Drug targeting in pulmonary sub-epithelial compartments predicted through systems pharmacology modelling
Elin Boger
RIA, IMED Biotech Unit, AstraZeneca R&D Gothenburg, Sweden
Objectives: Although a higher plasma exposure is observed after oral than inhaled dosing of salbutamol (2 mg and 400 µg, respectively), a higher pharmacological effect is obtained after inhalation [1-3]. This analysis aimed to evaluate if a newly developed inhalation PBPK-model could rationalize why inhaled salbutamol produces a higher pharmacological effect.
Methods: A whole-body inhalation PBPK-model, which places emphasis on mechanistically describing important processes for inhaled drug disposition was developed and implemented in MATLAB. Intratracheal (IT) and IV-administration of salbutamol to rats were simulated using drug-specific input parameters from AstraZeneca’s internal data-base. A single parameter, the membrane permeability P, was adjusted to fit the observed lung concentration profile after IT-delivery. The PK was subsequently translated from animal to man by: 1) switching from rodent to human physiological parameters, 2) using human PK-parameters [1, 4], and 3) considering inter-species differences in the regional deposition pattern.
Results: The developed model could describe the plasma PK after inhaled (400 µg) and oral administration (2 mg) of salbutamol in man, demonstrating that a higher plasma exposure is expected after the oral route. The model predicted a spatial heterogeneity in the free target site concentrations (sub-epithelium) of salbutamol after inhaled drug delivery with higher free levels in the lung as compared to the plasma. On the contrary, the free drug concentrations were predicted to be similar throughout the lung as well as in the plasma after oral administration.
Conclusions: The model could reproduce a lung-selective drug exposure of salbutamol, which has been indicated by results in clinical trials. The predicted free concentrations in the sub-epithelium (the effect site) after inhaled and oral treatment were in line with reported FEV1 measurements [2-3]. Interestingly, the model predicts a spatial heterogeneity of free drug concentrations in the lung. This has important implications for drug discovery programmes targeting the lung as it suggests that the lung should be treated as a heterogeneous organ during PK/PD-analyses.
References:
[1] Ward et al., Br J Clin Pharmac, 49(1), 15-22, 2000
[2] Singh et al., BMC Pulm Med, 14(176), 2014
[3] Willey and Grant, Br J Clin Pharmac, 3(4), 595-600, 1976
[4] Morgan et al., Br J Clin Pharmac, 22(5), 587-593, 1986