Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects

Abstract

AimThe aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects.MethodThis was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 μg for 7 days, then 800 μg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 μg infusion) in the other. FF PK and serum cortisol (inhaled 200 μg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed.ResultsEthnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%–55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 μg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1–30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated.ConclusionModestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.

A Randomized, Crossover Study to Investigate the Pharmacokinetics and Safety of Inhaled Fluticasone Furoate and Umeclidinium, Administered Separately and in Combination via Dry Powder Inhaler in Healthy Adult Volunteers

“…However, the PK characteristics of FF and UMEC have been extensively studied, and the data presented here are broadly consistent with these studies; in healthy volunteers, repeat-dose inhaled FF 200 mcg and 800 mcg had a plasma t max of 30-45 min (similar to the t max of 30 min reported here) and a t of 25.5-32.5 h [25].…”

“…A previous study has demonstrated higher FF systemic exposure following inhaled dosing in East Asian subjects compared with Caucasian subjects[25], although this was not associated with a clinically significant effect on serum cortisol, and therefore dose adjustment in East Asian subjects was deemed unnecessary. However, there were insufficient data to draw conclusions regarding differences in systemic exposure between AfricanAmerican/African and Caucasian subjects in the present study.…”

Fluticasone Furoate/Vilanterol: a Review of Its Use in Patients with Asthma

“…Systemic exposure to fluticasone furoate after inhalation was modestly (\50 %) higher in healthy East Asian (Chinese, Korean and Japanese) subjects than in healthy Caucasians [31]. However, the increased exposure was not associated with a clinically significant effect on serum cortisol; therefore, dose adjustment is not required in East Asian subjects [31].…”

“…However, the increased exposure was not associated with a clinically significant effect on serum cortisol; therefore, dose adjustment is not required in East Asian subjects [31]. Similar results are reported for fluticasone furoate in East Asian, Japanese and South East Asian patients with asthma; in these patients, vilanterol C max is predicted to be 220-287 % higher than in other racial groups, with no evidence of clinically significant effect on heart rate because of the higher C max [2].…”

Model‐based evaluation of pulmonary pharmacokinetics in asthmatic and COPD patients after oral olodaterol inhalation

“…• Smaller lungs and smaller airways in Asians were discussed to influence fluticasone furoate PK after inhalation [42] Sex (male, female)…”