Illuminating the Path of Treating Chronic Obstructive Pulmonary Disease (COPD): Exploring the PK Profiles of Approved Inhaled Medications

Chronic obstructive pulmonary disease (COPD) is a chronic bronchitis and/or emphysema characterized by airflow obstruction, which can further develop into common chronic diseases. Chronic obstructive pulmonary disease (COPD) is a partially irreversible chronic disease that affects approximately 384 million individuals globally. There are several approved classes of maintenance therapy medications for stable COPD treatment, including β2 agonists, anticholinergic agents, and their combination agents. Over the past two decades, only one COPD medication with a new target (PDE-4), roflumilast, has been approved.

Tiotropium, the first approved LAMA, inhibits smooth muscle cell contraction by inhibiting the binding of acetylcholine to M3 muscarinic receptors. Its structural features contribute significantly to its efficacy in COPD treatment. It also has shown more significant efficacy when used in combination with olodaterol hydrochloride (LABA). Therefore, this blog discusses data on the bronchodilator (tiotropium) and the combination drug (olodaterol hydrochloride) to illustrate the pharmacokinetics (PK) of inhaled bronchodilator medications.

What is the PK profile of tiotropium (LAMA)？

• Absorption: Inhalation is a crucial administration route for tiotropium, allowing the drugs to directly reach the target site in the bronchi and lungs. After inhalation administration, tiotropium is rapidly absorbed and effective, thus providing rapid and effective treatment for COPD’s airway obstruction symptoms.

• Distribution: Tiotropium has extensive tissue binding and no central nervous system distribution. The moderate to high plasma protein binding (PPB) reduces the concentration of free drugs in the systemic circulation, thereby reducing the risk of adverse systemic effects.

•  Metabolism: In vitro studies have shown that two metabolites (N-methylscopine and dithienylglycolic acid) do not enhance the efficacy of tiotropium or alter its safety or tolerability.

• Clearance (excretion): After intravenous injection (IV), 74% of the dose is excreted through the urine in its original form. After dry powder inhalation, 14% of the dose is excreted through the urine. The remaining dose is not absorbed by the intestines and is excreted in feces.

• Drug interactions (DDI): Tiotropium has a low risk of drug interaction (DDI). It does not inhibit cytochrome P450 enzymes 1A1, 1A2, 2B1, 2C9, 2C19, 2D6, 2E1, or 3A4. Additionally, the extremely low systemic exposure further reduces the risk of drug interactions.

Why the drug combination of tiotropium (LAMA) with olodaterol hydrochloride (LABA) is significantly effective for treating COPD

Tiotropium and olodaterol hydrochloride act on the M3 muscarinic receptors and β2 receptors on the airway smooth muscles, respectively, achieving bronchodilatory. They have similar PK profiles, including poor oral absorption, low systemic exposure, and rapid clearance. When the combination of tiotropium and olodaterol hydrochloride is administered by inhalation, the PK parameters of each component are similar to those observed with individual administration.

The key points of the PK profiles of inhaled COPD medications

Using the example of tiotropium inhalation formulation and tiotropium bromide/olodaterol hydrochloride combination inhalation formulation, the PK profiles of inhaled COPD medications were summarized as follows:

• High potency, which meets the requirement for low-dose inhalation administration

• Low gastrointestinal absorption, which reduces the risk of toxicity owing to systemic exposure

• Limited ability to cross the blood-brain barrier, which reduces the impact on the central nervous system

• Rapid clearance from the circulatory system decreases drug exposure to non-target tissues and organs.

Given the widespread prevalence of patients with COPD worldwide, the market prospects for inhaled COPD drugs are promising. Therefore, developing strategies for PK studies on COPD drugs needs more effort in the future.

If you want to learn more details about the PK profiles of inhaled medications, please read the article now.

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