Pharmacokinetics/Pharmacodynamics of Desloratadine and Fluoxetine in Healthy Volunteers

Abstract

The authors assessed the potential for a pharmacokinetic/pharmacodynamic interaction between desloratadine and fluoxetine. This randomized, placebo-controlled, open-label study was conducted in 54 healthy volunteers. Subjects received 1 of 3 treatments: desloratadine 5 mg plus fluoxetine 20 mg, desloratadine 5 mg plus placebo, or fluoxetine 20 mg plus placebo. Serial electrocardiograms (ECGs) were performed at baseline and day 35. Treatment effects on C(max) and AUC were assessed. During coadministration of desloratadine with fluoxetine, the ratio of the mean log-transformed C(max) and AUC values for desloratadine following concomitant fluoxetine therapy revealed a small increase in C(max) values of 15% (90% confidence interval [CI], 95%-139%) but no increase for AUC values (90% CI, 82%-123%). Corresponding values for 3-OH desloratadine demonstrated small increases in mean log-transformed C(max) and AUC ratios: 17% (90% CI, 100%-136%) and 13% (90% CI, 96%-132%), respectively. Statistical evaluation of the ratio of the mean C(max) and AUC values for fluoxetine following concomitant desloratadine therapy revealed small decreases of 9% (90% CI, 72%-115%) and 11% (90% CI, 69%-113%), respectively. Corresponding values for norfluoxetine demonstrated modest increases in mean log-transformed C(max) and AUC ratios: 22% (90% CI, 100%-139%) and 18% (90% CI, 101%-136%), respectively. Coadministration of desloratadine with a potent inhibitor of CYP2D6 did not result in clinically relevant changes in its pharmacokinetic parameters. Desloratadine administration was not associated with clinically important changes in the pharmacokinetics of fluoxetine, a drug metabolized by CYP2D6. The most common adverse event in all groups was headache (65%). Desloratadine plus fluoxetine caused no significant changes in ECGs or ventricular rate.

EFFECT OFCYP2D6*10ALLELE ON THE PHARMACOKINETICS OF LORATADINE IN CHINESE SUBJECTS

“…2) Loratadine may have been metabolized via CYP2D6 to a metabolite other than desloratadine. This is consistent with the observation that coadministration of desloratadine with a potent inhibitor of CYP2D6 (fluoxetine) did not cause significant changes in the plasma concentrations of desloratadine (Gupta et al, 2004).…”

“…2) Loratadine may have been metabolized via CYP2D6 to a metabolite other than desloratadine. This is consistent with the observation that coadministration of desloratadine with a potent inhibitor of CYP2D6 (fluoxetine) did not cause significant changes in the plasma concentrations of desloratadine (Gupta et al, 2004).In this in vivo study, we did not evaluate the effect of CYP3A4 polymorphisms, due to the relatively low prevalence of the mutant alleles in Chinese populations as well as their uncertain function in vivo. Previous studies showed that CYP3A4 inhibitors such as clarithromycin (Carr et al, 1998), erythromycin (Brannan et al, 1995, and ketoconazole (Kosoglou et al, 2000) significantly increased the plasma concentrations of loratadine.…”

A Long-Standing Mystery Solved: The Formation of 3-Hydroxydesloratadine Is Catalyzed by CYP2C8 But Prior Glucuronidation of Desloratadine by UDP-Glucuronosyltransferase 2B10 Is an Obligatory Requirement

“…dmd.aspetjournals.org (Cingi et al, 2013). All other relevant studies have examined the pharmacodynamic/pharmacokinetic interaction potential of desloratadine with CYP2D6 and CYP3A4 substrates, and desloratadine was found to have limited potential for drug-drug interactions (Gupta et al, 2001(Gupta et al, , 2004Banfield et al, 2002aBanfield et al, , 2002b. With respect to special populations, patients with moderate hepatic impairment have been shown to have elevated levels of desloratadine (2.4-fold increase in area under the curve); however, it has been reported that 3-hydroxydesloratadine exposure was similar between hepatically impaired and normal patients (Gupta et al, 2007).…”

Further Characterization of the Metabolism of Desloratadine and Its Cytochrome P450 and UDP-glucuronosyltransferase Inhibition Potential: Identification of Desloratadine as a Relatively Selective UGT2B10 Inhibitor

“…Few clinical studies have been performed to evaluate desloratadine as an inhibitor of CYP2D6 or CYP3A4. Desloratadine does not affect the pharmacokinetics of fluoxetine or azithromycin to a clinically significant extent (Gupta et al, 2001;Gupta et al, 2004). The previously reported requirement of UDPGlcUA in 3-hydroxydesloratadine formation led us to investigate the perpetrator potential of desloratadine toward 10 UGT enzymes expressed in liver (namely, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) and three UGT enzymes expressed in the gastrointestinal tract (namely, UGT1A7, UGT1A8, and UGT1A10) (Parkinson et al, 2013).…”