Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC-HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel.

Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug-related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open-label, 2-period crossover study in 20 healthy participants. Participants received either 24-h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC-MSn was performed using high-resolution mass spectrometry to identify drug-related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3-OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug-related compounds with the exception of the administered foslevodopa. 3-OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC-MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.

Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.

Opicapone Pharmacokinetics and Effects on Catechol- O -Methyltransferase Activity and Levodopa Pharmacokinetics in Patients With Parkinson Disease Receiving Carbidopa/Levodopa.

OBJECTIVES: Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease. METHODS: Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented. RESULTS: Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased. CONCLUSIONS: Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.

Ascorbic acid can alleviate the degradation of levodopa and carbidopa induced by magnesium oxide.

INTRODUCTION: Levodopa and carbidopa are reported to be degraded by magnesium oxide (MgO), which is often used as a laxative for patients with Parkinson's disease (PD). Ascorbic acid (AsA) can stabilize levodopa and carbidopa solutions; however, the effect of AsA on the degradation of levodopa and carbidopa induced by MgO has not been fully investigated. METHODS: The effect of AsA was evaluated using in vitro examinations, compared with lemon juice, and by measuring the plasma concentration of levodopa in a patient with PD. RESULTS: In vitro experiments showed that the relative concentrations of levodopa remained almost constant, and the relative concentrations of carbidopa decreased with time with addition of MgO. AsA mitigated this effect in a concentration-dependent manner, whereas the addition of lemon juice caused little change, although the pH decreased to the same extent. The results of levodopa pharmacokinetics of the patient showed that the area under the plasma concentration-time curve values from hour 0 to 8 were 53.00 µmol·h/L with regular administration and 67.27 µmol·h/L with co-administration of AsA. CONCLUSIONS: AsA can mitigate the degradation of carbidopa induced by MgO and may contribute to improving the bioavailability of levodopa in patients with PD.

A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson's disease.

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson's disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Novel therapeutic interventions for combating Parkinson's disease and prospects of Nose-to-Brain drug delivery.

Parkinson disease (PD) is a progressive neurodegenerative disorder prevalent mainly in geriatric population. While, L-DOPA remains one of the major choices for the therapeutic management of PD, various motor and non-motor manifestations complicate the management of PD. In the last two decades, exhaustive research has been carried out to explore novel therapeutic approaches for mitigating motor and non-motor symptoms of PD. These approaches majorly include receptor-based, anti-inflammatory, stem-cell and nucleic acid based. The major limitations of existing therapeutic interventions (of commonly oral route) are low efficacy due to low brain bioavailability and associated side effects. Nanotechnology has been exploited and has gained wide attention in the recent years as an approach for enhancement of bioavailability of various small molecule drugs in the brain. To address the challenges associated with PD therapy, nose-to-brain delivery utilizing nanomedicine-based approaches has been found to be encouraging in published evidence. Therefore, the present work summarises the major challenges and limitations with antiparkinsonian drugs, novel therapeutic interventions, and scope of nanomedicine-based nose-to-brain delivery in addressing the current challenges of antiparkinsonian therapy. The manuscript tries to sensitize the researchers for designing brain-targeted nanomedicine loaded with natural/synthetic scaffolds, biosimilars, and nucleic acids that can bypass the first-pass effect for the effective management of PD.

Amantadine Revisited: A Contender for Initial Treatment in Parkinson's Disease?

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

Fasting state is one of the factors associated with plasma levodopa fluctuations during levodopa‒carbidopa intestinal gel treatment.

INTRODUCTION: Some patients with Parkinson's disease (PD) undergoing levodopa‒carbidopa intestinal gel (LCIG) treatment experience motor fluctuations in the afternoon. The migrating motor complex, a specific periodic migrating contraction pattern occurring in the stomach and small intestine during the fasting state, can affect drug absorption. We aimed to compare the pharmacokinetic parameters between two conditions (with and without lunch) and assessed the influence of the fasting state on the levodopa pharmacokinetics in LCIG treatment. METHODS: We evaluated the levodopa pharmacokinetics from 12:00 p.m. to 6:00 p.m. in 10 LCIG-treated PD patients in the presence and absence of lunch. RESULTS: The maintenance dose of LCIG correlated strongly with the mean plasma concentration of levodopa in the absence (r = 0.94, coefficient of determination (R2) = 0.89, p < 0.001) or presence of lunch (r = 0.96, R2 = 0.93, p < 0.001). Comparison of the pharmacokinetic parameters revealed that the coefficient of variation was significantly greater in the condition without lunch than in the condition with lunch (p = 0.004): 16.73% (4.88%) without lunch and 9.22% (3.80%) with lunch. There were no significant differences in the mean plasma concentration of levodopa (p = 0.49) and area under the plasma concentration‒time curve (p = 0.27) between the two conditions. CONCLUSIONS: Plasma concentrations of levodopa fluctuated more in patients undergoing LCIG treatment without than with lunch. Our results indicate that a small amount of food intake may be a better corrective approach for worsening of symptoms in the fasting state rather than additional levodopa.

