Levodopa Formulations Research Articles

The Dopamine Transporter Is a New Target for Ischemic Stroke.

Dopamine transporter (DAT) can regulate DA homeostasis and has been implicated in many nervous system diseases. Whether DAT is involved in the protection against ischemic stroke is unclear. In vivo microdialysis measurements of DA were recorded in the ischemic penumbral area of mice with middle cerebral artery occlusion (MCAO). DAT coding gene, Slc6a3 mutation, and DAT overexpression animals were performed MCAO. Madopar (compound formulation of levodopa) and nomifensine (DA reuptake inhibitor) were administered in MCAO animals. Brain slices were prepared in Slc6a3 mutation or wild-type (WT) animals with MCAO to record miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). The effects of DA and its dopamine-1 receptor (D1R) antagonists (SCH-23390) on mEPSCs, mIPSCs, and neurons protection were recorded. MCAO caused a prominent increase in DA. Slc6a3 mutation significantly attenuated the ischemic injury, whereas DAT overexpression aggravated this injury. Both nomifensine and madopar protected against brain injury. Slc6a3 mutation and DA restored the disturbance of mEPSCs and mIPSC, and protected against neuron death, which was abolished by SCH-23390. DAT inhibition might be explored as a strategy for ischemic stroke prevention. DA and D1R involve in the restoration of synaptic dysfunction and neuron protection.

Levodopa versus levodopa sparing in early parkinson's disease: can we meet halfway?

Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.

Formulation, Optimisation and Evaluation of Levodopa and Entacapone Loaded Transdermal Patches for the Treatment of Parkinson’s Disease

Parkinson’s disease is an extrapyramidal motor disorder leading to progressive degeneration of neurons in substantia niagra, pars compacta and the dopaminergic tract. The most promising drugs used to treat Parkinson’s disease, i.e., levodopa and entacapoe have very low oral bioavailability because of first-pass metabolism, therefore to increase the bioavailability of levodopa and entacapone, these were incorporated in transdermal patches. Different formulations of the levodopa and entacapone drugs were prepared with different polymeric ratios, by using the solvent casting method and the formulations were evaluated for in-vitro and in-vivo tests, which focus on drug release and drug excipient compatibilities. Various models were applied to ascertain the kinetics of drug release by using in-vitro release data. Nine formulations were prepared and evaluated out of which F6 was found to be the best formulation, which contained HPMC and ethyl cellulose in the ratio of 2:3. It showed drug release of 99.11% in about 12 hours.

Sublingual apomorphine in the treatment of Parkinson's disease.

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials.

Therapeutic effect of an inhaled levodopa dry powder formulation on off episodes in patients with Parkinson's disease.

Limited treatment options with a rapid onset of action are available to treat off episodes in Parkinson's disease (PD) patients. Therefore, the development of rapid onset formulations, for instance with levodopa, is warranted, which was the reason to investigate an inhalable formulation of levodopa. The primary objective was to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients. The secondary objective was to compare the time until maximal effect and the maximal effect of inhaled levodopa versus oral levodopa. Open-label randomized two-way one-period crossover trial. Nine PD patients in the 'off state' received one dose of inhaled levodopa (90 mg) from Cyclops® and one dose of levodopa orodispersible tablet (100 mg) on two consecutive days in a randomized order. A timed tapping test, Timed Up and Go test (TUG test) and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score were performed pre-dose and on set time points up to 90 min post-dose as measure for motor function. In addition, blood samples were taken for a pharmacokinetic evaluation (T max, C max and area under the concentration time curve (AUC) 0-3 h). The maximal effect of inhaled levodopa was reached at 30 min (tapping test), at 75 min (TUG test) and at 60 min (UPDRS III). The positive effect on the UPDRS was statistically significant within 20 min after inhalation. After oral administration, C max and AUC 0-3 h were found to be significant higher (p = 0.028 and p = 0.028, respectively) than after pulmonary administration. T max was achieved significantly (p = 0.028) faster after inhalation. The motor function examinations showed a similar maximum clinical improvement after pulmonary and oral administration and although not significant, inhaled levodopa results in a shorter median duration to maximum clinical effect for the TUG and timed finger-tapping test compared with oral administration (TUG: inhalation 55.0 and oral 67.5 min, timed finger-tapping test: inhalation 35.0 and oral 57.5 min). After the levodopa inhalation, there were no adverse events observed and no significant differences found in long-function parameters. Inhaled levodopa from Cyclops® shows promising data as a rescue therapy for PD patients with off episodes, not responsive to the current oral therapies. The study protocol was approved by the local ethics board 'Regionale toetsingscommissie patiëntgebonden onderzoek' (RTPO) in Leeuwarden, The Netherlands (approval number RTPO1019). The study was registered in in the Dutch trial register (LTR) with identification number NL6876. From 5 March 2024 on, the research data on onderzoekmetmensen.nl are known as 'Overview of Medical Research in the Netherlands' (OMON). This means the use of the name LTR has thus been dropped. Now, it is registered in the OMON with the same identification number (NL6876, Effectiveness of inhaled levodopa in PD | Research with human participants (onderzoekmetmensen.nl)). All patients provided written informed consent.

Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Levodopa is currently the standard of care treatment for Parkinson’s disease, but chronic therapy has been linked to motor complications. Designing a controlled release formulation (CRF) that maintains sustained and constant blood concentrations may reduce these complications. Still, it is challenging due to levodopa’s pharmacokinetic properties and the notion that it is absorbed only in the upper small intestine (i.e., exhibits an “absorption window”). We created and validated a physiologically based mathematical model to aid the development of such a formulation. Analysis of experimental results using the model revealed that levodopa is well absorbed throughout the entire small intestine (i.e., no “absorption window”) and that levodopa in the stomach causes fluctuations during the first 3 h after administration. Based on these insights, we developed guidelines for an improved CRF for various stages of Parkinson’s disease. Such a formulation is expected to produce steady concentrations and prolong therapeutic duration compared to a common CRF with a smaller dose per day and a lower overall dose of levodopa, thereby improving patient compliance with the dosage regime.

Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism.

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.

Establishing a framework for quality of inpatient care for Parkinson's disease: A study on inpatient medication administration

BackgroundThe complexity of antiparkinsonian medications makes patients vulnerable to medication deviations. This study examines the frequency and outcomes of deviations between outpatient and inpatient medication administrations in patients with Parkinson's disease (PD). MethodsWe included hospital admissions of patients with PD during a 12-month period at the Cleveland Clinic Main and Fairview campuses. Outpatient regimens were compared with hospital medication administration records to establish rates of deviations in terms of levodopa equivalent daily dose (LEDD) difference, timing deviations/omissions of time-critical medications, substitution of levodopa compounds, and administration of antidopaminergic medications. Logistic regression analyses were used to investigate associations with length of stay (LOS), readmission rates, and mortality. ResultsThe study included 492 patients with 725 admissions. Of those on time-critical medications, 43% had a LEDD deviation and 19% had levodopa formulation substitutions. Of the admission days with known outpatient timing regimens, 47% had an average deviation of more than 30 min and 22% had at least one missed levodopa dose. LOS was longer with each additional day of over-dose (4%), under-dose (14%), missed dose (21%), timing deviation (15%) and substitution (19%), (all p < 0.0001). Administration of antidopaminergic medications (9.9% of admissions) was associated with increased 30-day readmission/death (OR 1.85, p = 0.041), 90-day mortality (OR 2.2, p = 0.018), and LOS (7.6 vs. 3.8 days, p < 0.0001). LEDD underdose was associated with 30-day readmission/death (OR 1.78, p = 0.025) and 90-day mortality (OR 1.14, CI 1.05–1.24, p = 0.002). ConclusionsDeviations between outpatient and hospital regimens, and administration of antidopaminergic medications, were associated with poor outcomes.

Off-time Treatment Options for Parkinson's Disease.

Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor - Opicapone-, two MAO-B inhibitors plus channel blocker - Zonisamide and Safinamide and one amantadine extended-release formulation - ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients' preference, caregiver's availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.

The risk of developing motor complications with Levodopa immediate versus dual release upon treatment initiation in Parkinson’s disease

IntroductionMotor complications (MCs) compromise therapy in many patients suffering from Parkinson’s Disease. By achieving more physiologic stimulation of dopamine-receptors, the continuous dopamine stimulation hypothesis suggests that longer-acting levodopa formulations may improve outcome. The aim of this study was to compare the duration until onset of MCs and motor disease progression in patients during their treatment initiation with either an immediate (IR) or a combined rapid- and sustained-release (i.e. dual-release; DR) levodopa formulation. MethodsUsing a sample of 69 patients, we applied time-varying survival regression analyses and linear mixed effect models to analyze the data. The latter involved preprocessing of the data to temporally align the response and predictors, including analyzing the extent of visit irregularity and potential predictors of visit intensity. ResultsThis retrospective study suggests that levodopa-benserazide DR is not superior to levodopa-benserazide IR in affecting duration until MCs and disease progression. Conversely, using DR levodopa-benserazide, similar disease progression was achieved with lower and more constant doses. ConclusionsThe effects of DR levodopa-benserazide might not be strong enough to delay onset of MCs. The development of more powerful levodopa formulations remains a pressing clinical need.

