A5, respectively), whereas CYP2J2 and CYP3A4 contributed to the formation of carebastine from hydroxyebastine. These findings were supported by chemical inhibition and kinetic analysis studies in human liver microsomes. The CL(int) of hydroxyebastine was much higher than that of ebastine and carebastine, and carebastine was metabolically more stable than ebastine and hydroxyebastine. In conclusion, our data for the first time, to our knowledge, suggest that both CYP2J2 and CYP3A play important roles in ebastine sequential metabolism: dealkylation of ebastine and its metabolites is mainly catalyzed by CYP3A4, whereas the hydroxylation reactions are preferentially catalyzed by CYP2J2. The present data will be very useful to understand the pharmaco*kinetics and drug interaction of ebastine in vivo.

3. Effect of age and gender on the pharmaco*kinetics of ebastine after single and repeated dosing in healthy subjects

B Pandit, S Rohatagi, M Gillen, M Aubeneau, B K Jensen, C Jan, G Rhodes Int J Clin Pharmacol Ther . 2001 Mar;39(3):126-34. doi: 10.5414/cpp39126.

Objectives:Ebastine is a potent and selective H1-receptor antagonist indicated for allergic rhinitis which undergoes extensive first pass metabolism by CYP3A4 to form an active metabolite, carebastine. The purpose of the study was to determine age- and gender-related differences in the pharmaco*kinetics of ebastine and carebastine.Methods:The upper recommended oral dose of 20 mg once daily was administered to 12 healthy young (22 to 38 years) and 12 healthy elderly (50 to 92 years; 8 m and 4 f) subjects for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours following the initial dose on Day 1 and for 72 hours following the dose on Day 5 using a sensitive LC/MS/MS assay. The minimum quantifiable limit (MQL) for the assay was 0.05 ng/ml and 1.0 ng/ml for ebastine and carebastine, respectively.Results:Mean area under the curve and Cmax values on Day 1 and Day 5 were similar for ebastine but approximately doubled for carebastine due to its longer half-life. Mean carebastine concentrations were approximately 10 to 20 fold higher than mean ebastine concentrations. For young subjects, the mean (%CV) ebastine t(1/2) was 5.76 (28.47) h and 20.38 (46.19) h on Day 1 and Day 5, respectively. Similarily, for young subjects, the mean (%CV) for carebastine t(1/2) was 7.03 (23.21) h and 26.12 (23.39) h on Day 1 and Day 5, respectively. This apparent prolongation of t(1/2) was probably due to lack of proper estimation of terminal half-life on Day 1 as fewer samples were collected for a shorter duration on Day 1. Using a multicomparison test for Cmin values, it was determined that steady state conditions were achieved by Day 5 for both age groups for ebastine and in young subjects for carebastine. The variability in ebastine pharmaco*kinetic parameters was higher than carebastine. A 50% increase in ebastine AUC(0-24) and Cmax values in elderly subjects, with no changes in t(1/2), could be explained by either increased absorption of ebastine in elderly subjects or due to a decrease in first pass metabolism. As ebastine shows a high first-pass effect, even a small change in this first pass can cause large changes in plasma exposure. The ebastine pharmaco*kinetic parameters for elderly subjects in this study lie between the values reported in young subjects in earlier studies. Hence, the apparent age-related pharmaco*kinetic difference for ebastine is probably due to the inherent variability in ebastine pharmaco*kinetics. There were no gender-related differences in either young or elderly subjects for mean AUC, Cmax, tmax and t(1/2) ebastine and carebastine values. Ebastine was absorbed rapidly with a median tmax of 1.25 to 2.25 h for both healthy young and elderly males and females on Day 1 and Day 5. There was a delayed appearance of carebastine as expressed by median tmax of 4.0 to 5.0 h, which did not change with age, gender or repeated administration. There were no clinically relevant differences between the groups of subjects with respect to adverse events or safety parameters.Conclusions:Thus, ebastine can be safely administered to elderly subjects with no clinically important age- or gender related differences in the pharmaco*kinetics of ebastine/carebastine.