DETERMINATION OF ROBUST OCULAR PHARMACOKINETIC PARAMETERS IN SERUM AND VITREOUS-HUMOR OF ALBINO RABBITS FOLLOWING SYSTEMIC ADMINISTRATION OF CIPROFLOXACIN FROM SPARSE DATA SETS BY USING IT2S, A POPULATION PHARMACOKINETIC MODELING PROGRAM

Robust determination of the concentration-time profile of anti-infecti ve agents in certain specialized compartments is often limited by the inability to obtain more than a single sample from such a site in any one subject, Vitreous humor and cerebrospinal fluid are obvious exampl es for which the determination of concentrations of anti-infective age nts is limited, Advances in pharmacodynamics have pointed out the impo rtance of understanding the profiles of drugs in the plasma and in spe cialized compartments in order to dose the drugs to obtain the best pa tient outcomes, Advances in population pharmacokinetic modeling hold t he promise of allowing proper estimation of drug penetration into the vitreous (dr other specialized compartment) with only a single vitreou s sample, in conjunction with plasma sampling. We have developed a rab bit model which allows multiple samples of vitreous to be obtained wit hout breaking down the blood-vitreous barrier. We have employed this m odel to test the hypothesis that robust estimates of vitreous penetrat ion by the fluoroquinolone ciprofloxacin can be obtained from a tradit ional intensive plasma sampling set plus a single vitreous sample. We studied 33 rabbits which were receiving 40 mg of ciprofloxacin per kg of body weight intravenously as short infusions and from which multipl e plasma and vitreous samples were obtained and assayed for ciprofloxa cin content by high-performance liquid chromatography. Data were analy zed by the iterative two-stage population modeling technique (IT2S), e mploying the iterative two-stage program of Forrest et al, (Antimicrob . Agents Chemother. 37:1065-1072, 1993). Two data sets were analyzed: all plasma and vitreous samples versus all plasma samples and the init ially obtained single vitreous sample, The pharmacokinetic parameter v alues identified were used to calculate the percent vitreous penetrati on as the ratio of the area under the concentration-time curve for the vitreous to that for the plasma, The values identified, 4% penetratio n for the full data set versus 3% penetration for the single vitreous sample data set, and their corresponding estimates were not statistica lly significantly different. We conclude that population modeling hold s promise for the analysis of penetration of antimicrobial agents into specialized spaces from which only single samples can be obtained, pa rticularly for patients with whom robust plasma sampling can be perfor med.