Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension

Abstract

A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.

Translational Model to Predict Pulmonary Pharmacokinetics and Efficacy in Man for Inhaled Bronchodilators

“…The successful extrapolation of the approach to predict the efficacy of inhaled bronchodilators to other target sites remains to be seen but we speculate that similar findings are anticipated when lung smooth muscle tissue is involved in combination with soluble compounds, as is the case for the studied bronchodilator drugs and recent pulmonary administered platelet‐derived growth factor receptor inhibitors . In cases of pulmonary administration of poorly soluble compounds, physiologically based pharmacokinetic approaches may offer a better alternative than the presented compartmental approach, because processes like mucociliary clearance are more easily modeled.…”

“…Their preclinical compartmental rat model was scaled to make reasonable predictions for the plasma exposure after inhalation of various neutral and basic drugs in humans. However, it only allowed for a mono‐exponential decline in pulmonary drug levels, which is an oversimplification, in particular for basic compounds . In addition, no further attempt was made to predict the actual lung concentrations, a consequence of the absence of any lung PK data in the model development.…”

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms

“…As the absorption of small drug molecules is frequently rapid following inhalation, (1) inhaled drugs need optimization of molecular structure and/or formulation to be retained in the lung for a sufficient period of time to allow for a sustained local effect. (2,3) Retention of total drug in the lung, however, as determined from preclinical in vivo experiments or clinical pharmacoki-netic (PK) studies, does not provide any information regarding the actual levels of free and pharmacologically active drug in the lung tissue. (4) Neither does it reveal how the exposure varies between the different lung regions and, most importantly, how this compares with the free levels in blood, that is, regional targeting.…”

“…In fact, there are no experimental methodologies available to do this, although indirect approaches such as target occupancy have been employed. (3,5) The inability to define the target site concentration(s) of inhaled drug even in preclinical species clearly poses a huge challenge for developing inhaled drug treatments with the objective of optimizing drug potency and targeting of relevant lung structures. Currently used methodologies to evaluate inhaled drug pharmacology and predicting therapeutic dosing in man seem to still largely depend on doseresponse studies in preclinical species with functional readouts at the level of the lung as a whole.…”

A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

“…Obviously, this assumption cannot be made for a targeted drug after inhaled delivery. We note that indirect approaches, such as target occupancy, have been used 3, 4, 5. However, these methods are target specific, time demanding to develop, and do not currently provide a high regional resolution.…”