Infusion Therapies and other Novel Drug Delivery for Parkinson’s disease New Avenues for Old Drugs
Levodopa – a revolutionary drug with drawbacks
After more than 50 years since its introduction as a treatment for Parkinson’s disease levodopa still stands out as the most effective of all available drugs when it comes to improving motor symptoms, restoring activities of daily living and maintaining quality of life of people affected by the disease. Although levodopa remains unchallenged as the ‘gold standard’ of symptomatic efficacy, in many people with Parkinson’s its long-term use is associated with the development of undesirable and often distressing changes in the effect of the drug. These are termed motor complications and include two types of problems: fluctuations in motor response and drug-induced involuntary movements called dyskinesias. The former consist of alternating periods of satisfactory control of PD symptoms in response to a dose of levodopa (‘ON’-periods) and other times where symptoms re-emerge (‘OFF’-periods). This is related to a shortening of the period during which an individual dose of the drug is able to exert its beneficial effects and creates a need for more frequent doses over the day and sometimes even during the night. The most common pattern of motor fluctuations is one where symptoms re-appear or worsen towards the end of the interval between doses and is called ‘wearing-off’ phenomenon, but there can also be seemingly unpredictable breakthroughs of parkinsonism during the course of a day, unexpected delays before an individual dose begins to work or even complete failure of a dose to produce an effect (see figure 1). The loss of a reliable and predictable beneficial effect of a subject’s customary oral drug regimen creates a multitude of distressing problems due to troublesome and disabling combinations of motor and non-motor impairments during OFF-periods: loss of mobility, tremor, painful foot cramping and a mix of non-motor experiences including anxiety, depression, pain and difficulties concentrating.
Mechanisms underlying motor fluctuations
The mechanisms underlying the development of motor fluctuations in response to levodopa in PD are complex and include both changes in the way the brain handles the drug (so-called ‘pharmacodynamic’ changes) and issues around the pharmacokinetics and gastro-intestinal transport and absorption of levodopa (see fig 2). A core problem lies in the fact that levodopa has a short half-life of only around 90 minutes such that oral intake of a dose will only produce sufficient blood drug-levels for a limited time resulting in alternating peaks and troughs as multiple doses are taken over the course of a day. While the brain is able to buffer these plasma level oscillations of levodopa initially, this capacity becomes compromised with continuing loss of dopamine neurons as the disease advances. In addition, the oral route of delivery of levodopa can become compromised by swallowing problems, delays in gastric emptying or competition between levodopa and amino acids (in protein rich foods) from the diet at its absorption site in the small intestine (duodenum and jejunum). All these factors result in discontinuous and erratic delivery of levodopa to its site of action in the brain, where it becomes converted to dopamine. Discontinuous drug delivery and ‘pulsatile’ stimulation of brain dopamine receptors is also believed to play a major role in the development of the second type of motor complications from levodopa, ie the development of dyskinesias in response to the drug.
Novel Drug Delivery for ‘Old’ Drugs – levodopa and apomorphine
Bypassing the oral delivery route of levodopa by using continuous intravenous infusions was first tried in the early 1980’s by clinicians in London, UK, as a means to largely abolish ON-OFF fluctuations and restore stable responses. These pilot studies were highly successful, but the approach was not ready for clinical routine use: the poor solubility of levodopa required large volumes of fluid to deliver the required daily dose and the acidity of the solution necessitated the insertion of intravenous catheters for safe delivery. A few years later, investigators in the US reported similar success with intraduodenal delivery of levodopa solution via nasogastric tubes – a much less invasive approach compared to central venous catheters. Still large volumes of around 2 liters per day were needed to keep levodopa in solution and it took another 20 years to remove this roadblock to practical clinical use. Swedish pharmacologists succeeded in developing a gel formulation of levodopa that could accommodate 20mg of the drug in only 1 ml so that only 100 ml would contain ample amounts of drug to cover most patients daily requirement. This levodopa/carbidopa intestinal gel (LCIG) formulation (see Fig.3) can be delivered into the small intestine via a strong external pump and a tube inserted by a minimally invasive procedure (percutaneous endoscopic gastrostomy (PEG) and has brought a breakthrough for the use of continuous levodopa infusions to manage refractory motor fluctuations in clinical practice. Next to markedly reducing daily OFF-time this approach has also been show to reduce levodopa induced dyskinesias.
Back in the 1980s one of the groups in London, who had pioneered the use of intravenous levodopa infusions, pursued a different route to overcome the problems they had encountered. The neurologists Andrew Lees and Gerald Stern went back to an old drug that had been noted for its antiparkinsonian efficacy already in the 1950s by the US neurologist Robert Schwab. Schwab and his colleagues had reported striking efficacy of apomorphine, but there was disappointment that the drug was not effective when given via the oral route and had to be administered by subcutaneous injections. Lees and Stern saw the potential of an easily soluble and potent dopamine agonist like apomorphine to be used as continuous subcutaneous infusions for the very same type of patients in whom they had earlier tested intravenous infusions of levodopa. The effects were truly remarkable and quickly led to the introduction of subcutaneous apomorphine (see Fig. 3) into the market in the UK and other European countries – long before the development of LCIG infusions.
Over the last few years the development of novel infusion and other non-oral delivery approaches of both levodopa and apomorphine has gained amazing momentum. A modified LCIG formulation has recently been marketed in Sweden and several other European countries. It contains the COMT inhibitor entacapone (hence the abbreviation LECIG for levodopa/entacapone/carbidopa intestinal gel see Fig 3)), which enables reduced daily infusion volumes needs and the use of smaller and lighter pumps. Trials testing novel levodopa formulations that can be administered subcutaneously are under way and offer hope for non-invasive levodopa infusions. Both apomorphine and levodopa have recently been re-formulated to allow for rapid absorption and onset of effect – an important need for patients experiencing OFF-periods in order to quickly abort these distressing episodes. Two novel formulations for such ‘on-demand’ use have recently been approved by the FDA - sublingual film formulation of apomorphine and an inhalation powder of levodopa for intrapulmonary delivery via an inhaler device (see Fig 3). These developments are a strong testimony to the fact that important innovations do not always depend on the discovery of new drugs, but that optimizing the delivery of ‘old’ drugs can also make a big difference for people living with Parkinson’s.
Werner Poewe, MD, is an Emeritus Professor of Neurology at the Department of Neurology, Medical University Innsbruck, Austria. Professor Poewe has spoken at many past World Parkinson Congresses and will be speaking this may in the WPC Virtual Congress on this topic of “Infusion and other novel drug delivery for treatment of PD”.
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