Particle size and gastrointestinal absorption influence tiotropium pharmacokinetics: a pilot bioequivalence study of PUR0200 and Spiriva HandiHaler

Abstract

Aims: Plasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva^® HandiHaler^® (HH). The ratio of tiotropium lung-to-oral deposition in PUR0200 was varied to investigate the impact of particle size on tiotropium pharmacokinetics, and the contribution of oral absorption to tiotropium exposure was assessed using charcoal block.

Methods: A seven-period, single-dose, crossover study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in five periods and Spiriva HH in two periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8 h after inhalation.

Results: PUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung-to-oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3 μg tiotropium) lung deposition was similar to Spiriva HH (18 μg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The C_max and AUC_0-0.5h of Spiriva HH with and without charcoal block were bioequivalent; however, Spiriva HH AUC_0-8h was lower when gastrointestinal absorption was inhibited with oral charcoal administration.

Conclusions: Pharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC_0-t than Spiriva HH due to reduced absorption of drug from the gastrointestinal tract.

Keywords: bioequivalence; clinical trials; drug delivery; inhalation.

Figure 1

CONSORT flow diagram. Forty‐two subjects were randomized to one of 14 pre‐defined treatment sequences. All subjects (n = 42) were randomized to receive one of five PUR0200 formulations or Spiriva HH without charcoal administration in six of the seven study periods. In one of the seven study periods, half of the subjects received Spiriva HH without charcoal block and the other half of subjects received Spiriva HH with charcoal block

Figure 2

Aerodynamic particle size distributions and aerosol properties of Spiriva HH and PUR0200. (A) aPSD of Spiriva HH (black bars), PUR0217a (white bars) and PUR0228c (grey bars) using the AIT cascade impaction system. Data represent the mean ± SD (n = 3) for each formulation. AIT depicts the amount of tiotropium recovered from the throat mimetic on the NGI. (B) Aerosol properties of different Spiriva HH lots. The MMAD, tiotropium dose recovered from the AIT (mouth‐throat) and the FPD < 5 μm of 10 different Spiriva HH lots are shown. Boxes show the 25th and 75th percentiles and median, and the whiskers define the minimum and maximum values. The individual data for each lot are shown (●)

Figure 3

PUR0200 formulation design space and comparison to Spiriva HH. (A) Five PUR0200 formulations (■) that varied in aPSD and nominal dose were manufactured and resulted in a design space defined by the FPD < 5 μm and MMAD of each formulation. The MMAD and FPD < 5 μm of nine different Spiriva HH lots (○) and the lot used in the clinical study (●) are shown. (B) The FPD < 5 μm (white bars), ISM (grey bars) and mouth‐throat deposition (M/T; black bars) of each clinical formulation as determined by in vitro cascade impaction. Dotted lines indicate the ISM and mouth‐throat deposition for the Spiriva HH batch used in the clinical study

Figure 4

Plasma concentration versus time profiles of PUR0200 and Spiriva HH. (A) Log‐linear plot and (B) linear‐linear plot of tiotropium plasma concentrations following inhalation of PUR0200; PUR0217a (n = 42; ●), PUR0228a (n = 41; ▲), PUR0228b (n = 41; △), PUR0228c (n = 42; ■) and PUR0230c (n = 42; ▼). (C) Log‐linear plot and (D) linear‐linear plot of tiotropium plasma concentrations following inhalation of Spiriva HH without charcoal block (n = 42; □), PUR0228c (n = 42; ■), Spiriva HH with charcoal block (n = 21; ○) and PUR0217a (n = 42; ●). Data are shown as mean for each group. Data for PUR0217a and PUR0228c are the same in each panel

Figure 5

In vitro‐to‐in vivo correlation of PUR0200 ISM and FPD < 5 μm with plasma exposure. The geometric mean C _max, AUC_0–0.5h or AUC_0–8h of each PUR0200 formulation (●) was plotted against the corresponding (A) ISM or (B) FPD < 5 μm. Data were analysed by linear regression analysis using GraphPad Prism 7. Data for Spiriva HH with (○) and without (□) charcoal block were not included in the regression analysis, but are shown

Figure 6

Equivalence of PUR0217a and PUR0228c to Spiriva HH. The geometric mean ratio (GMR) and 95%CI of C _max, AUC_0–0.5h and AUC_0–8h for each PUR0200 formulation compared to (A) Spiriva HH with charcoal block (○) or (B) Spiriva HH without charcoal block (●)