Comparative Multiple-Dose Pharmacokinetics of Controlled-Release Levodopa Products

Grahnén, A; Eckernäs, S.‐Å.; Collin, Christine; Ling-Andersson, A.; Tiger, Gunnar; Nilsson, Maj-Inger

doi:10.1159/000116858

Cited by 27 publications

(11 citation statements)

References 6 publications

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“…Overall, the pharmacokinetic findings of levodopa and 3-O-methyldopa in this study are in good agreement with multiple-dose data reported previously for Madopar DR [27]and Madopar HBS [17, 27]. …”

Section: Discussionsupporting

confidence: 92%

“…In healthy volunteers, daily doses of 600 mg (200 mg t.i.d.) of levodopa in the form of Madopar HBS resulted in a high incidence of adverse events probably related to drug administration such as nausea and vomiting [17]. The rationale of the present dosage regimen is based on therapeutic practice in parkinsonians and reduction in the incidence of adverse events previously observed in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

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Comparative Single- and Multiple-Dose Pharmacokinetics of Levodopa and 3-O-Methyldopa following a New Dual-Release and a Conventional Slow-Release Formulation of Levodopa and Benserazide in Healthy Volunteers

Crevoisier¹,

Monreal²,

Metzger³

et al. 2002

Eur Neurol

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The objective was to assess the single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following administration of a new dual-release and conventional slow-release formulation of levodopa/benserazide in the dose ratio of 4:1. In an open-label, two-way cross-over study, 20 healthy volunteers were randomized to receive first either Madopar^® DR or Madopar^® HBS for 8 days. Then they crossed over to the other formulation. A first dose of 200 mg levodopa and 50 mg benserazide (‘250’ mg) was given on day 1, ‘125’ mg t.i.d. on the subsequent 6 days (days 2–7), followed by ‘250’ mg on day 8. The two treatment periods of 8 days were separated by a wash-out period of at least 7 days. Blood samples were taken at specific times over a 12-hour period (day 1) or a 36-hour period (day 8). Plasma concentrations of levodopa and 3-O-methyldopa were measured by high-performance liquid chromatography for pharmacokinetic evaluation. The pharmacokinetics of levodopa after a single-dose administration (day 1) of Madopar DR and Madopar HBS were significantly different as reflected by the respective mean values of maximum plasma concentration (C_max 1.99 vs. 0.82 mg·l^–1), time to reach maximum concentration (t_max 0.7 vs. 2.6 h) and area under the plasma concentration-time curve (AUC_0–∞ 4.52 vs. 3.18 mg·h·l^–1). The respective values after multiple doses (day 8) were: C_max 1.98 vs. 0.93 mg·l^–1, t_max 0.7 vs. 2.3 h and AUC_0–∞ 4.84 vs. 3.96 mg·h·l^–1. The relative bioavailability (Madopar DR vs. Madopar HBS) was 1.73 on day 1 and 1.32 on day 8. Bioequivalence could not be demonstrated for log-transformed data of AUC and C_max within a predefined range of 80–125 and 70–143%, respectively. In conclusion, the observed differences in C_max, t_max and AUC are consistent with a faster rate and higher extent of levodopa absorption after administration of Madopar DR. Statistical evaluation of these kinetic data showed that Madopar DR is not bioequivalent to Madopar HBS.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Comparative Single- and Multiple-Dose Pharmacokinetics of Levodopa and 3-O-Methyldopa following a New Dual-Release and a Conventional Slow-Release Formulation of Levodopa and Benserazide in Healthy Volunteers

Crevoisier¹,

Monreal²,

Metzger³

et al. 2002

Eur Neurol

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“…This value is similar to that reported by Deleu et al (1991) in dogs. The values found in men ranged from 30 min to 2 h (Bredberg et al, 1990, Grahnen et al, 1992, Contin et al, 1993.…”

Section: Discussionmentioning

confidence: 98%

Hydrosoluble fiber (Plantago ovata husk) and levodopa II: Experimental study of the pharmacokinetic interaction in the presence of carbidopa

