Tailored therapy for motor fluctuations

At the EAN Congress 2022, a Bial satellite symposium discussed treatment options for motor fluctuations and presented new data on the pharmacokinetics of levodopa in combination with the COMT inhibitor opicapone.

Motor complications are common in people with Parkinson’s disease. A distinction is made between motor fluctuations (MF) and dyskinesias. “Fluctuations occur mainly with long-standing disease and many years of treatment,” explained Prof. Susan Fox, director of the Department of Neurology, University of Toronto (Canada), “but they can also affect people with early Parkinson’s.” In a study of PD patients with an average disease duration of 3.3 years (early PD), 25% already suffered from MF; these were associated with poorer quality of life¹.

MF arise because of the pulsatile action of levodopa (LD). Therefore, to prevent MF as much as possible, the LD dose should be kept as low as possible and the duration of action should be as long as possible(continuous dopaminergic stimulation, CDS⁾². Studies have shown that starting therapy with long-acting dopamine receptor stimulation results in less MF than treatment with LD ^alone3. “Dopamine agonists are not the be-all and end-all, however,” Prof. Fox said. “On the one hand, there is a risk of side effects, and on the other hand, the benefit in terms of movement disorders is less than with levodopa.”

Levodopa remains gold standard

Prof. Angelo Antonini, Head of the Division of Parkinson’s Disease and Movement Disorders, Neurological Clinic, University Hospital of Padua (Italy), presented a survey by the Bial company in which about 800 European movement disorder specialists were asked about their management of MF. 80% opted for a change in LD administration, 20% for addition of another drug⁴. Why the majority decision is not the best one is related to the physiology of dopamine ^release2. In advanced PD, there is hardly any dopamine storage capacity left and the peaks resp. Depths of LD plasma levels more rapidly lead to dyskinesias and OFF times. This has consequences for therapy:

• Increasing the LD dose (e.g., from 100 to 150 mg every 6 hours) is unfavorable because it increases plasma level peaks and the risk for dyskinesia.
• Increasing the frequency of LD administration (e.g., from 100 mg every 6 hours to every 4 hours) is unfavorable because the problem of plasma level peaks remains and the influence of meals on LD levels becomes ^stronger5.

Thus, the goal of CDS should be to avoid both very low and very high LD plasma levels, both to reduce the duration in OFF and to avoid dyskinesias triggered by high plasma ^levels6. In the STRIDE-PD trial, motor complications and dyskinesias had also been shown not to be associated with duration of LD therapy, but with longer disease duration and with higher LD ^doses7. This should be avoided if possible.

Advantages of Opicapone (^Ongentys®)

Prof. Joaquim Ferreira, Director of the Clinical Pharmacology Laboratory, University of Lisbon (Portugal), provided information on drugs that can optimize the effects of LD: Dopa decarboxylase inhibitors (DDC inhibitors: carbidopa, benserazide), catechol-O-methyltransferase inhibitors (COMT inhibitors: tolcapone, entacapone, opicapone), and monoamine oxidase B inhibitors (MAO-B inhibitors: selegiline, rasagiline, safinamide⁾⁸. With the addition of a DDC and a COMT inhibitor to LD (dual inhibition), a 30-50% reduction in plasma variability can be ^achieved9. Dual inhibition also allows for a reduction in LD dose and thus risk of MF.

In an open-label phase II study by the presenter (203-trial), 24 PD patient:s taking 500 mg LD and 125 mg carbidopa (LD / CD) in five doses daily were divided into two groups: One received new 400/100 mg LD / CD plus 50 mg/d opicapone in five doses, and the other group received 400/100 mg LD / CD plus 50 mg/d opicapone in four ^doses10. When taken in four doses, plasma level lows lifted, reducing the duration of OFF times, but slightly increased plasma level peaks were also seen. When taken in five doses, plasma level lows were also elevated, but in addition plasma level peaks were lower than when taken four times daily, which may be an advantage in terms of MF risk [BOX]. Compared with therapy without opicapone, the addition of opicapone with concomitant reduction by 100 mg/d LD / CD and four times daily intake decreased the fluctuation index of LD plasma level, and the bioavailability (area under the curve, AUC) of LD increased by 27%. “This is exactly what we want as clinicians,” Prof. Ferreira explained.

Clinical results were even better with the addition of opicapone with reduction of 100 mg/d LD / CD and five times daily dosing. Compared with therapy without opicapone, the fluctuation index of LD plasma levels was reduced by 40% and LD bioavailability (AUC) was increased by 29%. “Pharmacokinetic and clinical results indicate that five-times-daily dosing is beneficial for patients,” the speaker said.

To test these results, the prospective, open-label, phase IV ADOPTION trial is currently underway: approximately 100 PD patient:s on LD therapy three to four times daily and OFF time of 1-5 hours daily will receive an additional 50 mg/d opicapone or an additional 100 mg/d LD / DDC ^inhibitor11.

