Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies. / Shi, Changzhi; Ignjatović, Jelisaveta; Wang, Junwei; Guo, Yi; Zhang, Li; Cvijić, Sandra; Cun, Dongmei; Yang, Mingshi.
In: Chinese Chemical Letters, Vol. 34, No. 1, 107463, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies
AU - Shi, Changzhi
AU - Ignjatović, Jelisaveta
AU - Wang, Junwei
AU - Guo, Yi
AU - Zhang, Li
AU - Cvijić, Sandra
AU - Cun, Dongmei
AU - Yang, Mingshi
N1 - Funding Information: This work was financially supported by the Liaoning Pan Deng Xue Zhe Scholar (No. XLYC2002061), the National Natural Science Foundation of China (No. 81573380 ), and the Overseas Expertise Introduction Project for Discipline Innovation (“111 Project”) (No. D20029 ). D.Cun acknowledges financial support from the Guiding Project for Science and Technology of Liaoning Province (No. 2019-ZD-0448), and Ministry of Education Chunhui Program (2020). The authors acknowledge support from Ministry of Education Science and Technological Development , Republic of Serbia (No. 451-03-9/2021-14/200161 ). Publisher Copyright: © 2022
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Ciprofloxacin
KW - Controlled release
KW - Inhalation antibiotics
KW - Lung infections
KW - PBPK modeling
U2 - 10.1016/j.cclet.2022.04.061
DO - 10.1016/j.cclet.2022.04.061
M3 - Journal article
AN - SCOPUS:85139728347
VL - 34
JO - Chinese Chemical Letters
JF - Chinese Chemical Letters
SN - 1001-8417
IS - 1
M1 - 107463
ER -
ID: 324318730