n most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9pg/mL (range: 10.8 to 14.1 pg/mL) and AUC0-τ averaged 8.43 pg•h/mL (range: 4.2 to 18.8pg•h/mL). However, the fluticasone propionate Cmax and AUC0-τ increased to 318 pg/mL(range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL),respectively, after 7 days of coadministration of ritonavir (100 mg twice daily) withfluticasone propionate aqueous nasal spray (200 mcg once daily). This significant increase inplasma fluticasone propionate exposure resulted in a significant decrease (86%) in serumcortisol AUC.
Ketoconazole: In a placebo-controlled crossover trial in 8 healthy adult volunteers,coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) withmultiple doses of ketoconazole (200 mg) to steady state resulted in increased plasmafluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect onurinary excretion of cortisol.
In a placebo-controlled, crossover drug interaction trial in 20 healthy male and femalesubjects, coadministration of salmeterol (50 mcg twice daily) and ketoconazole, a strong CYP3A4 inhibitor, (400 mg once daily) for 7 days resulted in a significant increase in plasmasalmeterol exposure as determined by a 16-fold increase in AUC (ratio with and withoutketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of theswallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn fromsalmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects(2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration ofsalmeterol and ketoconazole did not result in a clinically significant effect on mean heartrate, mean blood potassium, or mean blood glucose. Although there was no statistical effecton the mean QTc, coadministration of salmeterol and ketoconazole was associated with morefrequent increases in QTc duration compared with salmeterol administration alone andplacebo administration.
Erythromycin: In a multiple-dose drug interaction trial, coadministration of orally inhaledfluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) didnot affect fluticasone propionate pharmacokinetics.
In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (amoderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase insalmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03],P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P<0.04), a 5.8-msecincrease in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasmapotassium.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityFluticasone propionate:
Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to1000 mcg/kg (approximately 10 times the MRHDID for adults on a mcg/m2basis) for 78 weeksor in rats at inhalation doses up to 57 mcg/kg (approximately equivalent to the MRHDID foradults on a mcg/m2basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro.
No significant clastogenic |
