Continuous subcutaneous infusion therapy using the levodopa prodrugs foslevodopa/foscarbidopa (LDp/CDp) enables continuous dopaminergic delivery and stabilizes plasma levodopa concentrations. 1 However, clinical response may not always parallel measured levodopa levels. Here, we report a case in which “off” periods persisted despite adequate plasma levodopa concentrations, and monitoring of plasma 3‐O‐methyldopa (3‐OMD), a long‐lasting metabolite of levodopa formed by catechol O‐methyltransferase (COMT) that inhibits the uptake of levodopa mediated by L‐type amino acid transporter 1 (LAT1) at the blood–brain barrier, contributed to treatment optimization.
A Japanese woman noticed left‐sided tremor at age 44 and was diagnosed with clinically established Parkinson's disease (PD) at age 46. She initially responded well to dopaminergic therapy, however, later developed wearing‐off and dyskinesia. Because she declined deep brain stimulation, LDp/CDp was initiated at age 61 as a non‐surgical device‐aided therapy after shared decision‐making. Sixteen months later, off‐period akinesia worsened despite escalation of the LDp/CDp infusion rate, and she was referred to our hospital for treatment optimization.
At admission, LDp/CDp was continuously infused at 0.29 mL/h (~49 mg/h as levodopa). On day 1, serial measurements of plasma levodopa and 3‐OMD concentrations and Movement Disorder Society‐Unified Parkinson Disease Rating Scale (MDS‐UPDRS) part III scores were obtained at 9:00, 12:00, 13:00, and 16:00 (Fig. 1). Although plasma levodopa concentrations remained within the reported therapeutic range, 2 plasma 3‐OMD concentrations were consistently high. We, therefore, estimated LAT1 inhibition by 3‐OMD and calculated a corrected levodopa concentration adjusted for this inhibition. Details of blood sampling, analytical methods, and calculation procedures are provided in the Supporting Information Methods. The corrected levodopa concentration remained low during the prolonged off state and appeared to correspond more closely to the clinical state than the observed levodopa concentration.
FIG. 1.
Time–concentration profiles of observed levodopa (l‐dopa), corrected l‐dopa, and 3‐O‐methyldopa (3‐OMD) during foslevodopa/foscarbidopa (LDp/CDp) therapy. Observed l‐dopa, corrected l‐dopa, and 3‐OMD concentrations are shown together with the estimated L‐type amino acid transporter 1 (LAT1) inhibition ratio, residual LAT1 uptake activity, and Movement Disorder Society‐Unified Parkinson Disease Rating Scale (MDS‐UPDRS) part III total scores. Corrected l‐dopa concentrations were calculated by multiplying the observed l‐dopa concentrations by the estimated residual LAT1 activity, which was derived from the inhibitory effect of plasma 3‐OMD on LAT1 using its inhibition constant (Ki) based on receptor occupancy theory. Opicapone 25 mg tablet was added on day 5. The dashed horizontal line indicates an l‐dopa concentration of 3000 ng/mL, and the slash in the plot area indicates a discontinuity in the time axis. See Supporting Information Methods for the calculation of estimated LAT1 inhibition and corrected levodopa concentration. COMT‐I, catechol O‐methyltransferase inhibitor.
Based on these findings, opicapone 25 mg tablet once daily was initiated on day 5. The daytime LDp/CDp infusion rate was maintained at 0.29 mL/h, whereas the nighttime infusion rate was reduced to 0.27 mL/h. On day 14, plasma 3‐OMD concentrations decreased to approximately one‐sixth of the day 1 values, resulting in an increase in corrected levodopa concentration, significant improvement in motor symptoms. At the 3‐month follow‐up, the motor improvement and corrected levodopa concentration were maintained on the same LDp/CDp regimen and opicapone 25 mg tablet once daily, without worsening of troublesome dyskinesia or hallucinations.
This case suggests that elevated 3‐OMD during long‐term LDp/CDp therapy may reduce the effective central availability of levodopa, possibly through competitive inhibition of LAT1‐mediated transport. 3 , 4 Furthermore, the marked increase in corrected levodopa concentration after COMT inhibitor initiation, accompanied by clinical improvement, supports the hypothesis that competitive inhibition of LAT1‐mediated levodopa transport by 3‐OMD may have played a key role in this patient's motor fluctuations. Although the corrected levodopa concentration is a simplified estimate and has not been validated as a direct measure of central levodopa availability, it may provide a useful framework for interpreting discrepancies between plasma levodopa levels and clinical response.
In patients with persistent off symptoms despite apparently adequate plasma levodopa concentrations, monitoring plasma 3‐OMD and estimating corrected levodopa concentration may help guide individualized treatment optimization, including COMT inhibitor add‐on therapy and adjustment of infusion rates. Because COMT inhibition may increase effective levodopa availability, long‐term monitoring for dyskinesia, hallucinations, and other dopaminergic adverse effects remain essential. Further studies are needed to determine whether progressive 3‐OMD accumulation is a common and clinically relevant issue during long‐term LDp/CDp therapy.
Author Roles
(1) Concept and design; (2) Acquisition, analysis, or interpretation of data; (3) Drafting of the manuscript; (4) Critical revision of the manuscript for important intellectual content; (5) Administrative, technical, or material support; (6) Supervision.
S.O.: 1, 2, 3, 4, 5
K.O.: 2, 5
Y.N.: 6
R.S.: 2, 5
T.A.: 2, 5
T.N.: 5
J.N.: 6
H.O.: 5, 6
M.S.: 1, 2, 3, 4, 5, 6
Disclosures
Ethical Compliance Statement: Ethical approval for this study was obtained from the institutional ethics committee of Keio University School of Medicine (approval number 20251194), and informed consent was obtained from this participant. Verbal informed consent for publication was obtained from the patient and formally documented in the medical record. 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.
Financial Disclosures and Conflicts of Interest: T.A. received research funding partly from Keio University, Center for Parkinson’s Disease Research. All other authors report no relevant financial relationships or conflicts of interest related to the material in this article. Author disclosures are available in the Supporting Information.
Supporting information
Data S1. Supplementary Methods. Determination of plasma concentrations of L‐Dopa and 3‐O‐methyldopa (3‐OMD) and calculation of corrected L‐Dopa concentration. This Supplementary Methods section describes the procedures for plasma L‐Dopa and 3‐O‐methyldopa quantification by high‐performance liquid chromatography with electrochemical detection and the methods used to estimate LAT1 inhibition and calculate corrected L‐Dopa concentration.
Data S2. COI_disclosure.
Acknowledgments
This study was supported by Keio University, Center for Parkinson's Disease Research to T.A. We thank the patient and her family members who were involved in this research. None of the study participants received financial incentives.
Potential conflict of interest: T.A. received research funding partly from Keio University, Center for Parkinson’s Disease Research. All other authors report no relevant financial relationships or conflicts of interest related to the material in this article.
Data Availability Statement
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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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supplementary Methods. Determination of plasma concentrations of L‐Dopa and 3‐O‐methyldopa (3‐OMD) and calculation of corrected L‐Dopa concentration. This Supplementary Methods section describes the procedures for plasma L‐Dopa and 3‐O‐methyldopa quantification by high‐performance liquid chromatography with electrochemical detection and the methods used to estimate LAT1 inhibition and calculate corrected L‐Dopa concentration.
Data S2. COI_disclosure.
Data Availability Statement
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.