Cognitive and Psychiatric Adverse Effects of Foslevodopa/Foscarbidopa in Patients with Parkinson's Disease

Abstract

Continuous subcutaneous foslevodopa-foscarbidopa infusion (fLD/fCD) is an emerging, minimally invasive device-aided therapy (DAT) supposed to provide steady dopaminergic stimulation 24 h a day. In the pivotal study fLD/fCD appeared to be an effective and well-tolerated therapeutic option for managing motor fluctuations in patients with advanced Parkinson's disease (PD).1 However, real-life efficiency and tolerance remain to be determined. Given the good safety profile of levodopa medications, we initiated fLD/fCD in 9 consecutive patients with advanced PD and motor fluctuations (Table 1). Five patients developed confusion and/or hallucinations and/or delirium after 2.6 days. To identify predictive factors of poor tolerance, we described patients with cognitive-psychiatric adverse effects (AE group) and those without (NoAE group) after a 1-month follow-up. The mean levodopa equivalent daily dose (LEDD) before the introduction of fLD/fCD was 1673.4 ± 691.6 mg in AE group versus 1493.7 ± 533.1 mg in NoAE group. Daytime and nighttime infusion rates tend to be higher in AE group due to a probably more severe motor state. To achieve adequate control of motor fluctuations, average LED of fLD/fCD had to be gradually increased to reach 2598.85 ± 1000.37 mg in AE group versus 2469.8 ± 606.29 mg in NoAE group after 1 month. With fLD/fCD reduction in the AE group, oral compensation was increased further, leading to a higher LEDD. Patients in AE group tended to be older at disease onset and treatment initiation, at a more advanced disease stage, and to have greater cognitive impairment than those in NoAE group. There was no difference in disease duration. In AE group, all patients had a previous history of confusion, and 4/5 had a history of hallucinations or delirium under dopaminergic treatments, no longer present at the time of treatment introduction. In NoAE group, only 1/4 patients had a history of hallucinations. fLD/fCD was discontinued in 1 patient during the first month due to persistent psychosis, despite drastic reduction in the infusion rate. In other patients, an anti-psychotic medication had to be introduced (1 patient) or increased (2 patients). Hospitalization length seems to be notably longer in the AE group, which is unexpected for a minimally invasive DAT. Our first real-life experience raises two critical warnings for the management of fLD/fCD. First, the risk of poor tolerance of fLD/fCD seems to be increased by older age, cognitive impairment and a previous history of confusion, hallucinations or delirium. This might be a consequence of specific pharmacokinetics profile of fLD/fCD, with unexpectedly high and prolonged levodopa plasma concentrations even at low infusion rates.2 We suggest that fLD/fCD should be avoided or used as a low-dose add-on treatment in this patient population. Second, the validity of the proposed conversion algorithm may be questioned as theoretical doses did not provide adequate improvement of motor fluctuations.3 In conclusion, fLD/fCD may not be a safe alternative to subcutaneous apomorphine when its use is contraindicated due to the patient's cognitive dysfunction or history of psychotic symptoms, nor to levodopa/carbidopa intestinal gel infusion as a means to avoid gastrostomy. Its role in the current therapeutic strategy therefore remains to be clarified. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. S.B.: 1A, 1B, 1C, 3A, 3B E.R.: 1A, 1B, 3A, 3B D.G.: 1A, 1B, 3B H.L.: 1A, 1B, 3B L.M.: 1A, 1B, 3B C.F.: 1B, 3B E.H.: 1B, 3B F.C.: 1B, 3B A.M.: 1A, 1B, 3B F.H.: 1A, 1B, 3A, 3B The authors have no acknowledgments to report. Ethical Compliance Statement: Patients included from our unit were informed about the objective of the study, and the collection of non-opposition to the retrospective use of medical data was carried out according to French law, good clinical practice and General Data Protection Regulation (GDPR). According to French law, the retrospective and observational nature of the study (data collection) did not require approval by an ethics committee. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: ER received honoraria for speeches from Orkyn, Aguettant, Elivie, Merz-Pharma, Janssen, Teva, International Parkinson and Movement Disorders Society and for participating in advisory boards from Merz-Pharma, Elivie, Teva, and BIAL. He received research support from Merz-Pharma, Orkyn, Elivie, Everpharma, AMADYS, Aguettant, ADCY5.org, Fonds de dotation Patrick Brou de Laurière, Agence Nationale de la Recherche, Dystonia Medical Research Foundation, Hope for Annabel, Cure Alternating Hemiplegia of Childhood Alternating Hemiplegia of Childhood Foundation, Alternating Hemiplegia of Childhood Association of Iceland, Association française de l'Hémiplégie Alternante, Alternating Hemiplegia of Childhood Kids of the Netherlands. HL received honoraria for speeches from Everpharma. LM served on scientific advisory boards for Abbvie, received honoraria for speeches from NHC, Elivie, Novartis, Orkyn (Air Liquide), received travel funding from Orkyn (Air Liquide). AM received honoraria for speeches from Merz-Pharma and travel funding from Elivie and Merz-Pharma. The other authors declare that there are no additional disclosures to report. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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