D. Zhou, J. Li, H. Xu, N. Al-Huniti; AstraZeneca, Waltham, MA

BACKGROUND: Concentrations of antibiotics in epithelial lining fluid (ELF) are critical for the antibiotic activity in pneumonia. Measurement of antibiotic ELF concentration is challenging in patients, especially for pediatrics. The objective of this analysis was to assess the ability of whole body PBPK model to predict lung concentration in human where ceftazidime was used as a model drug.
METHODS: A full PBPK model of ceftazidime was developed using Simcyp (v13, Sheffield, UK) based on its physicochemical properties and clinical observations. The total clearance of 115 ml/min and renal clearance of 110 ml/min were obtained from ceftazidime package insert. Simcyp’s predefined “Healthy Volunteers” (healthy) and “Renal 30-60 ml/min” (moderate renal impairment) populations were applied for sampling of virtual subjects.
RESULTS: The predicted mean plasma Cmax and AUC were 132.5 µg/mL and 434.1 µg/mL.h in healthy subjects after administration of 3 g ceftazidime q8h i.v. infusion, which are very close to the literature reported values (140 µg/mL and 454 µg/mL.h for Cmax and AUC, respectively [1]). The predicted mean plasma concentration of 57.1 µg/mL in moderate renal impairment subjects was also comparable to reported value of 39.6 µg/mL[2] after continous infusion of 4 g ceftazidime. The predicted lung-to-plasma AUC ratio was ~0.40 in both populations, which was comparable to the reported values of, 0.32 [1] and 0.20 [2] in healthy subjects and critically ill renal impairment patients, respectively.
CONCLUSION: The developed PBPK model adequately describes the ceftazidime PK, and reasonably predicted ceftazidime concentration in lung. Current analysis provides a good example of the ability to use PBPK modeling to predict lung penetration of antibiotic drugs.