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

Abstract

Aim: The 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.

Method: This 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.

Results: Ethnic 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.

Conclusion: Modestly 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.

Keywords: Caucasian; East Asian; fluticasone furoate; healthy subjects; pharmacodynamics; pharmacokinetics.

Figure 1

Study design schematic

Figure 2

Box and whisker plots for body weight normalized (μg kg⁻¹) C_max; (A) and AUC(0,∞) following after administration of i.v. FF 250 μg; (B). AUC(0,∞), area under the concentration–time curve from time zero extrapolated to infinity; C_max, maximum concentration; FF, fluticasone furoate

Figure 3

Mean\ ± SD plasma semi-log concentration–time profiles for FF after administration of inhaled FF 800 μg single and repeat dose; (A) and inhaled FF repeat dose 200 μg; (B). FF, fluticasone furoate; LLQ, lower limit of quantification; 3A: () Caucasian (repeat), () Caucasian (single), () Chinese (repeat), () Chinese (single), () Japanese (repeat), () Japanese (single), () Korean (repeat), and () Korean (single). 3B: () Caucasian, () Chinese, () Japanese and () Korean

Figure 4

Total FF lung dose absorbed–time profiles after administration of inhaled FF 800 μg single dose estimated from deconvolution analysis. FF, fluticasone furoate. () Caucasian, () Chinese, () Japanese, and () Korean

Figure 5

Geometric mean and 95% CI serum cortisol concentration–time profile (0–24 h) on day −1 (pre-FF); (A) and following 7 days repeat inhaled administration of FF 200 μg; (B). CI, confidence interval; FF, fluticasone furoate. () Caucasian, () Chinese, () Japanese and () Korean