2. Duodopa and Continuous Dopaminergic Stimulation
Levodopa, mostly combined with a peripheral aromatic amino acid decarboxylase inhibitor, such as carbidopa, has revolutionized the treatment of Parkinson’s disease and is still the most important drug treatment for Parkinson’s disease (LeWitt, 1989; Siderowf et al., 2000; Olanow et al., 2001).
Levodopa has a relatively short half-life in plasma, 1.5–2 h, but the duration of clinical benefit can last for many hours longer than its presence in plasma. In early cases of the disease, three times daily dosing of the drug is usually sufficient for a good response. After several years of levodopa treatment and progression of the disease, the duration of the response tends to become shorter with a return of parkinsonian symptoms and signs at the end of the dose interval (“wearing off”), sometimes with a rebound deterioration. In addition, a narrow dose or plasma concentration window for a good response becomes evident, below which the patient remains in a parkinsonian state with tremor, rigidity, and akinesia. A higher dose or plasma concentration than needed for an “on” response may be associated with dyskinesia (involuntary choreatic movements). Motor fluctuations and fluctuations of other bodily (e.g., pain) and mental (e.g., anxiety, depressed mood) symptoms of Parkinson’s disease are well known among neurologists and have been carefully described in the literature (e.g., Quinn, 1998; Olanow et al., 2001). Most responses to levodopa follow the rise and fall of plasma levodopa concentrations after each dose intake (“predictable fluctuations”). However, fluctuations have also been observed that are not related to plasma concentrations (“unpredictable fluctuations”).
In attempting to control motor fluctuations, a number of measures can be taken in order to reduce variability in anti-parkinsonian control by keeping the plasma concentrations of levodopa within an individual therapeutic window during most of the dose interval. Frequent administrations (every 1–2 hours) of low doses of the drug may be tried, but are not always successful (Quinn, 1998). Controlled release formulations of levodopa/carbidopa (e.g., Sinemet CR) have been developed. Concomitant administration of the COMT inhibitor entacapone is given in order to prolong the half-life of levodopa. Administration of dopamine receptor agonists, such as pergolide, bromocriptine, ropinirole, and paramipexole are also used as concomitant anti-Parkinson’s disease medication in order to extend the duration of dopamine receptor stimulation between the levodopa dose intervals. In spite of these attempts to achieve continuous dopamine receptor stimulation, many patients with motor fluctuations do not respond adequately and continue to suffer from severe and incapacitating symptoms. These patients would be under consideration for stereotaxic brain surgery for electrocoagulative lesioning (thalamotomy, pallidotomy) or installation of deep brain stimulation (DBS) equipment. As an alternative to achieve continuous dopamine receptor stimulation by different perorally administered drug combinations, attempts have been made to deliver levodopa by intravenous or enteral (intragastric, intraduodenal) infusion. Duodopa is one such example.
Duodopa, a water-based suspension of levodopa/carbidopa formulated for intraduodenal infusion via a duodenal tube inserted via a percutaneous endoscopic gastrostomy (PEG), or other surgery, is intended for Continuous Dopamine-Receptor Stimulation (CDS) in advanced Parkinson’s disease. The concept of CDS, as opposed to Intermittent (or pulsatile) Dopamine-Receptor Stimulation (IDS) with repeated oral levodopa/carbidopa intake, has been discussed in recent years as a means to treat “on-off” motor fluctuations and dyskinesia associated with long-term (several years) treatment with oral levodopa/carbidopa in advanced Parkinson’s disease (Nutt et al., 2000; Chase, 1998). CDS may also delay the development of motor fluctuations and dyskinesia in early Parkinson’s disease (Olanow et al., 2000).
The principle of Duodopa is to continuously infuse levodopa and carbidopa directly into the duodenum. Absorption problems with erratic gastric emptying, early metabolism, and competitive inhibition of intestinal absorption by LNAA (large neutral amino acids) will be markedly reduced and levodopa can be rapidly absorbed into the bloodstream. In clinical practice, Duodopa has been mostly used as monotherapy, which utilizes the continuous dopaminergic stimulation as far as possible without interference from concomitant anti-Parkinson’s disease drugs.
The target Parkinson’s disease patient population for treatment with Duodopa is on long-term treatment with oral levodopa/carbidopa, afflicted by disabling “on-off” motor fluctuations with or without dyskinesia and is not responding adequately to adjunct treatment with dopamine receptor agonists (including apomorphine) and/or COMT inhibitors such as entacapone. These are actually patients for whom stereotaxic brain surgery for electrocoagulative lesioning of certain brain regions (thalamotomy, pallidotomy) or installation of deep brain stimulation (DBS) equipment is considered. NeoPharma believes that treatment with Duodopa should become an alternative treatment option before a decision on brain surgical intervention is taken.
The dosage of levodopa should be strictly individualized according to our experience. Predefined dosage or dose schedules are impossible to use in the advanced stage of the disease. The possibility of individualizing the doses is one of the greatest advantages of infusion therapy with Duodopa. In clinical practice, the patient collaborates with the physicians and nurses responsible for dose adjustment. A patient can feel when an “off” period is approaching before it is noticeable by an observer. In that case, an extra dose of 10–20 mg might be taken in order to stabilize the condition. This is obvious when considering the great impact of levodopa pharmacokinetics on the patient’s mobility. If a “rescue tablet” of 50 or 100 mg would be taken, a marked peak would show in the levodopa concentration-time curve, disturbing the smooth steady-state concentration, and the patient would become dyskinetic for a while. Such a peak can actually have consequences for the rest of the day since the levodopa administration is constant, but shifted to a higher level by the extra tablet.
The pharmacokinetic data show that a relatively smooth plasma levodopa level is maintained during the Duodopa infusion. This implies an easier dosage regimen where very small adjustments in the infusion rate (0.1 ml/h [i.e., 2 mg/h]) can be made. When oral levodopa dosage is adjusted, the change is generally 50 or 100 mg per tablet at a time. Duodopa infusion thereby offers a lesser risk for overconsumption. Studies with Duodopa (Nilsson et al., 1998; Study Report No. NPP-001-99) have demonstrated that the plasma concentrations of levodopa show less variability over a treatment day than intermittent oral administration of levodopa. As a result, the patients on Duodopa showed less motor fluctuations and dyskinesia than with oral levodopa administration.
Some observations with relevance for the design of clinical studies with Duodopa have been made. Maintaining the blind in blinded studies with Duodopa is difficult, if at all possible, in practice. Patients who have felt the benefits of smooth levodopa delivery can easily recognize it again and distinguish it from ordinary oral medication. A study design where a dose for Duodopa infusion is set during a baseline period and used several weeks later is unsuitable if changes in the infusion rate will not be allowed. Pharmacodynamic changes with up and down regulation of brain dopamine receptors may alter the dose requirement over a few days with any antiparkinsonian therapy. Further, progression and unpredictable fluctuations in the disease state might have an impact on the dose needed. Thus, small dose adjustments must always be allowed, as needed, for ethical reasons. The use of “rescue tablets” to compensate for a subthreshold infusion rate disturbs the pharmacokinetics and, subsequently, the effects as described above. On the contrary, should the preset infusion rate be too high, the patient would be dyskinetic all the time for days or weeks, which would be unacceptable. Such a design is far from clinical practice, where small adjustments of the Duodopa dose are needed quite frequently in the initiation of Duodopa treatment and must be allowed at any time for the best possible outcome.
