| Popis: |
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/m2 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.2004.12.066 Table 1. DCL Day 1 DCL Day 7 FEX Day 1 FEX Day 7 AUC(0–24) (ng · hr/mL) Mean ± SD 40.29 ± 12.62 196.80 ± 53.76 2096 ± 1002 2357 ± 909 Cmax (ng/mL) Mean ± SD 2.48 ± 0.95 9.84 ± 2.67 367 ± 222 384 ± 180 Tmax (hrs) Median (Min, Max) 7 (2.5, 12) 7 (6, 12) 2.5 (1, 6) 1.5 (1, 6) C24h (ng/mL) Mean ± SD 1.62 ± 0.48 7.57 ± 2.26 11.0 ± 3.1 18.4 ± 8.5 |
Plný text