Treating Chronic Obstructive Pulmonary Disease (COPD): Analysis of 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, such as pulmonary heart disease and respiratory failure, with an increasing incidence rate with age. Chronic obstructive pulmonary disease (COPD) is a partially irreversible chronic disease that affects approximately 384 million individuals globally ¹. According to the World Health Organization’s statistics in 2019, approximately 3.23 million people died from COPD, accounting for approximately 6% of global deaths and making it the third leading cause of death worldwide ².

The causative factors of COPD include smoking, air pollution, kitchen smoke inhalation, airway hyperresponsiveness diseases, and genetic factors. The pathophysiology of COPD is generally associated with oxidative stress, protease-antiprotease imbalances, immune mechanisms, cellular senescence, cell-repair mechanisms, cell necrosis, and autophagy ³.

The diagnosis and treatment of COPD primarily follow the guidelines provided by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Patients with COPD are classified A, B, C, or D based on the severity of airflow limitation (forced expiratory volume [FEV]₁ value), and the nature and severity of their symptoms (mean response time and COPD assessment test) ⁴. The commonly used medications for stable COPD include bronchodilators and anti-inflammatory drugs. Bronchodilators primarily encompass β2 receptor agonists, anticholinergic agents, and methylxanthines, whereas anti-inflammatory drugs mainly comprise glucocorticoids, PDE-4 inhibitors, antibiotics, mucolytics, and antioxidants. This article illustrates the structural characteristics and PK profile of the bronchodilator (tiotropium) and the combination drug (olodaterol hydrochloride).

Overview of medications for stable chronic obstructive pulmonary disease (COPD)

There are nine approved classes of maintenance therapy medications for stable COPD treatment. These include short-acting β2 agonists (SABA), long-acting β2 agonists (LABA), short-acting anticholinergic agents (SAMA), long-acting anticholinergic agents (LAMA), a combination of a SABA and a LAMA (SABA + SAMA), a combination of a LABA and a LAMA (LABA + LAMA), a combination of a LABA and inhaled corticosteroids (LABA + ICS), triple therapy (LABA + LAMA + ICS), and PDE-4 inhibitors. Over the past two decades, only one COPD medication with a new target (PDE-4), roflumilast, has been approved ⁵.

According to GOLD guidelines, for GOLD A or B patients in a stable phase with mild symptoms, LAMAs or LABAs may be administered. LABA + LAMA can be used for the treatment of patients with moderate to severe disease. Compared to monotherapy, dual therapy (LABA + LAMA) considerably improves patient outcomes and reduces COPD exacerbation. For patients with moderate to very severe COPD, triple therapy (LABA + LAMA + ICS) may be used.

Tiotropium, the first approved long-acting anticholinergic drug, continues to play an important role as a first-line treatment for COPD and has shown more significant efficacy when used in combination with olodaterol hydrochloride.

What is tiotropium（LAMA）and its structural characteristics?

According to GOLD guidelines, tiotropium is a long-acting bronchodilator that should be introduced early in the disease trajectory (GOLD II stage). It can also be used consistently in all subsequent stages of COPD (GOLD III and IV stages). Tiotropium is a long-acting anticholinergic drug (LAMA) that inhibits smooth muscle cell contraction by inhibiting the binding of acetylcholine to M3 muscarinic receptors ⁶.

The structural features of tiotropium contribute significantly to its efficacy in COPD treatment (Figure 1). The presence of two thienyl rings enhances the affinity of tiotropium to muscarinic receptors and controls its dissociation half-life. Its high affinity for M3 receptors and its long dissociation half-life make tiotropium a long-acting anticholinergic medication. Similar to its predecessor, ipratropium, tiotropium also contains a quaternary ammonium group, which partially restricts its gastrointestinal absorption and prevents it from crossing the blood-brain barrier. These properties reduce the risk of systemic anticholinergic side-effect and central nervous system toxicity ⁷.

Figure 1. Structure of tiotropium (LAMA)

PK profile of tiotropium (LAMA)

(1)  Absorption of tiotropium (LAMA)

Inhalation administration device: Inhalation is a crucial administration route for tiotropium, allowing the drugs to directly reach the target site in the bronchi and lungs. Tiotropium can be administered by inhalation using an aerosol device.