Improving levodopa delivery: IPX203, a novel extended-release carbidopa-levodopa formulation

IntroductionIPX203 is a novel oral extended-release (ER) formulation of carbidopa (CD) and levodopa (LD) developed to address the short half-life and limited area for absorption of LD in the gastrointestinal tract. This paper presents the formulation strategy of IPX203 and its relationship to the pharmacokinetics (PK) and pharmacodynamic profile of IPX203 in Parkinson’s disease (PD) patients. MethodsIPX203 was developed with an innovative technology containing immediate-release (IR) granules and ER beads that provides rapid LD absorption to achieve desired plasma concentration and maintaining it within the therapeutic range for longer than can be achieved with current oral LD formulations. The PK and pharmacodynamics of IPX203 were compared with IR CD-LD in a Phase 2, open-label, rater-blinded, multicenter, crossover study in patients with advanced PD. ResultsPharmacokinetic data showed that on Day 15, LD concentrations were sustained above 50% of peak for 6.2 h with IPX203 vs. 3.9 h with IR CD-LD (P = 0.0002). Pharmacodynamic analysis demonstrated that mean MDS-UPDRS Part III scores prior to administration of the first daily dose were significantly lower among patients receiving IPX203 than IR CD-LD (LS mean difference –8.1 [25.0], P = 0.0255). In a study conducted in healthy volunteers, a high-fat, high-calorie meal delayed plasma LD Tmax by 2 h, and increased Cmax and AUCtau by approximately 20% compared with a fasted state. Sprinkling capsule contents on applesauce did not affect PK parameters. ConclusionThese data confirm that the unique design of IPX203 addresses some of the limitations of oral LD delivery.

Concomitant use of magnesium oxide significantly decreases absorption of levodopa preparations in patients with Parkinson’s disease

IntroductionConstipation is one of the most frequent non-motor symptoms of Parkinson's disease (PD), and magnesium oxide (MgO) is a frequently used laxative. This study aimed to investigate the effect of concomitant use of MgO on the pharmacokinetics of levodopa preparations in patients with PD. MethodsWe prospectively enrolled 35 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and motor symptoms with and without MgO. The impact of alterations in pH and the addition of MgO on the solubility of levodopa formulations were also evaluated under in vitro conditions. ResultsConcomitant use of MgO significantly reduced the maximum plasma concentration of levodopa (Cmax) (from 7.66 ± 3.74 μmol/L to 5.82 ± 3.69 μmol/L; p = 0.006) and area under the plasma concentration–time curve 3 h after drug administration (AUC3h, from 9.64 ± 3.23 μmol·h/L to 7.39 ± 3.15 μmol·h/L; p < 0.001), and further decreased carbidopa Cmax (from 64.02 ± 27.02 ng/mL to 38.83 ± 21.94 μmol/L; p < 0.001) and AUC3h (from 130.58 ± 65.64 ng/mL to 76.48 ± 52.24 ng·h/mL; p < 0.001). The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III score also deteriorated significantly (from 30.71 ± 11.34 to 32.06 ± 11.22; p = 0.007). MgO significantly affected the pharmacokinetics of levodopa and carbidopa. This also applied when the findings were analyzed by sex and age. In vitro dissolution experiments revealed a decrease in the relative concentrations of levodopa, carbidopa, and benserazide as the pH increased and in the presence of MgO suspension, with the most prominent impact on benserazide. ConclusionsConcomitant use of MgO and levodopa should be discouraged to improve levodopa absorption.

Effect of Surface Charge Density of a w/o/w Emulsion on the Brain Targeting of Levodopa in Rats for the Treatment of Parkinson’s Disease

Background: Amidst levodopa being considered as the “Gold standard” in the treatment of Parkinson’s disease (PD), it still has critical therapeutic issues with its dose regimen and dosage forms leading to severe adverse drug effects, decreased drug efficacy during chronic use, and requires an enforced “drug holiday” in PD patients. Hence, in this study, we designed a novel levodopa and carbidopa water-in-oil-in-water (w/o/w) formulation for bioavailability improvement in the central nervous system (CNS). Methods: The new one-in-one embedment of the w/o/w levodopa and carbidopa emulsion formulation was obtained by a double emulsion technique. The plasma and brain levels following intravenous administration of the emulsions in rats were determined. Results: The incorporation of stearylamine (a cationic surfactant) considerably increased the surface charge density of the emulsion droplets. This formulation exhibited a narrow particle size distribution enabling parenteral administration. The formulation also provided a high drug loading capacity. In in vivo study, this novel formulation significantly increased the bioavailability of levodopa in the CNS (P &lt; 0.001). The strong resistance to desorption (due to higher charge density) and the presence of positive charge on the particles upon dilution may be the main reason for enhanced brain levels of levodopa. Conclusion: Our current formulation F5 may decrease the dose of levodopa, leading to decreased adverse effects and dosing problems, thus appreciably benefit PD patients in the future.

