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Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease

Bergquist, Filip ; Ehrnebo, Mats ; Nyholm, Dag ; Johansson, Anders ; Lundin, Fredrik ; Odin, Per LU orcid ; Svenningsson, Per ; Hansson, Fredrik ; Bring, Leif and Eriksson, Elias , et al. (2022) In Neurology 99(10). p.965-976
Abstract

Background and ObjectivesIntestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease.MethodsA concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label,... (More)

Background and ObjectivesIntestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease.MethodsA concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations.ResultsWith dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient.DiscussionIt is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.Trial Registration InformationClinicalTrials.gov identifier: NCT03419806. Registration first posted on February 5, 2018, first patient enrolled on February 16, 2018.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurology
volume
99
issue
10
pages
965 - 976
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85138146797
  • pmid:35705502
ISSN
0028-3878
DOI
10.1212/WNL.0000000000200804
language
English
LU publication?
yes
id
2997cacb-8c6d-48cb-b986-56e7fb2df980
date added to LUP
2023-01-19 11:30:28
date last changed
2024-06-13 23:19:26
@article{2997cacb-8c6d-48cb-b986-56e7fb2df980,
  abstract     = {{<p>Background and ObjectivesIntestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease.MethodsA concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations.ResultsWith dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient.DiscussionIt is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.Trial Registration InformationClinicalTrials.gov identifier: NCT03419806. Registration first posted on February 5, 2018, first patient enrolled on February 16, 2018.</p>}},
  author       = {{Bergquist, Filip and Ehrnebo, Mats and Nyholm, Dag and Johansson, Anders and Lundin, Fredrik and Odin, Per and Svenningsson, Per and Hansson, Fredrik and Bring, Leif and Eriksson, Elias and Dizdar, Nil}},
  issn         = {{0028-3878}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{10}},
  pages        = {{965--976}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Neurology}},
  title        = {{Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease}},
  url          = {{http://dx.doi.org/10.1212/WNL.0000000000200804}},
  doi          = {{10.1212/WNL.0000000000200804}},
  volume       = {{99}},
  year         = {{2022}},
}