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Hindawi Publishing Corporation Parkinson’s Disease Volume 2015, Article ID 369465, 7 pages http://dx.doi.org/10.1155/2015/369465 Clinical Study L-Dopa Pharmacokinetic Profile with Effervescent Melevodopa/Carbidopa versus Standard-Release Levodopa/Carbidopa Tablets in Parkinson’s Disease: A Randomised Study Fabrizio Stocchi,1 Laura Vacca,1 Paola Grassini,1 Stephen Pawsey,2 Holly Whale,2 Stefano Marconi,3 and Margherita Torti1 1 Institute of Neurology, IRCCS San Raffaele, Via della Pisana 235, 00163 Rome, Italy 2Vernalis (R&D) Ltd., Reading Road, Winnersh, Berkshire RG41 5UA, UK 3Chiesi Farmaceutici SpA, 43100 Parma, Italy Correspondence should be addressed to Fabrizio Stocchi; [email protected] Received 12 March 2015; Revised 5 May 2015; Accepted 18 May 2015 Academic Editor: Jan O. Aasly Copyright © 2015 Fabrizio Stocchi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objectives. To characterize the pharmacokinetic profile of levodopa (L-dopa) and carbidopa after repeated doses of the effervescent tablet of melevodopa/carbidopa (V1512; Sirio) compared with standard-release L-dopa/carbidopa in patients with fluctuating Parkinson’s disease. Few studies assessed the pharmacokinetics of carbidopa to date. Methods. This was a single-centre, randomized, double-blind, double-dummy, two-period crossover study. Patients received V1512 (melevodopa 100 mg/carbidopa 25 mg) or L- dopa 100 mg/carbidopa 25 mg, 7 doses over 24 hours (Cohort 1), 4 doses over 12 hours (Cohort 2), or 2 doses over 12 hours in combination with entacapone 200 mg (Cohort 3). Pharmacokinetic parameters included area under the plasma-concentration time curve (AUC), maximum plasma concentration (max), and time to max (max). Results. Twenty-five patients received at least one dose of study medication. L-dopa absorption tended to be quicker and pharmacokinetic parameters less variable after V1512 versus L-dopa/carbidopa, both over time and between patients. Accumulation of L-dopa in plasma was less noticeable with V1512. Carbidopa exposure and interpatient variability was lower when V1512 or L-dopa/carbidopa was given in combination with entacapone. Both treatments were well tolerated. Conclusions. V1512 provides a more reliable L-dopa pharmacokinetic profile versus standard-release L-dopa/carbidopa, with less drug accumulation and less variability. This trial is registered with ClinicalTrials.gov NCT00491998. 1. Introduction bioavailability, and short half-life, play an important role in the occurrence of fluctuations9 [ , 10]. Levodopa (L-dopa) plus peripheral dopa-decarboxylase In order to reach its site of absorption in the small inhibitor (carbidopa or benserazide) is the mainstay of intestine, orally administered L-dopa has to pass through therapy in Parkinson’s disease [1]. However, motor and non- motor complications emerging during chronic treatment thestomachandthusisreliantongastricemptying,whichis become increasingly more common with advancing disease often delayed in Parkinson’s disease patients due to the effects [2, 3]. Complications, dyskinesias and response fluctuations, of the disease, its treatments, and dietary intake [11–14]. include end-of-dose wearing “off,”sudden “on”/“offs,”delayed Gastric akinesia is common in advanced Parkinson’s disease time to “on,” and response failures [4]. Factors interfering and may lead to rapid rises in plasma L-dopa concentrations with L-dopa delivery and absorption may induce motor when delayed gastric emptying results in an oral dose of L- fluctuations [5–8]. Thus, limitations in the physical prop- dopa sitting in the stomach for some time before it passes into erties and pharmacokinetics of L-dopa, poor solubility, low the duodenum where it is immediately absorbed [15]. This 2 Parkinson’s Disease “dose-dumping” effect is hereafter referred to as “apparent determined by the investigator and no other L-dopa therapies accumulation.” Another problem that hinders optimal were permitted. In practice, most patients were already absorption of oral L-dopa is poor solubility when formulated established on a suitable stable dose of L-dopa/carbidopa at as a tablet [15]. Compared with conventional tablets, L-dopa recruitment and thus did not undergo a formal run-in period. solutions pass more easily through the stomach thereby In the double-blind phase, patients were assigned to one of ensuring better absorption, but their use is limited by poor three treatment cohorts based on the patient’s usual dosing aqueous solubility and degradability of L-dopa in solution regimen: the first dose of study medication was administered [16]. to patients at 08:00 hours, and subsequent doses were admin- V1512 is an effervescent tablet