Major advances in Parkinson's disease over the past two decades and future research directions

Developments in levodopa formulations and the standardisation of deep brain stimulation (DBS) substantially improved clinical management of patients with Parkinson's disease before the turn of the century. As a result of these developments, Parkinson's disease has become a chronic disorder and it is associated with a plethora of non-motor disabling complications. Cognitive impairment is now a major complication of Parkinson's disease.1 Patients gradually develop from being cognitively normal, to having mild cognitive impairment and then dementia as part of a continuum of progressive pathological changes in the brain, including misfolded protein deposition and neuronal loss.

Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. AbbVie.

Different dissolution conditions affect stability and dissolution profiles of bioequivalent levodopa-containing oral dosage forms

Parkinson’s disease is frequently treated with combinations of levodopa/carbidopa and, at the occurrence of motor fluctuations, levodopa/carbidopa/entacapone. For these (and other) medications, using generic versions can reduce costs. To show that generic drugs are equivalent to the originator drug, regulations usually refer to the bioavailability of active ingredients, which is influenced by the selected dosage form and the chosen excipients. However, while registration trials administer drugs under standardized conditions, these conditions often do not reflect the conditions of patients’ daily intake. Thus, this study aimed to characterize levodopa combinations from different manufacturers in biorelevant media.Dissolution profiles of bioequivalent levodopa/carbidopa combinations and levodopa/carbidopa/entacapone combinations were tested in different media, such as tap water, gastric fluid without pepsin and whole milk. Results showed distinct discrepancies in the drugs’ dissolution profiles between manufactures. Using whole milk as a dissolution medium led to the most differing dissolution profiles. Furthermore, carbidopa was unstable in tap water and milk, and it rapidly degraded. This effect was less pronounced if entacapone was present. In contrast to reports in the literature, stability testing did not show that vitamin C helps to protect against carbidopa degradation. Entacapone hardly dissolved in an acidic environment.This study found that dissolution of bioequivalent levodopa formulations varied with changing media. Further, the stability of carbidopa was found to be critical. As an implication, an acidic environment must be ensured when these drugs are applied, and generic exchange of levodopa combinations should be considered only with great caution.

Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson’s disease patients

Biorelevant in vitro release models are valuable analytical tools for oral drug development but often tailored to gastrointestinal conditions in ‘average’ healthy adults. However, predicting in vivo performance in individual patients whose gastrointestinal conditions do not match those of healthy adults would be of great value for optimizing oral drug therapy for such patients. This study focused on establishing patient-specific in vitro and in silico models to predict the in vivo performance of levodopa extended-release products in Parkinson’s disease patients. Current knowledge on gastrointestinal conditions in these patients was incorporated into model development. Relevant in vivo pharmacokinetic data and patient-specific in vitro release data from a novel in vitro test setup were integrated into patient-specific physiologically-based pharmacokinetic models. AUC, cmax and tmax of the computed plasma profiles were calculated using PK-Sim®. For the products studied, levodopa plasma concentration–time profiles modeled using this novel approach compared far better with published average plasma profiles in Parkinson’s disease patients than those derived from in vitro release data obtained from the ‘average’ healthy adult setup. Although further work is needed, results of this study highlight the importance of addressing patient-specific gastrointestinal conditions when aiming to predict drug release in such specific patient groups.

