Prediction of pharmacokinetic parameters of inhaled indacaterol formulation in healthy volunteers using physiologically-based pharmacokinetic (PBPK) model.

ABSTRACT

BACKGROUND: Inhaled formulations are the first choices for treating asthma and chronic obstructive pulmonary disease (COPD), attracting the increasing investment and development in the pharmaceutical industry. Both the equivalence of local and systemic exposures need to be considered when assessing the equivalence of generic inhaled drugs, which has become a dilemma in the development of generic inhaled drugs. There is an urgent need for reliable methods such as physiologically-based pharmacokinetic (PBPK) model to assist in the development of inhaled drugs. METHOD: To test the strategy that in silico simulation is an effective tool in developing inhaled products and further assessing their clinically feasibility, a long-acting beta2-adrenergic agonists indacaterol, which was referred as the first-line therapy for patient with COPD, was selected as a tool drug. The PBPK model was established and the predicted plasma concentration curve was obtained by inputting the physicochemical properties of indacaterol and adjusting model parameters. The accuracy of simulation was verified by an alignment with the actual data. The main factor affecting PK in vivo was investigated by parameter sensitivity analysis. The biological equivalent size of indacaterol was investigated by virtual bioequivalence analysis. RESULTS: The models of indacaterol after intravenous and oral administration were established and confirmed, and used as a background for PBPK model of inhaled administration. All those models showed favorable stability and applicability. Appropriate lung deposition was generated in the PBPK model, and the predicted plasma profile of indacaterol was consistent with the clinical actual observation values. Particle size is the most important factor affecting the PK of indacaterol in vivo. Furthermore, virtual bioequivalence simulation exhibited statistically comparable results between the particle size fluctuates in the range of 3.5-6.5 µm and baseline levels (D90 = 5 µm). CONCLUSIONS: The PBPK model can simulate the pharmacokinetics and lung deposition of indacaterol, which will be a powerful tool to assist the development of inhaled drugs.