formulation of L-dopa istered every 2 hours for patients in Cohort 1 (total of 6 doses methyl ester (also known as melevodopa) and carbidopa. over 12 hours) and every 3 hours for patients in Cohorts 2 and Melevodopa is approximately 250 times more soluble than 3 (4 doses over 12 hours (see Supplementary Table 1 available L-dopa, allowing rapid and complete dissolution, and the online at http://dx.doi.org/10.1155/2015/369465)). Levodopa resulting solution rapidly reaches the absorption site [17]. was administered every 2 hours with the goal of obtaining a Furthermore, at physiological pH, melevodopa exists in constant levodopa level and every 3 hours to mimic the most the nonionized form whereas L-dopa exists in the ionized common clinical practice in patients with motor fluctuations. from, and the resulting greater lipophilicity of melevodopa EntacaponewasgiventoCohort3every4hoursforthe enhances its absorption across the intestinal wall [17]. Studies same reason. Within each cohort, patients were randomized performed in animals and humans have shown complete pre- (computer-generated randomization with a block size of 4) hepatic hydrolysis to L-dopa and rapid intestinal absorption to receive V1512 solution plus placebo tablets in the first that is not influenced by gastric pH [16, 18–20]. These factors treatment period followed by L-dopa/carbidopa tablets plus suggestthattheonsetofactionofmelevodopashouldoccur placebosolutioninthesecondtreatmentperiod,orviceversa. sooner compared with conventional oral L-dopa formula- Patients in Cohort 3 also received 200 mg entacapone (Com- tions, and this has been confirmed in clinical studies21 [ , 22]. tan;Novartis,OrionPharma,Basel,Switzerland)witheach The primary objective of this study was to characterize dose of active treatment. The treatment sequence allocation the pharmacokinetic profile of L-dopa after repeated doses was concealed from the investigator. The two double-blind of V1512 compared with standard-release L-dopa/carbidopa treatment periods were separated by a 2-day washout, during tablets in patients with fluctuating Parkinson’s disease. which patients received the same standardized regimen they had received during the run-in phase (or their usual Parkin- 2. Methods son’s treatment if they did not undergo a run-in period). Investigators at site were responsible for enrolling patients The study was conducted at the Institute for Research and into the trial; a pharmacist was responsible for assignment of Medical Care in San Raffaele, Rome, Italy, after approval by patients to treatment interventions and the study drug was the Ethics Committee and was performed in accordance with administered by a study nurse. The active V1512 and placebo the Declaration of Helsinki and Good Clinical Practice. V1512 effervescent tablets were identical in appearance and produced solutions with the same appearance and taste. 2.1. Patients. Eligible patients were aged >30 years with a However, the placebo L-dopa/carbidopa tablet was slightly 2 body mass index (BMI) of 18.5–29.9 kg/m inclusive and different in appearance to the active L-dopa/carbidopa tablet a clinical diagnosis of Parkinson’s disease according to the (in terms of markings) and thus, each tablet was placed in Brain Bank criteria [23]. Patients had motor performance a narrow opaque tube for administration to the patient. The fluctuations with >2 hours total daily “off” and ≥1hourdelay patient, investigator, Medical Monitor, and Clinical Monitor to “on” time with afternoon doses and were permitted to take remained blinded, whereas the site pharmacist and the other Parkinson’s therapies (dopamine agonists, monoamine nurse who administered study medication had access to the oxidase-B inhibitors) provided the doses had been stable randomization list. for at least 2 weeks before study entry. Other comorbidities Patients remained in the study unit during treatment hadbeenstableforatleast4weeksandfemalesweretobe days, treatment administration was supervised, and all were of nonchildbearing potential. Patients were informed of the given standardized low-protein meals. Each dose of V1512 objectives, procedures, and risks of study participation and was a single effervescent tablet (125.6 mg melevodopa (equiv- gave written informed consent. alent to 100 mg L-dopa) and 25 mg carbidopa) dissolved in 150 mL water, which was ingested at the same time as a 2.2. Study Design. In this single-centre, randomized, double- placebo tablet. During the other treatment period, an L- blind, double dummy, two-period, crossover study, subjects dopa/carbidopa standard-release tablet (containing 100 mg were randomized to treatment with molar equivalent doses

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