adjustment of the study design taking into account the receipt of primary data

This is a pilot Phase I open-label randomized single-dose two-period crossover study (in the EDDIS project) evaluating the bioequivalence, pharmacokinetics (PK), safety, and tolerability of inhaled afatinib dimaleate compared with the reference oral afatinib dimaleate in healthy volunteer smokers.

The study will enroll healthy adult volunteers smoker to assess the systemic exposure and lung deposition of inhaled afatinib dimaleate. Participants will receive both the test inhaled formulation and the reference oral formulation in separate periods with delayed phase between treatments.

Key endpoints include maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), and lung deposition assessed via bronchoalveolar lavage (BAL), frequency of occurrence of side effects and cases of toxicity during the studies

Participants will receive either a single dose of inhaled afatinib dimaleate or a 40 mg oral dose of afatinib dimaleate in a randomized sequence, with a 7-day washout period between treatments.

The inhaled formulation of afatinib dimaleate is administered via a single-use, maintenance-free ultrasonic nebulizer (by SWITZERLAND TEAM) that generates aerosol particles of a defined size, ensuring predictable bioavailability and targeted alveolar deposition. Each inhalation session consists of a predefined number of physiological breaths, facilitating efficient drug uptake into the lungs at therapeutically relevant doses.

Key assessments include blood sampling for pharmacokinetic (PK), LC-MS/MS, analysis, bronchoalveolar lavage (BAL) to evaluate pulmonary drug deposition, and spirometry to assess pulmonary safety.tests, CT.

The investigators aim to obtain data on the role of pulmonary P-glycoprotein (P-gp) transporters in actively expelling afatinib dimaleate back into the alveolar space, as well as its metabolism by cytochrome P450 enzymes (CYP3A4) during inhalation.

Additionally, statistically significant data on both drug lung deposition (DLD) and drug-induced lung injury (DILI) will be analyzed.

Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-∞), will be evaluated through plasma sampling. BAL will be performed in a subset of participants to assess direct pulmonary drug deposition. Safety and tolerability will be monitored through adverse event reporting, laboratory testing, and spirometry.

Inclusion Criteria:

• Healthy male and female volunteers aged 21 to 55 years
• Body mass index (BMI) from 18.5 to 30.0 kg/m²
• Smokers or people who use e-cigarettes or vapes
• No history of serious lung disease or respiratory disorders
• No history of EGFR-targeted therapy or chemotherapy
• Ability to give informed consent and comply with study procedures

Exclusion Criteria:

• Pregnancy or lactation. (for female participants - 2 negative tests 10 days and 3 days before the start of the study)
• Significant cardiovascular, hepatic, renal or neurological disorders. (ECG 30 days or earlier before the start of the study)
• Recent use of any study drug (within 30 days) or prescription drugs that may affect the metabolism of afatinib
• Known hypersensitivity to afatinib, its salts or derivatives of afatinib or related compounds
• Рarticipation in other studies