Colorimetric determination of carbidopa in anti-Parkinson drugs based on 4-hydroxy-3-methoxybenzaldazine formation by reaction with vanillin

In this paper is reported the selective colorimetric detection and quantification of carbidopa, an inhibitor of aromatic amino acid decarboxylase, in the co-presence of levodopa as dopamine precursor in pharmaceutical formulations for the treatment of Parkinson’s disease. The method is based on the selective condensation reaction between the hydrazine group from carbidopa and the formyl functional group of vanillin, a natural flavoring agent, in acidified alcoholic solution. The yellow color development (λmax ~ 420 nm) due to the formation of 4-hydroxy-3-methoxybenzaldazine (HMOB) was observed for carbidopa only, whereas levodopa, lacking the hydrazine group, did not color the solution, as expected. The calibration curves for two tablet formulations of levodopa in combination with carbidopa (4:1) were superimposable with levodopa/carbidopa (4:1), as well as carbidopa alone, in standard solution, i.e., the excipients and additives did not interfere with carbidopa determination, corresponding to a mean recovery about 105%. The linear dynamic range was between 5.00 and 50.0 mg L−1 with very good reproducibility within this range (CVav% about 3–4%) and very good sensitivity, with limits of quantification of about 1 mg L−1. The colorimetric method developed here is very simple, inexpensive, and effective for drug estimation and quality control of pharmaceutical formulations.Graphical abstract

Newly Approved and InvestigationalDrugsfor Motor Symptom Control in Parkinson's Disease.

Motor symptoms are a core feature of Parkinson’s disease (PD) and cause a significant burden on patients’ quality of life. Oral levodopa is still the most effective treatment, however, the motor benefits are countered by inherent pharmacologic limitations of the drug. Additionally, with disease progression, chronic levodopa leads to the appearance of motor complications including motor fluctuations and dyskinesia. Furthermore, several motor abnormalities of posture, balance, and gait may become less responsive to levodopa. With these unmet needs and our evolving understanding of the neuroanatomic and pathophysiologic underpinnings of PD, several advances have been made in defining new therapies for motor symptoms. These include newer levodopa formulations and drug delivery systems, refinements in adjunctive medications, and non-dopaminergic treatment strategies. Although some are in early stages of development, these novel treatments potentially widen the available options for the management of motor symptoms allowing clinicians to provide an individually tailored care for PD patients. Here, we review the existing and emerging interventions for PD with focus on newly approved and investigational drugs for motor symptoms, motor fluctuations, dyskinesia, and balance and gait dysfunction.

COMT Inhibitors in the Management of Parkinson's Disease.

Levodopa treatment remains the gold standard for Parkinson's disease, but shortcomings related to the pharmacological profile, notably, oral administration and the consequent occurrence of motor complications, have led to the development of several add-on levodopa treatments or to research to improve the method of delivery. Motor fluctuations, and to a lesser extent non-motor fluctuations, concern half of the patients with Parkinson's disease after 5 years of disease and patients identified them as one of their most bothersome symptoms. Catechol-O-methyl transferase inhibitors (COMT-Is) are one of the recommended first-line levodopa add-on therapies for the amelioration of end-of dose motor fluctuations in patient with advanced Parkinson's disease. Currently, two peripheral COMT-Is are considered as first-line choices - entacapone (ENT), which was approved by the US Food and Drug Administration in 1999 and the European Committee in 1998; and opicapone (OPC), which was approved by the European Committee in 2016. A second-line COMT-I that requires regular hepatic monitoring, tolcapone (TOL), was approved by the Food and Drug Administration in 1998 and the European Committee in 1997. Of note, OPC also received Food and Drug Administration approval in 2021, but it is still only marketed in a few countries, including Germany, UK, Spain, Portugal, Italy, Japan, and USA, while ENT and TOL have a wider market. Our narrative review summarizes the pharmacokinetic/pharmacodynamic properties, clinical efficacy in terms of motor fluctuations, motor/non-motor symptoms, quality of life, and safety data of these three COMT-Is, as evidenced by randomized clinical trials, as well as by real-life observational studies. Overall, a phase III non-inferiority trial showed a similar effect between ENT and OPC on off-time (-60.8 min/day and -40.3 min/day, vs placebo, respectively), with a possible additional off-time reduction of 39 min/day, obtained when there is a switch from ENT to OPC. Concomitantly, TOL can reduce off-time by an average of 98 min/day. A significant though discrete concomitant reduction on the Unified Parkinson's Disease Rating Scale motor section (2-3 points) is obtained with all three drugs vs placebo. Data on quality of life are fewer and more heterogeneous, with positive results obtained especially in open-label studies. Effects on non-motor symptoms were investigated as secondary outcome only in a few studies, frequently by means of non-specific scales and a benefit was observed in open-label studies. Dopaminergic adverse effects were the most frequent, dyskinesia being the most common for the three drugs eventually requiring levodopa dose reductions. No urine discoloration and a very low incidence of diarrhea were found with OPC compared with ENT and TOL. Regular hepatic monitoring is needed only for TOL. A combination of COMT-Is with new formulations of levodopa, including the subcutaneous, intrajejunal, or new extended-release formulation, merits further exploration to improve the management of both mild and severe motor fluctuations.