Fernández

Carriedo

Sierra

et al. 2005

European Neuropsychopharmacology

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Levodopa combined with carbidopa constitutes one of the most frequent medication in the treatment of Parkinson's disease. Plantago ovata husk (water-soluble fiber) improves levodopa absorption conditions, but when this drug is administered with carbidopa, fiber could reduce its effectiveness. The purpose of this study is to investigate whether the presence of P. ovata husk modifies in rabbits the bioavailability and other pharmacokinetic parameters of levodopa (20 mg/kg) when administered by the oral route with carbidopa (5 mg/ kg). We have also studied whether pharmacokinetic modifications are fiber-dose dependent (100 and 400 mg/kg). When levodopa and carbidopa were administered with 100 mg/kg P. ovata husk, the value of AUC for levodopa diminishes 29.7% (sign, n = 6, P b 0.05) and C max 28.1% (sign, n = 6, P b 0.05) in relation to the values obtained when these drugs were administered without fiber. If the dose of fiber was 400 mg/kg, the decrease was smaller: 20.4% for AUC (no significant difference) and 24.6% for C max (sign, n = 6, P b 0.05), that may indicate an inhibitory action of AADC by the fiber or any of its partial hydrolysis products. On the other hand, since certain time on, levodopa concentrations are always higher in the groups that receive fiber: 210 min with 100 mg/kg and 150 min with 400 mg/kg. The administration of P. ovata husk with levodopa/carbidopa to patients with Parkinson disease could be beneficial and in particular in those patients who also suffer constipation due to an improvement of levodopa kinetic profile with higher final concentrations, a longer plasma half-life and lower C max .

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“…The biphasic release properties of the new formulation allow a relatively early peak concentration to be attained which subsequently is maintained within the therapeutic concentration range for several hours. The peak concentration is attained more rapidly than with conventional slow-release formulations such as Madopar ® HBS and Sinemet ® CR [19]. To reduce the incidence of adverse events, it is usually advised to administer levodopa-containing formulations after a meal.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Studies with a Dual-Release Formulation of Levodopa, a Novel Principle in the Treatment of Parkinson’s Disease

Dingemanse¹,

Kleinbloesem²,

Crevoisier

et al. 1998

Eur Neurol

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The objectives of the two studies reported here were the investigation of the influence of tablet breaking and food on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new levodopa/benserazide formulation with a biphasic drug delivery profile (Madopar^® DR). Both studies had an open-label, randomised, two-way crossover design and were conducted in 12 healthy young subjects. The pharmacokinetics of levodopa and 3-OMD after one intact or two halved tablets were very similar with average C_max and t_max 1.9 mg·l^–1 and 1.2 h, respectively. Administration of the formulation after a standard breakfast did not influence the extent of levodopa absorption but increased the absorption rate. C_max and t_max were on average 2.1 mg·l^–1 and 1.3 h, respectively, in the fed condition and 1.5 mg·l^–1 and 2.5 h in the fasted condition. The presence of food did not markedly affect the plateau in levodopa levels between about 1 and 3 h after intake. In conclusion, the release characteristics in healthy subjects of the new levodopa/benserazide formulation are influenced only to a minor extent by concomitant intake of food or by tablet breaking.

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Comparative Multiple-Dose Pharmacokinetics of Controlled-Release Levodopa Products

Cited by 27 publications

References 6 publications

Comparative Single- and Multiple-Dose Pharmacokinetics of Levodopa and 3-O-Methyldopa following a New Dual-Release and a Conventional Slow-Release Formulation of Levodopa and Benserazide in Healthy Volunteers

Comparative Single- and Multiple-Dose Pharmacokinetics of Levodopa and 3-O-Methyldopa following a New Dual-Release and a Conventional Slow-Release Formulation of Levodopa and Benserazide in Healthy Volunteers

Hydrosoluble fiber (Plantago ovata husk) and levodopa II: Experimental study of the pharmacokinetic interaction in the presence of carbidopa

Pharmacokinetic Studies with a Dual-Release Formulation of Levodopa, a Novel Principle in the Treatment of Parkinson’s Disease

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