Identification of anti-Parkinson's Disease Lead Compounds from Aspergillus ochraceus Targeting Adenosin Receptors A2A.

Two novel alkaloids compounds together with fifteen know metabolites were identified from Aspergillus ochraceus. The stereochemistry features of the new molecules were determined via HRESIMS, NMR, ECD, and XRD analyses. Amongst these, compounds two compounds exhibited potential efficacy as anti-Parkinson's disease with the EC50 values of 2.30 and 2.45 µM, respectively. ADMET prediction showed that these compounds owned favorable drug-like characteristics and safe toxicity scores towards CNS drugs. Virtual screening analyses manifested that the compounds exhibited not only robust and reliable interactions to adenosine receptors A2A , but also higher binding selectivity to A2A receptors than to A1 and A3 receptors. Molecular dynamics simulation demonstrated the reliability of molecular docking results and the stability of the complexes obtained with the novel compounds and A2A receptors in natural environments. It is the first time that anti-PD lead compounds have been identified from Aspergillus ochraceus and targeting adenosine A2A receptors.

Population pharmacokinetic analysis of apomorphine sublingual film or subcutaneous apomorphine in healthy subjects and patients with Parkinson's disease.

Apomorphine is an on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD). A joint parent-metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine-sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and "OFF" episodes were analyzed using nonlinear mixed-effects modeling. Apomorphine PK was adequately described by a two-compartment model with first-order transit absorption via both routes of administration and first-order metabolism to apomorphine-sulfate with one-compartment disposition and first-order elimination. Bioavailability of apomorphine sublingual film was ~ 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration-time curve [AUC0-∞ ]), with greater weight resulting in lower exposure. Model-predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC0-24 , 66.7 ng•h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96-1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC0-24 , 75.4 and 80.0 ng•h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90-0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and "OFF" episodes, regardless of demographic and clinical characteristics.

Deciphering the Role of Nanoparticle-based Treatment for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that exerts a huge burden on our society. The occurrence of this neurodegenerative disease has been increasing day-by-day. PD can be a serious concern if the patients are left untreated. However, conventional treatment has many side-effects and less bioavailability in the brain. Therefore, the necessary measurement is required to solve the limitations of PD treatment. Nanotechnology has made a major contribution to comprehend PD pathogenesis. Nanotechnology can provide efficient therapies that have reduced side-effects and increased bioavailability in the brain. This review emphasizes the emerging promise of nanoparticle-based treatment, drug delivery, and other therapeutic approaches for PD. Besides, the advantages of different approaches on nanotechnology platforms are far better over conventional therapy in the treatment of PD.

Nanotechnology Driven Approaches for the Management of Parkinson's Disease: Current Status and Future Perspectives.

Parkinson's disease (PD) is believed to be one of the commonly found adult-onset movement disorder occurring due to neurodegeneration and striatal dopamine deficiency. Although clinical diagnosis depends on the occurrence of bradykinesia and other cardinal motor features, PD is linked with many non-motor symptoms that are responsible for overall disability. Among several factors, genetic and environment-related factors are thought to be the major ones accountable for PD. Comprehensive research has shown that a number of drugs are effective in providing symptomatic relief to the patients suffering from PD. But some drug molecules suffer from significant drawbacks such as poor bioavailability and instability, therefore, they sometimes fail to deliver the expected results. Hence, to resolve these issues, new promising novel drug delivery systems have been developed. Liposomes, solid lipid nanoparticles, nanoemulsion, self-emulsifying drug delivery system (SEDDS), niosomes are some of the novel drug delivery system (NDDS) carriers that have been explored for enhancing the CNS concentration of levodopa, apomorphine, resveratrol, and other numerous drugs. This paper elucidates various drugs that have been studied for their potential contribution to the treatment and management of PD and also reviews and acknowledges the efforts of several scientists who successfully established various NDDS approaches for these drugs for the management of PD.

Discovery of Novel Compounds Targeting DJ-1 as Neuroprotectants for Parkinson's Disease by Virtual Screening and In Silico Method.