Ongentys ^® (Opicapone) 50 mg hard capsules. Opicapone is a peripheral, selective and reversible catechol-O-methyltransferase (COMT). Indications: Ongentys is used as add-on therapy to levodopa/DOPA decarboxylase inhibitors (DDCI) in adult patients with PD with end-of-dose motor fluctuations in whom stabilization cannot be achieved with these combinations. Dosage/Application: The recommended dose of opicapone is 50 mg once daily at bedtime, to be taken at least one hour before or after levodopa combination medications. Opicapone potentiates the effects of levodopa. Therefore, levodopa dosage adjustment is often necessary in the first days to first weeks after starting treatment with Opicapone. No dose adjustment is required in elderly patients. No dose adjustment is required in patients with renal impairment because opicapone is not excreted by the kidney. Use of Ongentys is not recommended for patients with hepatic dysfunction (Child-Pugh class A, B, C) or in the presence of cirrhosis. Contraindications:pheochromocytoma, paraganglioma, or other catecholamine-secreting neoplasms. History of malignant neuroleptic syndrome and/or nontraumatic rhabdomyolysis. Concurrent use with monoamine oxidase inhibitors (MAO-A and MAO-B inhibitors) other than those used in Parkinson’s disease. Hypersensitivity to the active substance or any of the excipients. Warnings and Precautions: Dose adjustments of existing Parkinson’s disease therapy: Ongentys is to be used in addition to treatment with levodopa. Therefore, the precautions applicable to treatment with levodopa should also be considered for Ongentys. Opicapone potentiates the effects of levodopa. To reduce levodopa-related dopaminergic side effects, it is often necessary to adjust the daily levodopa dose by extending the dosing interval and/or reducing the amount of levodopa taken per dose during the first days to first weeks after starting treatment with Ongentys, depending on the patient’s clinical condition. Psychiatric disorders: Behavioral abnormalities in the sense of impulse control disorder may occur in patients treated with dopamine agonists and/or other dopaminergic substances. Other: Increases in liver enzymes have been reported in studies with nitrocatechol inhibitors of catechol-O-methyltransferase (COMT). Patients with progressive anorexia, asthenia, and weight loss within a relatively short period of time should have a comprehensive medical evaluation including monitoring of liver function. One hard capsule of Ongentys contains 148 mg of lactose and less than 1 mmol (23 mg) of sodium. Interactions: Influence of Ongentys on other drugs:Drugsmetabolized by COMT: Opicapone may interfere with the metabolism of drugs containing a catechol group that are metabolized by COMT, such as rimiterol, isoprenaline, epinephrine, norepinephrine, dopamine, dopexamine, or dobutamine, resulting in an enhancement of the effects of these drugs. When opicapone is used, careful monitoring of patients treated with these drugs is recommended. Monoamine oxidase (MAO) inhibitors: The combination of opicapone with MAO inhibitors could result in the inhibition of most of the metabolic pathways responsible for the metabolism of catecholamines. Concomitant use of opicapone and MAO inhibitors for the treatment of PD, such as rasagiline (up to 1 mg/day) and selegiline (up to 10 mg/day in an oral dosage form or 1.25 mg/day in a buccal absorption dosage form), is permitted. No experience is available on the concomitant use of opicapone with the MAO-B inhibitor safinamide. Tricyclic Antidepressants and Norepinephrine Reuptake Inhibitors: Limited experience is available on the concomitant use of opicapone with tricyclic antidepressants or norepinephrine reuptake inhibitors. In vitro data: In in vitro studiesusing human liver microsomes, modest inhibition of CYP1A2 and CYP2B6 was observed. Opicapone inhibited CYP2C9 activity. No interaction with the transporters OAT1, OAT3, OATP1B3, OCT1, OCT2, BCRP, P-gp/MDR1, BSEP, MATE1, and MATE2-K is expected. Opicapone is aweak inhibitor of CYP2C8 and OATP1B1 in vitro. In vivo data: Repaglinide: is a sensitive CYP2C8 and OATP1B1 substrate. A study in healthy volunteers showed that 50 mg of opicapone at steady state had no effect on systemic exposure of repaglinide. Warfarin: After concomitant administration of multiple doses of 50 mg Opicapone 1x daily and a single dose of 25 mg warfarin, the _Cmax of warfarin S and R (substrates of CYP2C9, 3A4, and 1A2) remained unchanged. Influence of Other Substances on Opicapone: Quinidine: In a study in healthy volunteers, a 37% decrease (AUC0-tlast) in systemic opicapone exposure was seen when a single dose of 50 mg opicapone was given together (within 1 hour) with a single dose of quinidine (600 mg). Therefore, special attention is required when there is a need to use inhibitors of P-gp together with opicapone, as their concomitant administration should be avoided. Dispensing category: [B]. Marketing authorization holder: Bial SA, Nyon. Date of information: July 2020.

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