Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas aeruginosa. Maintaining a high local concentration of inhaled antibiotics for an extended time in the lung is crucial to ensure an adequate antimicrobial efficiency. In this study, we aim to investigate whether an extended exposure of ciprofloxacin (CIP), a model fluoroquinolone drug, in the lung epithelial lining fluid (ELF) could be achieved via a controlled-release formulation strategy. CIP solutions were intratracheally instilled to the rat lungs at 3 different rates, i.e., T0h (fast), T2h (medium), and T4h (slow), to mimic different release profiles of inhaled CIP formulations in the lung. Subsequently, the concentration-time profiles of CIP in the plasma and the lung ELF were obtained, respectively, to determine topical exposure index (ELF-Plasma AUC Ratio, EPR). The in silico PBPK model, validated based on the in vivo data, was used to identify the key factors that influence the disposition of CIP in the plasma and lungs. The medium and slow rates groups exhibited much higher EPR than that fast instillation group. The ELF AUC of the medium and slow instillation groups were about 200 times higher than their plasma AUC. In contrast, the ELF AUC of the fast instillation group was only about 20 times higher than the plasma AUC. The generated whole-body PBPK rat model, validated by comparison with the in vivo data, revealed that drug pulmonary absorption rate was the key factor that determined pulmonary absorption of CIP. This study suggests that controlled CIP release from inhaled formulations may extend the exposure of CIP in the ELF post pulmonary administration. It also demonstrates that combining the proposed intratracheal installation model and in silico PBPK model is a useful approach to identify the key factors that influence the absorption and disposition of inhaled medicine.