जैवसमतुल्यता एवं जैवउपलब्धता जर्नल

अमूर्त

The Pharmacokinetics of Fluticasone Furoate and Vilanterol Following Single Inhaled Administration in Combination and Intravenous Administration of Individual Components in Healthy Subjects

Ann Allen, Ludovic Apoux, Jo Bal, Joseph Bianco, Alison Moore, Ramiya Ravindranath, Lee Tombs and Rodger D Kempsford

Fluticasone furoate (FF)/vilanterol (VI), a novel inhaled corticosteroid/long-acting β 2 -agonist combination, is being developed as a once-daily inhaled treatment for asthma and chronic obstructive pulmonary disease. The two studies described here assess FF dose proportionality and VI equivalence across the clinical strengths of FF/ VI and the absolute bioavailability of the components administered as FF/VI in combination via the dry powder inhaler (DPI) intended for commercial use. Study 1 (NCT01213849) was a randomized, open-label, three-way crossover, single- dose study in healthy subjects designed to assess whether the systemic exposure of FF increased proportionately and VI systemic exposure was constant across different strength combinations of FF/VI (four inhalations of FF/ VI; 50/25 μg, 100/25 μg and 200/25 μg). Study 2 (NCT01299558) was an open-label, non-randomized, three- way crossover, single-dose study in healthy subjects conducted to determine the absolute bioavailability of FF/VI inhalation powder. Both FF and VI have high plasma clearance and extensive distribution into tissues. Overall, FF systemic exposure, as measured by AUC (0–t’) , was dose proportional over the 200-800 μg FF dose range. The less than dose proportional increase seen for FF C max is likely due to rate limited absorption from the lung. FF acts topically in the lung, whilst systemic exposure is related to safety. Consequently, the lack of dose proportionality for FF C max would be considered not to impact efficacy. Equivalence of VI exposure across the three FF/VI dosage strengths was demonstrated for AUC (0–t’) and C max . Following a single inhaled dose of FF/VI administered via DPI the absolute bioavailabilities of FF and VI were estimated to be 15% (90% confidence interval [CI]: 13%, 18%) and 27% (90% CI: 22%, 35%), respectively. FF showed longer retention in the lung than VI following inhaled administration, with the time for 90% of the total to be absorbed from the lung being on average 35.2 hours and 3.8 hours, respectively.