Lung Cancer, Melanoma, Oral Cancer
Conditions
Keywords
Afatinib Dimaleate, BIBW2992 Dimaleate, GIOTRIF, GILOTRIF
Brief summary
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
Detailed description
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.
Interventions
DRUGAfatinib Dimaleat
printed capsule containing 40 mg afatinib dimaleate
BIOLOGICALinhalation of afatinib dimaleate
inhalation stable form of afatinib dimaleate at an equivalent therapeutic dose in a single-use maintenance-free ultrasonic inhaler with controlled frequency and number of inhalations
Sponsors
Petrov, Andrey
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be randomly assigned to receive inhaled or oral Afatinib Dimaleate treatment first, followed by a washout period, after which they will receive the alternative treatment Participants will receive either a single dose of inhaled afatinib dimaleate or 40 mg of oral afatinib dimaleate in a randomized sequence with a 7-day washout period between treatments. Inhaled afatinib dimaleate (liquid) is delivered using a maintenance-free, single-use ultrasonic nebulizer that generates aerosol particles of a defined size with the most efficient gas-dynamic characteristics for alveolar deposition. Each inhalation session consists of a defined number of breaths, which ensures the most efficient uptake of afatinib dimaleate aerosol in the lungs.
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax (maximum observed plasma concentration) | up to 48 hours post-dose | quantitative measurement of afatinib dimaleate in plasma |
| afatinib dimaleate urinary concentrations | up to 96 hours | quantitative measurement of afatinib dimaleate in urine of inhaled and oral afatinib dimaleate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC (Area Under the Plasma Concentration-Time Curve) | up to 48 hours post-dose/inhalations | the total afatinib dimalete exposure integrated over time |
Countries
New Zealand
Outcome results
None listed