“The main advantages of inhalation models are inherent to the direct delivery of active agents into the airways. As a result, inhalation is most beneficial for therapeutics targeted at either the airways or the pulmonary vasculature.

“It all comes down to balancing therapeutic effects with adverse reactions. Current thinking has it that the highest concentrations achieved at the site of injury/dysfunction will produce the highest efficacy for the therapeutic. In contrast, the exposure of healthy parts of the body could result in secondary pharmacology leading to undesirable effects. So pharmacologists must aim to increase the exposure levels in the dysfunctional tissues, while minimizing the exposure of the rest of the body, i.e. targeted delivery. While it is difficult to target internal organs, the lungs are readily accessible via inhalation.

“In the case of airway dysfunction such as bronchial hyperreactivity, asthma, fibrosis, etc., the delivery of an active agent into the alveoli should result in therapeutic efficacy, however one defines this. There is no need to transition from the alveolar surface to the adjacent vasculature; the site of action of the therapeutic is actually within the alveoli or underlying parenchymal tissues. In the case of pulmonary vascular dysfunction such as pulmonary arterial hypertension, for instance, the active ingredient needs to be inhaled and propelled into the alveoli, and then transition from the alveolar surface into the underlying vessels. This adds one level of complication at the time of formulating the active ingredient for inhalation.

“The bottom line is that in relation maximizes exposure within the lungs (and into the pulmonary vasculature if formulated properly), while minimizing the systemic exposure which could result in adverse effects.

“The change in administration paradigm involves a new pharmacokinetics profile; the PK properties associated with an oral or intravenous administration differ significantly from those of an inhaled formulation. Systemic circulating levels increase rapidly in the case of oral or intravenous administration, while the opposite is hopefully true in inhalation; the aim is to keep the active ingredient within the lungs for as long as is necessary to achieve maximum efficacy, and actually have as little active ingredient as possible transition into the bloodstream where it can affect other organs.

“At IPST, we pair our initial inhalation delivery runs with measurements of exposure in the lungs and in the blood. Normally, as material disappears from the lungs, it will appear in the bloodstream, and be eliminated by either the liver or the kidneys or a combination of both. Following the initial tests, adjustments are made to the concentration of active ingredient in the inhaled formulation, to achieve the pulmonary exposure which has been shown in the past to be efficacious. In parallel, adjustments are also made to the particulate size in order to maximize the delivery of active ingredient to those areas of the lungs where the therapeutic effect is necessary. Smaller particle sizes translate into successful delivery of the active ingredient deeper into the lungs, while larger particle sizes tend to travel less readily. Finally, the nature of the excipient or formulation ingredients used is also adjusted to maximize the residence time within the lungs in order to achieve the greatest efficacy possible.

“While juggling these parameters (concentration, particle size, formulation ingredients) and optimizing the ventilation conditions, repeat PK studies guide our efforts. Once all conditions have been optimized, we moved to pharmacodynamics monitoring, to ascertain whether greater efficacy has been achieved through targeted delivery. A PK/PD relationship is established for the inhaled formulation. This is usually followed by an assessment of adverse effects, short of toxicity. Functional measurements are made which monitor any secondary pharmacology to demonstrate enhanced efficacy on the one hand, and minimized adverse effects on the other.

“Altogether, switching a oral or intravenous administration program to inhalation can take as little as four weeks. A well designed strategy involves defined milestones, scheduled pauses to analyze the progress of the effort. When the ability to enhance the inhalation parameters (including formulation) is combined with the ability to measure both efficacy and safety for a new formulation, administration conditions are generally achieved which open up interesting therapeutic windows in innovative new drugs, as well as existing ones which were administered by more traditional routes.

Dan Salvail is (almost) always at the office. Usually, a quick and informal call is sufficient to make quite a bit of progress on a tentative strategy or study design.

T: +1.819.820.1515 / dsalvail@ipstherapeutique.com