Tiotropium exhibits low oral bioavailability and high lung deposition in various animal species and humans. The absolute bioavailability of tiotropium in healthy humans is only 2%–3% of the oral dose, with oral bioavailability in mice, rats, rabbits, and dogs being 0.02%, 0.5%, <0.1%, and 6.3%, respectively, indicating poor gastrointestinal absorption ⁸. After inhalation of tiotropium, the absolute bioavailability in healthy humans is 19.5% of the inhaled dose. Approximately 80% of the inhaled Tiotropium dose is swallowed and enters the gastrointestinal tract, while an additional 17% of the inhaled dose reaches the lungs (Figure 2). As the dose reaching the lungs is almost fully bioavailable, while the systemic bioavailability of the total administered dose is low, fewer systemic effects are pharmacologically reflected relatively.

Figure 2. Absorption process of tiotropium after inhalation

Blood drug concentration: After inhalation administration, tiotropium is rapidly absorbed and effective, thus providing rapid and effective treatment for COPD’s airway obstruction symptoms. After inhalation, a small amount of tiotropium enters the systemic circulation for distribution and metabolism. The maximum plasma concentration of tiotropium can be observed within 5 min after inhalation, and the maximum plasma concentration in steady state is 15-19 pg/mL after continuous administration once-daily for 2–3 weeks. Based on maximum plasma concentration (C_max), The area under the plasma concentration time curve (AUC_0-t), and urine excretion data, multiple doses to steady state can result in 2-3 times accumulation, and continued use of tiotropium will not lead to further accumulation⁷ (Figure 3).

Figure 3. Plasma concentration after inhalation administration for 14 consecutive days ⁷

(2)  Distribution of tiotropium (LAMA)

Tiotropium has a volume of distribution of 32 L/kg in humans and approximately 26 L/kg in animals, indicating that the drug has extensive tissue binding and no central nervous system distribution. 72% of tiotropium is bound to human plasma proteins, which is approximately three times higher than that in animal species (15.5%–21.7%). The moderate to high plasma protein binding reduces the concentration of free drugs in the systemic circulation, thereby reducing the risk of adverse systemic effects.

(3)  Metabolism of tiotropium (LAMA)

In vitro studies have shown that the first step of tiotropium metabolism is hydrolysis of the ester bond, which produces two metabolites (N-methylscopine and dithienylglycolic acid). Both of these metabolites are pharmacologically inert and thus do not enhance the efficacy of tiotropium or alter its safety or tolerability. The oxidized metabolites of N-methylscopine are metabolized by CYP2D6 and CYP3A4, which undergo thienyl ring oxidation and subsequent conjugation with glutathione.

(4)  Clearance (excretion) of tiotropium (LAMA)

Drugs that enter the systemic circulation need to be rapidly cleared or excreted to minimize the risk of drug retention in the body. 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. After IV in healthy male subjects, the total clearance of tiotropium is 880 mL/min, with renal clearance at 669 mL/min. The terminal elimination half-life of inhaled tiotropium is 5–6 days.

(5)  Drug interactions (DDI) of tiotropium (LAMA)

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.

Drug Combination: tiotropium (LAMA)/ olodaterol hydrochloride (LABA)

Olodaterol hydrochloride is a LABA, and the combination drug of olodaterol hydrochloride (LABA) with tiotropium (LAMA) was approved by the FDA in 2015 ^9,10. Tiotropium and olodaterol hydrochloride act on the M3 muscarinic receptors and β2 receptors on the airway smooth muscles, respectively, achieving bronchodilatory (see Figure 4).

Figure 4. Mechanism of action of tiotropium (LAMA) and olodaterol hydrochloride (LABA)

Olodaterol hydrochloride and tiotropium have similar PK profiles, including poor oral absorption, rapid onset of action, low systemic exposure, no central nervous system distribution, 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. Human PK data for tiotropium and olodaterol hydrochloride are shown in Table 1.

Table 1. Summary of human pharmacokinetic data for tiotropium and olodaterol hydrochloride

*Inhalation Administration; C_max, maximum plasma concentration; T_max, time to reach the maximum plasma concentration; V_ss, volume of distribution at steady state; CL, total body clearance.

As demonstrated in Figure 5, the combination therapy of olodaterol hydrochloride and tiotropium has more pronounced therapeutic effects than monotherapy 

Figure 5. Comparison of the therapeutic effects of tiotropium and olodaterol hydrochloride in combination therapy vs. monotherapy ¹¹

Conclusions

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 strategies for inhaled medications, please talk to a WuXi AppTec expert today to get the support you need to achieve your drug development goals.

Authors: Qian Li, Lijuan Hou, Lijia Gao, Jing Jin

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