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Comforts and Concerns in PK-based Bioequivalence Studies of Inhalation Products

PRESENTED TO:  AAPS PharmaSci 360 Annual Meeting 2018
PRESENTED BY:  N. Rayad, J. He.


▪ Generic orally-inhaled products (OIPs) are warranted as safe, effective and affordable medications.

▪ Regulatory agencies – far from harmonized – require in vitro, in vivo PK, and/or PD studies to demonstrate bioequivalence (BE)/therapeutic equivalence (TE) to innovator products:

o FDA → weight-of-evidence approach (PK is one component).
o EMA → a stepwise approach (PK with charcoal blockade).
o Health Canada → aggregated evidences (similar to FDA’s).

BioPharma Services Inc. (BPSI) has a proven track record and extensive experience with PK-BE studies for OIPs.



1. Highlight the prominent PK properties of some OIPs.
2. Investigate the variability of OIPs in PK/BE clinical trials.
3. Summarize BPSI experience, designs and challenges in PK/BE.
4. Identify the safety profiles (in terms of AEs).
5. Highlight regulatory guidelines for these complex generics.


  • Spacer for pMDIs
    ▪ VHC (AeroChamber plus valved holding chamber) & VS (Volumatic spacer); both:
    → reduced total systemic exposure by 38% and 68%, respectively compared to no spacer use (fig 1).
    → showed high inter-subject CV%, yet ISCV% was slightly lower for VS compared to VHC.
    ▪ VHC was superior to VS in terms of:
        ▪ Absorption (46% higher exposure; fig 1).
        ▪ Passing BE criteria.
  • Bioequivalence Study Design, PK profiles & BE comparisons
    Design: 2-way crossover; replicate design (for HVD); and two stage design (for attaining sufficient statistical power).
    ▪ T and R comparison → based on rate (Cmax and Tmax) & extent (AUCt) of absorption.
    ▪ Cmax → as early as 6 min with salmeterol, formoterol, budesonide and tiotropium; the Tmax was around 1h for fluticasone.
    Partial AUC0-30 → surrogate for efficacy if very quick lung absorption precludes significant gut absorption (e.g. salmeterol).
  • Charcoal Blockade resulted in:
    Formoterol: reduced enteral absorption of a proportion of inhaled drug (fig 2 and 3).
    Budesonide: almost same exposure as without charcoal.

Table (1): PK parameters (mean ±S.D.) of different inhalation drugs


Inhalation Drugs AUC0-30 (pg.h/mL) AUinf (pg.h/mL) Cmax (pg/ml) Tmax (H) Lambda (1/H) T1/2 (H)
Budesonide 230±160 1290±747 665±479 0.2±0 0.192±0 3.8±1
Formoterol 4±2 39±24 12±8 0.1±0 0.08±0 10±3
Fluticasone NA 1400±565 193±68 0.9±0 0.07±0 13±2
Salmeterol 64±20 406±116 247±142 0.06±0 0.05±0 14±4
Tiotropium NA 85±69 9±5 9±0 0.03±0 40±35

*AUCt is AUC 0-72


  • Drugs studied were fluticasone, salmeterol, budesonide, formoterol, tiotropium bromide and combinations thereof.
  • PK-BE studies were conducted on total of 580 NHVs; design/scope shown below:

Scope of PK/BE studies at BPSI 

    • Mono & combo inhalation products
    • Metered-dose & dry-powder inhalers (pMDIs or DPIs)
    • Charcoal blockade (with & without charcoal)
    • Different types of spacers (VHC and VS)
    • Two-way crossover, adaptive (2-stage) or fully replicate design
Pk profiles of fluticasone & salmeterol upon inhalation of Seretide Evohaler pMDI using different spacers.
Mean reduction in PK parameters by means of charcoal blockade on formoterol absorption from Symbicort DPI
PK profiles showing the effect of charcoal blockade on formoterol absorption upon inhalation of Symbicort DPI

(Comforts & concerns – BPSI experience):

  • Subjects and staff training and standardized inhalation technique were optimized for lung deposition of drug and reduced variability; such as the following:
    MDI, a steady and gentle inhalation in coordination with actuation.
    DPI, rapid, forceful and deep inhalation.
  • High variability: batch-to-batch variability; hooked on a formulation and active agent; the sample size and study design (adaptive, replicate and finally a 2-way crossover)

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