Salmeterol and fluticasone propionate given as a combination - Lack of systemic pharmacodynamic and pharmacokinetic interactions

Objective. To investigate the potential for systemic pharmacodynamic and ph armacokinetic interactions between inhaled salmeterol and fluticasone propi onate when repeat doses of the two drugs are given in combination to health y subjects. Methods: Twenty-eight healthy subjects received salmeterol 100 mug, salmete rol 100 mug/fluticasone propionate 500 mug and fluticasone propionate 500 m ug via a Diskus dry powder inhaler twice daily for 11 days according to a r andomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 mug on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and g lucose levels] and fluticasone propionate ton 24-h urinary cortisol and mor ning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta (2)-adrenoceptors and beta (2)-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 1 0. Dosing continued on the evening of day 10 and on day 11, and on day 12 t he effect of repeat-dose treatment with salmeterol and salmeterol/fluticaso ne propionate on the systemic effects of cumulative doses of inhaled salbut amol (up to a total dosage of 3200 mug) was evaluated. Results. All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences be tween the single-dose and repeat-dose salmeterol groups. The systemic pharm acodynamic effects of inhaled salmeterol were not affected by the co-admini stration of fluticasone propionate. Eleven days of treatment with salmetero l induced tachyphylaxis to the systemic effects of cumulative doses of salb utamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary co rtisol excretion (22.4 mug compared with 48.6 mug with placebo), but this w as unaffected by the co-administration of salmeterol. Morning plasma cortis ol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta (2)-adrenoceptors and no correlation of beta (2)-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only dur ing the first half-hour after dosing. Go-administration of fluticasone prop ionate did not affect the peak plasma concentration (C-max) of salmeterol. For fluticasone propionate, there were no statistically significant differe nces between salmeterol/fluticasone propionate and fluticasone propionate w ith respect to C-max, plasma concentration at the end of the dosing interva l (C-t), terminal elimination half-life (t(1/2)) Or time to C-max (t(max)). The area under the concentration-time curve within a dosing interval (AUC( t)) for fluticasone propionate after inhalation of salmeterol/fluticasone p ropionate was statistically significantly higher (about 8%) than after inha lation of fluticasone propionate alone (P = 0.0135). However, the 90% confi dence intervals (CIs) for the AUC(t) and C-max ratios for the two treatment s were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). Conclusion: These results in healthy subjects indicate that there is no sys temic pharmacodynamic or pharmacokinetic interaction between inhaled salmet erol and fluticasone propionate when given in combination.