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Methods: An intravenous bolus of vancomycin (20 mg/kg), gentamicin (50 mg/kg), tacrolimus (0.1 mg/kg), mycophenolate (40 mg/kg), cyclosporine (5 mg/kg), phenytoin (10 mg/kg), phenobarbital (30 mg/kg), valproic acid (50 mg/kg), carboplatin (19 mg/kg), cisplatin (3 mg/kg), methotrexate (15 mg/kg), digoxin (0.02 mg/kg), or theophylline (12 mg/kg) was administered into the ear vein (n = 4 – 6) of rabbits. Serial (0 – 72 h post-dose) blood and ISF concentrations (collected via an ultrafiltration probe) were determined by validated analytical assays. Area-under-the curves (AUCs) were generated by non-compartmental pharmacokinetic (PK) analysis.
Results: Vancomycin (mean±SD, 75.3±3.9 vs. 89.8±7.8 μgxh/mL), gentamicin (176.1±22.1 vs. 188.8±18.3 μgxh/mL), and carboplatin (5667.3±716.7 vs. 5004.1±836.9 μgxh/L) showed no significant difference in AUCs in ISF and blood, respectively. Other AUCs were lower (phenobarbital, valproic acid, cisplatin, methotrexate, digoxin, and theophylline) or not measureable (tacrolimus, mycophenolate, cyclosporine, and phenytoin) in ISF with our extraction technique. When a drug was detectable, a reduced Cmax and increased Tmax were evident in ISF, but their concentration-time profiles were similar between the two matrices (except for gentamicin).
Conclusion: Using a comprehensive panel of drugs in a single experimental setting, we have identified agents that can be quantified in ISF. The similarity between concentration-time curves for most drugs in the two matrices suggests feasibility of TDM in ISF. The apparent delayed Tmax can be corrected with pharmacokinetic modeling. Based on these findings, human studies examining feasibility of ISF monitoring are being planned in the clinic. The ultimate goal is to eliminate blood sampling in patients for whom it is difficult.