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

Abstract

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.

Dual-release formulation, a novel principle in l -dopa treatment of Parkinson’s disease

“…The bioavailability of dual-RF and slow-RF is lower than that of immediate-RF. 2,3,10 The C max of the dual-RF is about 50% that of immediate-RF. This probably explains why these two patients did not switch to "on.…”

“…The most frequent adverse events were dystonia (dual-RF, 11; slow-RF, 10), chorea (dual-RF, 7; slow-RF, 4), sleepiness (dual-RF, 9; slow-RF, 7), and headache (dual-RF, 6; slow-RF, 3). No events caused premature withdrawal.…”

“…To counterbalance this problem, a dual-release formula (dual-RF) has been developed, consisting of threelayer tablets combining immediate-and slow-release properties. [2][3][4] This study compared the clinical effects, pharmacokinetics, safety, and tolerability of the L-dopa and benserazide dual-RF with an equal dose of slow-RF in fluctuating patients with PD. …”

Levodopa

“…Such formulations and delivery routes include dispersible Levodopa preparations or Levodopa prodrugs with high water solubility like Levodopa-methyl-ester and Levodopa-ethyl-ester [52][53][54][55][56] , all aimed at achieving faster peak plasma levels after oral ingestion as well as dual release formulations of Levodopa designed to overcome the delay in C max of sustained released preparations. 57 Enteral infusions of Levodopa bypass the stomach and thus avoid gastric emptying as a factor for delayed and erratic Levodopa absorption. Using infusion pumps they also provide a means of constant Levodopa delivery with similar plasma level profiles to i.v.…”

COMT Inhibition by Tolcapone Further Improves Levodopa Pharmacokinetics when Combined with a Dual-Release Formulation of Levodopa/Benserazide

“…This breakable 3-layer matrix tablet is based on a biphasic drug delivery, which optimizes the levodopa profile – with rapid absorption and sustained concentration thereafter [14, 15]. Compared to slow-RF, the bioavailability of levodopa with dual-RF increases by 45% [14].…”