Single‐Dose and Steady‐State Pharmacokinetic and Pharmacodynamic Evaluation of Therapeutically Clinically Equivalent Doses of Inhaled Fluticasone Propionate and Budesonide, Given as Diskus® or Turbohaler® Dry‐Powder Inhalers to Healthy Subjects

Abstract

Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare thePK/PDproperties of clinically equivalent, single, and multiple doses of dry-powder formulations of inhaled fluticasone propionate (FP 200 and 500 microg via Diskus) and budesonide (BUD, 400 and 1,000 microg via Turbohaler). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/ mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes afterinhalation of FP with no influence of dose ordosingregimen. After a single dose of 1000 microg BUD and 500 microg FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP respectively. On average, the area under the curve (A UC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas A UC estimates were 50% to 80% higherforFP at steady state, indicating accumulation. However, the steady-state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP. Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 microg dose and 36% for the 1,000 microg dose). For FP only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 microg dose and 27% for the 500 microg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice-daily doses in healthy subjects, the systemic effects of FP delivered via Diskus on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler.

Analysis of Fenoterol and Ipratropium Transfer from Human Lung Tissue into Human Plasma Using a Dynamic Dialysis Model

“…This is consistent with the report of higher flux rates of continuous flow systems compared to side-by-side systems [8]. The concentration profile in the plasma compartment of our model system was similar to the plasma concentration courses after inhalation of single doses FP by healthy volunteers [16][17][18][19]. In our flow-through system we determined a t max of 0.5h for FP.…”

“…In our flow-through system we determined a t max of 0.5h for FP. The t max values reported in clinical studies varied between 0.3h and 0.6h (doses of 250 and 500µg, respectively, FP [16]), 0.9h (1000µg FP [19]), 1.5h (200 or 500µg FP [17]) and 1-2h (1000µg FP [18]). Thus, the t max data recorded in our model was within the range of reported In vivo results.…”

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach

“…CV is coefficient of variation. Between-subject and betweenoccasion variability (BOV) parameters are based on educated guesses and were selected to match variability in AUC and C max (coefficient of variation ∼50%) that was observed in literature (15)(16)(17)(18). To give the simulations a more realistic framework, BOV terms were considered for F Lung , F C , and k muc as they represent pulmonary parameters that may be expected to vary between occasions that are one week apart (typical timeframe for bioequivalence study including a washout period).…”

“…BOV terms were added to the model to allow simulating PK bioequivalence studies, which are usually conducted in a crossover design. Since BOV estimates for parameters representing pulmonary deposition (F Lung and F C ) are not available in literature, educated guesses were used and optimized by comparing results (AUC and C max ) from preliminary simulations to observed data (15)(16)(17)(18). Moreover, the model predicted width of the confidence intervals for T/ R ratios for AUC and C max (approximately ±10% for a sample size of 40-60 subjects; see BResults^section) agree very well with those from published PK bioequivalence trials for inhaled drugs (21)(22)(23).…”

“…Between-subject variability (BSV) and residual variability terms (RV) were taken from the previously published validated model for FP (13). Between-occasion variability (BOV) terms were based on educated guesses and preliminary simulations where the variability in AUC and C max (coefficient of variation ∼50%) that is typically observed in clinical trials (15)(16)(17)(18) was matched (see BDiscussion^). It should be noted that the outcome of the bioequivalence trials is independent of the selection of the BSV terms as the trials are simulated in a crossover design.…”