Aims Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral L -dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of L -dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of L -dopa given as standard release L -dopa/carbidopa. Methods Six different doses of L -dopa/carbidopa were investigated in this placebocontrolled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups ( n = 14-16). Two different L -dopa/carbidopa doses were administered to each subject (50/ 12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/ 25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of L -dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(0,12 h) of L -dopa to a similar extent at all doses of L -dopa/carbidopa, that is by about 30-40% compared with placebo ( P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C max values for L -dopa at all L -dopa/ carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of L -dopa were maintained for a longer period at all doses of L -dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-Omethyldopa (3-OMD) to about 55-60% of the placebo treatment level ( P < 0.001, 95% CI -0.72, -0.35) and increased the mean AUC(0,12 h) of 3,4-dihydroxyphenylacetic acid (DOPAC) 2-2.6-fold compared with placebo ( P < 0.001, 95% CI 0.60, 1.10). The mean AUC(0,12 h) of 3-methoxy-4-hydroxy-phenylacetic acid (HVA) following entacapone was approximately 65-75% of that observed with placebo ( P < 0.001-0.05, 95% CI -0.76, -0.01) at each L -dopa/carbidopa dose except the 50/12.5 mg dose ( P > 0.05, 95% CI -0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC L -dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD ( P < 0.001, 95% CI -0.85, -0.68) and HVA ( P < 0.001, 95% CI -1.01, -0.18) in plasma at each L -dopa/carbidopa dose, whereas the AUC DOPAC/AUC L -dopa ratio was increased again at all doses ( P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did L -dopa/carbidopa affect the pharmacokinetics of entacapone.H. Heikkinen et al. 364
Aims The aim of this study was to compare lung deposition of budesonide administered from two dry powder inhalers, Giona® Easyhaler® 200 µg/dose and Pulmicort® Turbuhaler® 200 µg/dose by utilizing a pharmacokinetic method. Methods This was an open, randomized, crossover study in 33 healthy subjects. The study consisted of four treatment periods separated by at least 4 wash‐out days. Equivalence in lung deposition was assessed after a single inhaled 1000 µg (5 × 200 µg) dose of budesonide from Giona® Easyhaler® and from Pulmicort® Turbuhaler®. Concomitant oral charcoal administration (40 g) was used to prevent gastrointestinal (GI) absorption of budesonide. The efficacy of the charcoal was studied after oral administration of a budesonide 2 mg capsule. The subjects were trained to inhale the study drugs with controlled flow rates, which resulted in an equal pressure drop (4 kPa) across both inhalers. Venous blood samples for the determination of budesonide concentrations in plasma were drawn before and at predetermined time points up to 8 h after drug administration. Budesonide concentrations in plasma were determined using liquid chromatography‐tandem mass spectrometry. Several pharmacokinetic parameters were estimated, the area under the budesonide concentration in plasma vs time curve from dosing to infinity (AUC(0, ∞)) being the primary response variable. Equivalence in lung deposition was concluded if the 90% confidence interval (CI) for the Easyhaler® : Turbuhaler® ratio of AUC(0, ∞) fell within the limits of 0.8–1.25. Results The mean AUC(0,∞) value after Easyhaler® treatment was 3.48 (standard deviation (SD) 0.93) ng ml−1 h and after Turbuhaler® treatment 3.46 (1.13) ng ml−1 h. The Easyhaler® : Turbuhaler® AUC(0, ∞) ratio was 1.02 and the 90% CI was from 0.96 to 1.09. The mean Cmax values (SD) for budesonide in plasma after Easyhaler® and Turbuhaler® treatments were 1.22 (0.41) ng ml−1 and 1.29 (0.44) ng ml−1, respectively. There was no statistically significant difference (P = 0.39) between the median tmax for Easyhaler® (30 min) and Turbuhaler® treatment (23 min). Charcoal impaired the GI absorption of budesonide by 96%. The occurrence of adverse events was similar during both treatments. Conclusions The results show that the lung deposition of budesonide from Giona® Easyhaler® 200 µg/dose and Pulmicort® Turbuhaler® 200 µg/dose dry powder inhalers is equivalent. The charcoal block used to prevent GI absorption of swallowed budesonide was found to be effective.
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