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Prevalence of the slow metabolizer (SM) phenotype and single dose pharmacokinetics (PK) of desloratadine (DCL) in a population of healthy adults
Author(s) -
Frick G. S.,
Blum R. A.,
Kovacs S. J.,
Vitow C.,
Stewart J. A.,
Kraft W. K.
Publication year - 2004
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.2003.11.033
Subject(s) - pharmacokinetics , cmax , dosing , population , pharmacology , chemistry , adverse effect , absorption (acoustics) , medicine , environmental health , physics , acoustics
Purpose To characterize the PK of DCL and 3‐OH‐DCL in SMs compared with normal metabolizers (NMs). DCL is metabolized to 3‐OH‐DCL by an unidentified enzyme(s). The product insert for DCL states that ~7% of the general population are apparent SMs, with higher prevalence estimates in blacks (~20%). Methods Blood samples were collected pre‐dose and at 1, 2, 3, 4, 6, 7, 8, 12, and 24 hrs following a single oral 5 mg dose of DCL. Plasma was assayed for DCL and 3‐OH‐DCL by LC/MS/MS and exposure measures computed by non‐compartmental methods using WinNonlin; C max and T max were determined from observed data. SMs were identified by AUC (3‐OH DCL) :AUC (DCL) ratios <0.1. Results 170 non‐smoking, male and female subjects 18–55 yrs of age received DCL. 14 of 170 (8.2%) subjects were identified as SMs; 7 had no measurable 3‐OH‐DCL concentrations. In addition to decreased hydroxylation, absorption appears delayed (possibly impaired) in SMs. DCL exposures are tabulated below. (see Table) Conclusions Plasma concentrations of DCL rise and fall more slowly in SMs. Consequently, SMs will accumulate DCL with recommended dosing and will be more susceptible to concentration‐related adverse effects. Clinical risks of prolonged increased DCL exposure in SMs require further study, as do the underlying genotypes conferring different phenotypes for DCL PK. A mechanistic basis for both impaired absorption and metabolism is not immediately apparent. Clinical Pharmacology & Therapeutics (2004) 75 , P9–P9; doi: 10.1016/j.clpt.2003.11.033NMs SMsAUC (0–24) pghr/mL C max pg/mL T max h C 24h pg/mL AUC (0–24) pghr/mL C max pg/mL T max h C 24h pg/mLMin 9995 969 1 113 26916 1450 6 1128 Max 55776 5730 7 1470 73118 3777 24 3080 Median 26242 2252 3 442 40168 2227 12 1582 Mean 27114 2425 507 41955 2263 1782 SD 9384 875 250 13066 663 623 CV% 34.6 36.1 49.3 31.1 29.3 35.0