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Pharmacokinetics (PK) of multiple oral doses of desloratadine (DCL) and fexofenadine (FEX) in a population of healthy adults identified phenotypically as desloratadine slow metabolizers (DSMS)
Author(s) -
Kraft W.,
Blum R. A.,
Frick G. S.,
Vitow C.,
Stewart J. A.,
Kovacs S. J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.066
Subject(s) - desloratadine , pharmacokinetics , fexofenadine , crossover study , dosing , population , medicine , chemistry , pharmacology , placebo , alternative medicine , environmental health , pathology
Purpose To characterize the PK of DCL and FEX in adults identified as DSMs. Methods This was a randomized, double blind, crossover study with a 21‐day washout between treatments. DSM subjects received DCL 5 mg or FEX HCI 180 mg QD for 7 days during each treatment period. Serial blood sampling was performed on days 1 and 7, trough samples were collected on Days 5 and 6 and samples were collected 48, 72, 96, 120, and 144 hrs after the Day 7 dose. Plasma was assayed for DCL, 3‐OH‐DCL, and FEX by LC/MS/MS. Results 18 subjects (15 M, 3 F) with a mean (SD) age of 32.2 (±7.33) years and BMI of 27.0 (±3.7) kg/m 2 were enrolled. Exposure to DCL increased 5‐fold on Day 7. Relatively low concentrations of 3‐OH‐DCL were quantifiable more often on Day 7 than Day 1. The disposition of FEX was consistent with previous reports in subjects and patients, with no significant accumulation after 7 days of dosing. Mean (SD) half‐lives of 112±56.2 and 17.2±7.3 hrs were estimated for DCL and FEX, respectively, compared with 27 hrs reported for DCL normal metabolizers. Conclusions In DSMs substantial accumulation of DCL was observed; however, steady‐state was not reached by Day 7, which suggests continued accumulation with treatment beyond 7 days. There was no apparent alteration of FEX PK in DSMs. The safety of prolonged increased DCL exposure in a variety of clinical settings has not been established. The metabolic pathway responsible for the DSM phenotype remains unknown. (see Table) Clinical Pharmacology & Therapeutics (2005) 77 , P45–P45; doi: 10.1016/j.clpt.2004.12.066DCL Day 1 DCL Day 7 FEX Day 1 FEX Day 7AUC (0–24) (ng · hr/mL) Mean ± SD 40.29 ± 12.62 196.80 ± 53.76 2096 ± 1002 2357 ± 909 C max (ng/mL) Mean ± SD 2.48 ± 0.95 9.84 ± 2.67 367 ± 222 384 ± 180 T max (hrs) Median (Min, Max) 7 (2.5, 12) 7 (6, 12) 2.5 (1, 6) 1.5 (1, 6) C 24h (ng/mL) Mean ± SD 1.62 ± 0.48 7.57 ± 2.26 11.0 ± 3.1 18.4 ± 8.5