Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease

Abstract

The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. Methods: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. Results: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. Interpretation: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD.

Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion

“…Previous work demonstrated that foslevodopa/ foscarbidopa SC infusion was able to maintain stable LD exposure in healthy volunteers [4]; however, tolerable LD exposures in healthy volunteers are notably lower than what is reported in PD patients. High LD exposures in non-dopamine deficient healthy volunteers are associated with troublesome side effects making the exploration of higher foslevodopa/foscarbidopa doses in the healthy volunteer study population impractical.…”

“…Foslevodopa/foscarbidopa is in development for the treatment of motor complications for patients with advanced PD (aPD) and is intended to be delivered continuously for 24 h/day. The stability of LD exposure from foslevodopa/foscarbidopa CSCI has been already demonstrated in healthy volunteers [4]. The current work characterizes the LD and CD pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients.…”

“…A total of 28 subjects (N = 28) were initially enrolled in the study (N = 13 in Part 1 and N = 15 in Part 2) from seven sites in the United States. Part 1 of this study used a 4:1 foslevodopa:foscarbidopa ratio; however, a clinical study demonstrated that the bioavailability of CD was higher than expected following foslevodopa/foscarbidopa CSCI [4]. Following consultation with the United States Food and Drug Administration (FDA), the drug formulation was modified during the study to match the 4:1 exposure of oral LD/CD, which was obtained by reducing the amount of foscarbidopa relative to the amount of foslevodopa.…”

“…The degree of fluctuation for LD was determined from hours 16-72 as a transformation of the determined PK parameters (C max -C min )/C ave for each subject. As a comparator to the LD PK following the foslevodopa/foscarbidopa infusion, oral LD PK data was simulated using linear scaling from previously published oral LD/CD data in healthy volunteers [4]. The simulations represent 3 separate oral doses of 100/400 mg LD/CD administered every 5 h. The steady state LD exposure was determined for each subject as the AUC from hours 16-72 divided by 56 h (time difference over the AUC 16-72 interval) following foslevodopa/foscarbidopa infusion.…”

Parkinson’s disease – a review of pathogenesis, recent advances in management, and challenges of care in sub-Saharan Africa

“…These include continuous intestinal delivery of levodopa-carbidopa gel via percutaneous gastrojejunostomy [92], which, according to some studies, is comparable to DBS for the treatment of motor fluctuations in advanced PD [93]. Others include inhaled levodopa-carbidopa [94] and a subcutaneous levodopa-carbidopa infusion [95].…”