Pharmacokinetics of estradiol valerate and medroxyprogesterone acetate in different age groups of postmenopausal women.

OBJECTIVES: To study whether ageing affects the pharmacokinetics of estradiol valerate (E2V) or medroxyprogesterone acetate (MPA) in postmenopausal women. METHODS: Forty-six postmenopausal women from two essentially similar pharmacokinetic studies were divided into three age categories: under 60 years (n = 15), between 60 and 65 years (n = 18) and over 65 years (n = 13). They all were treated for 12 days or 14 days with four galenically identical tablets containing combinations of 1 mg or 2 mg E2V and 2.5 mg or 5 mg MPA. The studies followed an open, randomised cross-over design with no washout between the periods. Serum estradiol and MPA concentrations were measured at steady state on study day 12 or 14 of each period. RESULTS: No statistically significant differences were observed in the peak concentration (Cmax), time to peak (t(max)), AUC or elimination half-life for estradiol or MPA between the different age groups. In spite of the lack of statistical significance the AUC was on an average 1.6-fold and Cmax 1.40-fold higher in the oldest group of women than in the youngest group and age was found significant as a continuous variable for AUC and Cmax for MPA but not for estradiol. CONCLUSIONS: The results suggest that there would be no significant changes in the pharmacokinetics of estradiol between women under 60 and over 65 years of age. However, a significant trend towards higher MPA concentrations and bioavailability was observed with increasing age. The results suggest that from the pharmacokinetic point of view the relationship between estradiol and MPA dose to be used in elderly could be different from that in younger postmenopausal women, while no pharmacokinetic reasons to use lower estradiol doses in the elderly were observed.

Equivalent lung deposition of budesonide in vivo: a comparison of dry powder inhalers using a pharmacokinetic method.

AIMS: The aim of this study was to compare lung deposition of budesonide administered from two dry powder inhalers, Giona Easyhaler 200 microg/dose and Pulmicort Turbuhaler 200 microg/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 microg (5 x 200 microg) 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, infinity)) 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, infinity) fell within the limits of 0.8-1.25. RESULTS: The mean AUC(0,infinity) 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, infinity) ratio was 1.02 and the 90% CI was from 0.96 to 1.09. The mean C(max) 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 t(max) 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 microg/dose and Pulmicort Turbuhaler 200 microg/dose dry powder inhalers is equivalent. The charcoal block used to prevent GI absorption of swallowed budesonide was found to be effective.

Entacapone improves the availability of L-dopa in plasma by decreasing its peripheral metabolism independent of L-dopa/carbidopa dose.

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 placebo-controlled, 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-O-methyldopa (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-dihydroxy-phenylacetic 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. CONCLUSIONS: The 200 mg dose of entacapone similarly and significantly increases the AUC of L-dopa by changing the metabolic balance of L-dopa independent of the L-dopa/carbidopa dose and therefore entacapone is likely to have a similar L-dopa potentiating effect independent of L-dopa dose.