A population pharmacokinetic-metabolism model for individualizing ciprofloxacin therapy in ophthalmology.
The purpose of this study was to construct a population pharmacokinetic (PK) metabolism (MB) model to describe ciprofloxacin (C) concentrations in plasma and vitreous and aqueous humors in 26 patients. Ciprofloxacin was given as a 3-day oral prophylactic treatment to 26 patients before vitrectomy. Plasma, vitreous, and aqueous humor samples were collected from patients at different times on the day of surgery. Patients were phenotyped for CYP 1A2 activity using caffeine. Ciprofloxacin and caffeine concentrations were determined using validated HPLC assays. All concentrations of ciprofloxacin were simultaneously modeled using a four-compartment PK-MB model. Creatinine clearance and CYP 1A2 activity were modeled as surrogate markers of renal and hepatic clearances, respectively. Population PK was performed with IT2S, and simulations were performed with ADAPT-II. No eye infections were observed in any of the patients enrolled in the study, and there were only minimal effects on vitreous and aqueous concentrations after ocular drops were added to the oral treatments. The model that best described the concentrations of ciprofloxacin in serum and in aqueous and vitreous humor was a four-compartment PK linear model. Simulated AUCs of ciprofloxacin mean concentrations in the aqueous and vitreous humors were 17 +/- 9 and 10 +/- 8% of the systemic AUC, respectively. The terminal elimination half-life of the compound was (mean +/- SD) 5.0 +/- 2.8 hours. The apparent volume of distribution (Vss/F) was calculated to be 122.1 +/- 39.7 L. This PK-MB model may be very useful in optimizing treatments of various eye infections with ciprofloxacin. The results of this study suggest that giving ciprofloxacin orally for 2 days preceding surgery may prevent endophthalmitis from occurring, consequently abrogating the need for administering antibiotics via intraocular injections.
Di Marco
Marika Pasternyk
MP
Faculté de Pharmacie, University of Montreal, Montreal, Canada.
Chen
John
J
Wainer
Irving W
IW
Ducharme
Murray P
MP
D000284:Administration, Oral; D000287:Administration, Topical; D000368:Aged; D000890:Anti-Infective Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009883:Ophthalmic Solutions; D010641:Phenotype; D013997:Time Factors; D014821:Vitrectomy
D000890:Anti-Infective Agents; D009883:Ophthalmic Solutions; D002939:Ciprofloxacin; D019388:Cytochrome P-450 CYP1A2