Dataset Information

Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.

ABSTRACT:

Objective

To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP.

Study design

The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping 9 single nucleotide polymorphisms in the CYP3A4, CYP3A5, and CYP3A7 genes. Genotype information was compared with asthma control scores (0=well controlled to 15=poorly controlled), determined using a questionnaire modified from the National Heart Lung and Blood Institute's Expert Panel 3 guidelines.

Results

Our study cohort comprised 734 children with asthma (mean age, 8.8±4.3 years) and was predominantly male (61%) and non-Hispanic white (53%). More than one-half of the children (56%; n=413) were receiving an inhaled glucocorticoid daily, with FP the most frequently prescribed agent (65%). Among the children receiving daily FP, single nucleotide polymorphisms in CYP3A5 and CYP3A7 were not associated with asthma control scores. In contrast, asthma control scores were significantly improved in the 20 children (7%) with the CYP3A4*22 allele (median, 3; range, 0-6) compared with the 201 children without the CYP3A4*22 allele (median, 4; range, 0-15; P=.02). The presence of CYP3A4*22 was associated with improved asthma control scores by 2.1 points (95% CI, 0.5-3.8).

Conclusion

The presence of CYP3A4*22, which is associated with decreased hepatic CYP3A4 expression and activity, was accompanied by improved asthma control in the FP-treated children. Decreased CYP3A4 activity may improve asthma control with inhaled FP.

SUBMITTER: Stockmann C

PROVIDER: S-EPMC3620714 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Publications

Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.

Stockmann Chris C Fassl Bernhard B Gaedigk Roger R Nkoy Flory F Uchida Derek A DA Monson Steven S Reilly Christopher A CA Leeder J Steven JS Yost Garold S GS Ward Robert M RM

The Journal of pediatrics 20130103 6

<h4>Objective</h4>To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP.<h4>Study design</h4>The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping 9 single nucleotide polymorphisms in the CYP3A4, CYP3A5, and CYP3A7 genes. Genotype information was compared with asthma control scores (0=well ...[more]

PMID: 23290512

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Project description:BackgroundThe efficacy and safety of fluticasone propionate/formoterol fumarate pressurized metered-dose inhaler (pMDI) (fluticasone/formoterol; Flutiform®; 100/10 µg b.i.d.) was compared with fluticasone propionate (Flixotide® Evohaler® pMDI; 100 µg b.i.d.) and fluticasone/salmeterol (Seretide® Evohaler® pMDI; 100/50 µg b.i.d.) in a pediatric asthma population (EudraCT number: 2010-024635-16).MethodsA double-blind, double-dummy, parallel group, multicenter study. Patients, aged 5-<12 years with persistent asthma ⩾ 6 months and forced expiratory volume in 1 s (FEV1) ⩽ 90% predicted were randomized 1:1:1 to 12 weeks' treatment. The study objectives were to demonstrate superiority of fluticasone/formoterol to fluticasone and non-inferiority to fluticasone/salmeterol.ResultsA total of 512 patients were randomized: fluticasone/formoterol, 169; fluticasone, 173; fluticasone/salmeterol, 170. Fluticasone/formoterol was superior to fluticasone for the primary endpoint: change from predose FEV1 at baseline to 2 h postdose FEV1 over 12 weeks [least squares (LS) mean difference 0.07 l; 95% confidence interval (CI) 0.03, 0.11; p < 0.001] and the first key secondary endpoint, FEV1 area under the curve over 4 hours (AUC0-4 h) at week 12 (LS mean difference 0.09 l; 95% CI: 0.04, 0.13; p < 0.001). Per a prespecified non-inferiority margin of -0.1 l, fluticasone/formoterol was non-inferior to fluticasone/salmeterol for the primary endpoint (LS mean difference 0.00 l; 95% CI -0.04, 0.04; p < 0.001) and first key secondary endpoint (LS mean difference 0.01; 95% CI -0.03, 0.06; p < 0.001). Fluticasone/formoterol was non-inferior to fluticasone/salmeterol for the second key secondary endpoint, change from predose FEV1 over 12 weeks (treatment difference -0.02 l; 95% CI -0.06, 0.02; p < 0.001), but was not superior to fluticasone for this endpoint (LS mean difference 0.03 l; 95% CI -0.01, 0.07; p = 0.091). All treatments elicited large improvements from baseline to week 12 for the Pediatric Asthma Quality of Life Questionnaire (LS mean change 0.76 to 0.85 units) and Asthma Control Questionnaire (LS mean change -1.03 to -1.13 units). Few severe exacerbations were seen (fluticasone/formoterol: two; fluticasone/salmeterol: two). All treatments were well tolerated.ConclusionsThis study supports the efficacy and safety of fluticasone/formoterol in a pediatric asthma population and its superiority to fluticasone.

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Project description:IntroductionIn recognition of the value of long-term real-world data, a postauthorization safety study of the inhaled corticosteroid (ICS) fluticasone propionate and long-acting ?2-agonist (LABA) formoterol fumarate (fluticasone/formoterol; Flutiform®) was conducted.MethodsThis was a 12-month observational study of outpatients with asthma aged ? 12 years in eight European countries. Patients were prescribed fluticasone/formoterol according to the licensed indication, and independently of their subsequent enrolment in the study. They were then treated according to local standard practice. The study objectives were to evaluate the safety and effectiveness of fluticasone/formoterol under real-world conditions.ResultsThe safety population for this study comprised 2539 patients (mean age 47.7 years; 94.3% aged ? 18 years; 63.4% female). Most patients (1538/2539, 60.6%) had switched to fluticasone/formoterol from another ICS/LABA, primarily due to lack of efficacy (1150/2539, 45.3%). Three quarters (77.4%) of patients were treated for 12 months, and 80.6% continued fluticasone/formoterol treatment after the study. Adverse events (AEs) occurred in 60.0% patients, and 10.2% had AEs considered possibly related to fluticasone/formoterol [most commonly asthma exacerbation (2.0% patients), dysphonia (1.8%) and cough (1.1%)]. Thirty-six severe AEs, but no serious AEs, were considered possibly related to fluticasone/formoterol. The proportion of patients with controlled asthma (based on Asthma Control Test score ? 20) increased from 29.4% at baseline to 67.4% at study end (last observation carried forward). The proportion of patients experiencing at least one severe exacerbation decreased from 35.8% in the year prior to enrolment to 9.8% during the study. Improvements from baseline to study end were also observed in Asthma Quality of Life scores and physician/patient reports of satisfaction with treatment.ConclusionIn this real-world postauthorization safety study, fluticasone/formoterol demonstrated a safety profile consistent with that seen in controlled clinical trials, with effectiveness in improving asthma control.

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Dataset Information

Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.

Objective

Study design

Results

Conclusion

Publications

Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.

Similar Datasets

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