AIM: To screen the zinc database for structurally similar molecules to compound 23 that targets DJ1 for use as a neuroprotective agent for Parkinson's disease. BACKGROUND: Parkinson's disease (PD) is the second most common chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons of the substantia nigra. To date, several proteins account for the recessive familial PD-forms, namely, Parkin, PINK-1, DJ-1, SNCA, PARK2, and LRRK2 Genes. DJ1 is one of the important central points that may be targeted for PD therapy. Recently, Compound 23 has been observed to exert the neuroprotective effect against neurodegeneration in a PD model, but due to its toxic substructure, the hunt for better nontoxic compounds continues. OBJECTIVE: The overall objective of our work is to apply in silico approaches to screen structure similar compounds that interact potentially with DJ1 and may serve as a good therapeutic molecule for PD. METHODS: Initial data mining was done from the zinc database and then screened compounds were additionally screened with toxicity checker, carcinopred, ADMET analysis and docking analysis. RESULTS: The basic screening of database for structurally similar chemicals to compound 23 resulted in 50 compounds, which were further screened to twenty-three and finally seven compounds have been screened based on the toxicity and carcinopred test. Later, the seven compounds were docked and analysed for docking efficiency with DJ1. Our result of molecular docking and molecular simulation analysis highlights Molecule 42(SS2) to exhibit best binding affinity against DJ-1 protein target and can be proposed to be used as a therapeutic agent to modulate neurodegenerative proteins. CONCLUSION: Therefore, we conclude the discovery of novel, non-toxic, non-carcinogenic, ADMET investigated, capable of crossing BB barrier but structurally similar compounds to Compound-23, specifically molecule 42(SS2) and potentially molecule 34(SS1) to be used as neuroprotective agents for Parkinson's disease.

Effect of Opicapone Tablets on Levodopa and 3-O-Methyldopa Pharmacokinetics in Healthy Japanese Subjects: Phase 1 Study.

This study evaluated the effect of a small-tablet formulation of opicapone for use in clinical trials in Japan on the pharmacokinetics of levodopa (l-dopa) and 3-O-methyldopa (3-OMD). In an open-label, 3-period, single-sequence crossover phase 1 study in 80 healthy Japanese males (aged 20-45 years; body mass index, 18.5 to <30.0 kg/m2 ), 10 mg of l-dopa/carbidopa 100 was administered 3 times daily on day 0 (period 1) and day 12 (period 3), and opicapone tablets (5, 10, 25, or 50 mg; n = 20 each group) were administered once daily for 11 days (period 2). During periods 1 and 3, plasma concentrations of l-dopa and 3-OMD were measured and pharmacokinetic parameters (maximum observed plasma concentration, time at which maximum concentration was observed, area under the plasma concentration-time curve from time 0 to 5 hours [AUC5h ] and from time 0 to 24 hours [AUC24h ] following each dose, terminal half-life) of plasma l-dopa and 3-OMD were determined along with the geometric mean ratio (period 3/period 1) of AUC24h for l-dopa and 3-OMD. Maximum concentration of l-dopa for the first, second, or third doses of l-dopa/carbidopa did not significantly increase with increasing opicapone dose. The AUC of l-dopa increased with increasing opicapone dose but tended toward a peak plateau with opicapone doses of 25 mg and higher. Geometric mean ratios (90% confidence intervals) of AUC24h were 5 mg, 1.16 (1.10-1.21); 10 mg, 1.26 (1.23-1.30); 25 mg, 1.51 (1.44-1.57); 50 mg, 1.60 (1.54-1.66). Opicapone tablets were well tolerated. In Japanese healthy subjects, increases in plasma exposure to l-dopa appear to level off with opicapone doses of 25 mg and higher, which may be relevant for optimal dosing among Japanese patients with Parkinson disease.

Improving the Delivery of Levodopa in Parkinson's Disease: A Review of Approved and Emerging Therapies.

Levodopa is the most effective drug for the treatment of Parkinson's disease, but its use as an oral medication is complicated by its erratic absorption, extensive metabolism and short plasma half-life. On long-term use and with disease progression, there is a high incidence of motor and non-motor complications, which remain a major clinical and research challenge. It is widely accepted that levodopa needs to be administered using formulations that result in good and consistent bioavailability and the physiologically relevant and continuous formation of dopamine in the brain to maximise its efficacy while avoiding and reversing 'wearing off' and dyskinesia. However, the physicochemical properties of levodopa along with its pharmacokinetic and pharmacodynamic profile make it difficult to deliver the drug in a manner that fulfils these criteria. In this review, we examine the problems associated with the administration of levodopa in Parkinson's disease and how the use of novel technologies and delivery devices is leading to a more consistent and sustained levodopa delivery with the aim of controlling motor function as well as non-motor symptoms.

A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson's disease: translational gaps or a failing industry innovation model?

INTRODUCTION: Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients. AREAS COVERED: We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns. EXPERT OPINION: Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.

Liver says no: the ongoing search for safe catechol O-methyltransferase inhibitors to replace tolcapone.

Catechol O-methyltransferase (COMT) inhibitors are valuable co-adjuvant drugs in the clinical management of Parkinson's disease (PD), and recent data also suggest therapeutic benefits in other neurological disorders associated with dopamine depletion. However, the relationship between tolcapone administration with fatal cases of drug-induced liver damage gave COMT inhibitors a bad reputation as hepatotoxic drugs. Thus, there is a pressing need to feed the pipeline with safe COMT inhibitors to replace tolcapone, the only currently available COMT inhibitor that effectively reaches the brain. Recent efforts led to promising phenolic and nonphenolic COMT inhibitors, which allow isoform-specific targeting and avoid the toxicological and pharmacokinetic (PK) shortcomings of classic nitrocatechols. Here, we describe advances made in this field over the past 5 years.