Comparative bioequivalence study between a novel matrix transdermal delivery system of fentanyl and a commercially available reservoir formulation.

AIM: To determine the pharmacokinetics, safety and performance of a novel matrix formulation of fentanyl. METHODS: Transdermal fentanyl was administered as the novel matrix and the Durogesic reservoir formulations (24 subjects, 100 microg h(-1)) in a randomized, fully replicate, four-way crossover study. Serum concentrations of fentanyl were assayed by LC/MS/MS. Pharmacokinetic parameters of fentanyl and performance (adherence and skin irritability) were evaluated. RESULTS: Test/reference ratio (90% confidence intervals) for AUC(0-t), AUC(inf) and C(max) were 105.5% (99.4, 112.0), 105.3% (99.3, 111.6) and 111.4% (100.4, 123.6), respectively. Adherence and skin irritability results of the two formulations were similar. CONCLUSION: The two formulations are expected to result in similar efficacy for the management of severe pain.

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.

The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein.

The objective of this study was to determine the effects of grapefruit juice and seville orange juice on dextromethorphan (DM) pharmacokinetics. Eleven healthy volunteers were studied over a 3-week period consisting of 5 study days each separated by a three-day washout. All subjects refrained from drinking caffeine containing beverages (coffee, soda, etc.) 8 h before orally taking DM (30 mg) with 200 ml water, 200 ml grapefruit juice, 200 ml water, 200 ml seville orange juice, and 200 ml water on Study Days 1 to 5. Aliquots of urine samples were assayed and analysed for DM, and the DM metabolites dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan using a validated HPLC method employing a phenyl column and a fluorescence detection. Results suggests that DM could provide some useful information on P-glycoprotein or related membrane efflux protein activity in the human gastro-intestinal tract. Bioavailability (F) of DM increased significantly with grapefruit and seville orange juice, but only returned to half the baseline value after three days of washout. This confirms that grapefruit and seville orange juice are long-lasting and perhaps irreversible inhibitors of gut CYP3A/P-glycoprotein. Grapefruit and seville orange juice appeared to have the same overall effect on DM pharmacokinetics. In addition, this paper presents a novel method of phenotyping for CYP2D6, CYP3A and P-glycoprotein using DM as a probe.