The PK of IBU (a CYP2C9 substrate) in patients with CF are extremely variable and can be unpredictable. IBU disposition was characterized in 26 patients with CF (5.5 to 29.6 years of age, 16.8-74.6 kg, BSA=0.73-1.93 m2) who received a single oral dose (20.7-27.9 mg/kg) of the drug. IBU was quantitated by HPLC and PK parameters determined by Bayesian estimation. CYP2C9 genotype was determined from leukocyte-derived genomic DNA using PCR RFLP. CYP2C9 genotype distribution was as follows: *1*1, n=14; *1*2, n=8; *1*3, n=2; *2*2, n=l and *2*3, n=1. IBU clearance (CL/F=ml/min/kg) (mean=1.49; range .71-2.59) was significantly correlated to body surface area (r2=0.39; p<.001), body weight (r2=0.36, p=.001), and age (r2=0.31; p=.003). CL/F in subjects with the *1*1 genotype (1.7±0.42) was significantly (p=0.02) greater than that observed in subjects with the *1*2 genotype ( 1.2±0.43). The mean subject age was not different between these subpopulations (e.g., *1*1 = 11.9 yr vs *1*2= 16.9 yr). Stepwise linear regression revealed that BSA (p<0.0001) or age (p=0.004) but not CYP2C9 genotype were significant determinants of IBU CL/F. Conclusion: Variability in the CL/F of IBU in CF is multifactorial and to a great degree is influenced by developmental differences in PK.
ASJC Scopus subject areas
- Pharmacology (medical)