'Accordion' Pill May Reduce Levodopa Fluctuations in Parkinson's

Daniel M. Keller, PhD

October 07, 2018

HONG KONG — A new technology promises to deliver levodopa at more constant levels over time.

It depends on a folded, accordion-like structure inside a gelatin capsule. When swallowed, the capsule dissolves, releasing the folded film within it, which then unfolds in the stomach and remains there for more than eight hours under normal dietary conditions.

This "Accordion Pill" (AP) contains a biodegradable, multilayer film folded as one would fold a piece of paper to make a fan. In its open state, it forms a small, pleated sheet that resides in the stomach until it breaks down enough to crumple up, allowing it to pass through the pylorus.

"During the gastroretention time, all drugs are being released in a predefined manner in the stomach and from there to the upper part of the GI [gastrointestinal tract]," Nadav Navon, PhD, MBA, Intec Pharma, Jerusalem, explained to Medscape Medical News. "Levodopa is a classic example for a drug that needs that technology because levodopa suffers from a narrow absorption window…actually, only in the duodenum."

For Parkinson's disease (PD), when the accordion first unfolds into a sheet, it immediately releases carbidopa and levodopa, and then it continues to release a steady dose of levodopa above the duodenum. Retention in the stomach is the result of mechanical properties of the film structure. Two-dimensional structures are retained in the stomach longer than three-dimensional ones.

Speaking at a poster session here at the International Congress of Parkinson’s Disease and Movement Disorders 2018, Navon presented the results of studies of gastric retention of the AP in the stomachs of normal volunteers and in PD patients.

One study enrolled 18 PD patients (mean age 61.1 ± 10.0 years; 15 male) with a mean disease duration of 8.9 ± 4.6 years, and 17 were taking medications other than PD treatments. Patients were Hoehn & Yahr stages 2 (n =3), 2.5 (n = 8), and 3 (n = 7). Eleven healthy volunteers were also enrolled.

Volunteers were excluded if they had any prior GI surgery, current GI conditions, or were taking any medications that could promote gastric emptying.

The studies used a three-way cross-over design to test three formulations of the AP with sheets differing in tensile strength and elasticity. To measure gastric retention, on test days study subjects took these AP's containing iron oxide with their regular morning PD treatment following an overnight fast, with a greater than 48 hours washout between tests.

Gastric retention of the AP was followed by MRI. The subjects drank 240 mL of water to improve MRI image quality. Standardized meals were provided to the subjects.

MRI scans were done at 3, 5, 7, 9, 11, and 13 hours after pill ingestion. If gastric clearance had not occurred by 13 hours, subjects were scanned approximately 24 hours later and daily for one week or until the AP was cleared.

The mean gastric retention times among PD patients for the three formulations were similar at 11.8, 13.5, and 13.9 hours. Healthy volunteers retained the AP in the stomach for a mean of 12.7 ± 5.7 hours. PD is known to slow gastric emptying.

Ten PD patients reported six forms of adverse events (AEs): three headache, two nausea, two vomiting, and one each diarrhea, asthenia, and back pain. All AEs were mild except in one person who reported a serious event of general weakness/worsening of PD.

One healthy volunteer had pain during an MRI after ingesting the AP, but it resolved without sequelae.

The US Food and Drug Administration required the company to perform endoscopy studies to show that the prolonged residency of the film in the stomach did not cause ulcers or gastric erosions and that the films were evacuated from the stomach and did not accumulate there.

Challenges for Levodopa Therapy

Challenges for levodopa therapy have been that it is absorbed only in the upper gastrointestinal tract and has a short half life in the presence of carbidopa, making it hard to maintain levodopa plasma levels within its narrow therapeutic window.

Unlike current extended release tablets or other slow release formulations, the AP stays in the stomach (above the duodenum) for up to 12 hours, thus allowing more constant drug levels and potentially helping to avoid motor fluctuations.

Navon said studies showed that peak to trough ratios were "reduced by an order of magnitude" compared with immediate release levodopa therapy. In addition, after 6 days of taking the APs, patients woke up in the morning with "around 500 ng/mL in the system in comparison to around zero with the immediate release," indicating "steady state pharmacokinetics of a drug that suffers from a narrow absorption window with a very short half-life."

An AP containing carbidopa and levodopa is in phase 3 development for PD, with the potential to improve efficacy and safety of treatment with levodopa. The pills will be intended to be taken twice or three times daily.

Peter LeWitt, MD, Henry Ford Health System, Detroit, an investigator in the AP development, commented that the simultaneous release of carbidopa and levodopa when the AP is ingested is not ideal, and it would be better if the carbidopa could be released a half hour before the levodopa. But he said the present technology nonetheless looks very good.

Joseph Quinn, MD, Oregon Health and Science University, Portland, commented to Medscape Medical News that he thinks the AP has potential for more continuous delivery of levodopa over time, "and that could be helpful for people who are fluctuators." He noted that the current study shows only gastric retention times but not drug levels over time.

He said he does not think this technology may have any particular advantages over other strategies for continuous release of levodopa, but the available options "are still not satisfactory," citing as an example Rytary (Impax Laboratories) extended release carbidopa/levodopa capsule, calling it somewhat of an improvement, "but there are still patients whose disease cannot be controlled with oral medication even with that preparation."

Quinn said a big question is whether levodopa plasma levels are as stable as the company claims, and if the product shows a clinical efficacy advantage compared with other products.

The AP technology may have applications beyond levodopa delivery, such as for drugs with a narrow absorption window in the stomach, poorly soluble drugs, drugs requiring a low pH, and for those acting locally in the stomach or upper gastrointestinal tract.

The study was funded by Intec Pharmaceuticals. Navon is an employee of Intec Pharmaceuticals. Dr Quinn has received research support from abbvie and Sanofi. Dr LeWitt has received compensation for advisory services, consulting, research grant support, or speaker honoraria from AbbVie, Acadia, Acorda Therapeutics, Inc., Adamas, Biogen Idec, Biotie, Cynapsus, Depomed, Impax, Insightec, Intec, International Parkinson's Disease and Movement Disorders Society, Ipsen, Kyowa, Lundbeck, Luye, Michael J. Fox Foundation for Parkinson's Research, NeuroDerm, Noven, Parkinson Study Group, Pfizer, Pharma 2B, ProStrakan, SynAgile, Teva, Tremor Research Group, UCB, US WorldMeds, World Parkinson Congress, and XenoPort.

International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2018: Abstract 253. Presented October 6, 2018.


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