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

INTRODUCTION: IPX203 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\u27s disease (PD) patients. METHODS: IPX203 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. RESULTS: Pharmacokinetic 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. CONCLUSION: These data confirm that the unique design of IPX203 addresses some of the limitations of oral LD delivery

Geminin-Deficient Neural Stem Cells Exhibit Normal Cell Division and Normal Neurogenesis

Neural stem cells (NSCs) are the progenitors of neurons and glial cells during both embryonic development and adult life. The unstable regulatory protein Geminin (Gmnn) is thought to maintain neural stem cells in an undifferentiated state while they proliferate. Geminin inhibits neuronal differentiation in cultured cells by antagonizing interactions between the chromatin remodeling protein Brg1 and the neural-specific transcription factors Neurogenin and NeuroD. Geminin is widely expressed in the CNS during throughout embryonic development, and Geminin expression is down-regulated when neuronal precursor cells undergo terminal differentiation. Over-expression of Geminin in gastrula-stage Xenopus embryos can expand the size of the neural plate. The role of Geminin in regulating vertebrate neurogenesis in vivo has not been rigorously examined. To address this question, we created a strain of Nestin-Cre/Gmnnfl/fl mice in which the Geminin gene was specifically deleted from NSCs. Interestingly, we found no major defects in the development or function of the central nervous system. Neural-specific GmnnΔ/Δ mice are viable and fertile and display no obvious neurological or neuroanatomical abnormalities. They have normal numbers of BrdU+ NSCs in the subgranular zone of the dentate gyrus, and GmnnΔ/Δ NSCs give rise to normal numbers of mature neurons in pulse-chase experiments. GmnnΔ/Δ neurosphere cells differentiate normally into both neurons and glial cells when grown in growth factor-deficient medium. Both the growth rate and the cell cycle distribution of cultured GmnnΔ/Δ neurosphere cells are indistinguishable from controls. We conclude that Geminin is largely dispensable for most of embryonic and adult mammalian neurogenesis

Etude de l'expression neuronale des chémokines de la famille CXC (Stromal cell-Derived Factor-1) et CC (Monocyte Chemoattractant Protein-1) et de leur récepteur dans le système nerveux central (implications possibles dans les fonctions cérébrales et neuroendocriniennes)

Bien que les chémokines et leurs récepteurs aient été identifiés et bien étudiés dans le système immunitaire, récemment il a été suggéré qu'elles joueraient aussi un rôle dans le système nerveux central (SNC). L'établissement d'une cartographie précise des chémokines/récepteurs dans le SNC nous a semblé une étape essentielle à la compréhension de leurs effets centraux. Ainsi, le présent travail a eu pour but d'établir chez le rat, une cartographie détaillée de la distribution neuroanatomique des chémokines/récepteurs. Nos études ont porté sur les chémokines Stromal cell-Derived Factor-1 (SDF-1) et Monocyte Chemoattractant Protein-1 (MCP-1) et leur récepteur respectif CXCR4 et CCR2. Tout d'abord, nous avons démontré par autoradiographie quantitative que les sites de liaison du [125]SDF-1 sont distribué de manière homogène dans le cerveau, alors que des sites de liaison du [125]MCP-1 ont une nette régionalisation. Ensuite nous avons établi, par immunohistochimie en fluorescence, que les récepteurs CXCR4, CCR2 ainsi que leur ligands sont exprimés de manière constitutive par les neurones, au niveau des structures neuroanatomiques précises. Par ailleurs, nous avons clairement établi que ces chémokines/récepteurs sont exprimés par les neurones cholinergiques et dopaminergiques. SDF-1, MCP-1 et CXCR4 sont aussi co-localisés avec la vasopressine dans noyaux supraoptiques (SON) et paraventriculaires (PVN) de l'hypothalamus et avec la MCH (melanin concentrating hormone) dans l'hypothalamus latéral. Nous avons aussi mis en évidence la présence du MCP-1 au niveau des trajets vasopressinergiques, de la couche interne de l'éminence médiane et de la neurohypophyse. Au cours d'une déshydratation, nous avons montré une nette diminution de l'expression du MCP-1 et du CXCR4 au niveau du PVN et du SON. L'ensemble des résultats originaux obtenus au cours de cette thèse nous a permis d'ouvrir un champ de recherche nouveau concernant les fonctions neuromodulatrices des chémokines.Besides their well-established role in the immune system, chemokines play a role in physiological and pathological brain functions. Knowledge of cellular and regional distribution of chemokines and their receptors in the brain is essential to further understand their cerebral functions. The aim of this study was to establish a detailed neuroanatomical mapping of chemokine and their receptors in rat brain. We focused on chemokines Stromal cell-Derived Factor-1 (SDF-1) and Monocyte Chemoattractant Protein-1 (MCP-1) and their receptors CXCR4 and CCR2 respectively. Firstly, by quantitative autoradiography we demonstrated that [125]SDF-1 binding sites were almost uniformly distributed throughout the brain. In contrast, [125]MCP-1 binding sites were highly regionalized in precise neuroanatomical structures. Furthermore, by dual immunohistochemistry we provide evidence that both of these chemokine/receptor couples were constitutively expressed by neurons in neuroanatomical structures such as cerebral cortex, substantia innominata, hypothalamic nuclei, substantia nigra and motoneurons. We demonstrated for the first time that SDF-1, CXCR4, MCP-1 and CCR2 were expressed in cholinergic and dopaminergic neurons. We also provide evidence that SDF-1, CXCR4 and MCP-1 colocalized with vasopressin in magnocellular neurons of supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. MCP-1-immunoreactivity was also observed in vasopressinergic processes projecting from magnocellular neurons, internal layer of eminence median and posterior pituitary; suggesting that MCP-1 might be a neurosecretory chemokine. In dehydrated rat, MCP-1 and CXCR4 expression decreased in both SON and PVN. Interestingly, in the lateral hypothalamus SDF-1, CXCR4 and MCP-1 colocalized with MCH-expressing neurons. Altogether, original results obtained here open up a new field of research on neuromodulatory functions of chemokines and suggest their implication in regulation of neuroendocrine functions.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Real-World Experience with Carbidopa-Levodopa Extended-Release Capsules (Rytary®): Results of a Nationwide Dose Conversion Survey

Background. The introduction of carbidopa-levodopa extended-release (CD-LD ER) capsules (Rytary®) did not go as smoothly as expected, largely due to difficulty around dose conversion from available immediate-release (IR) levodopa (LD) formulations. The dose conversion table in the CD-LD ER prescribing information was similar to the table used in the pivotal clinical trial and is considered by many prescribing HCPs to be less than optimal. By the end of the dose conversion period in that trial, dosing in 76% of subjects was adjusted for symptom control; roughly 60% of patients required a higher dose and about half required more frequent administration than the recommended TID dosing. Objective. The primary objective of our nationwide (US) survey was to determine the dose conversion strategy most commonly employed by CD-LD ER frequent prescribers. The survey also aimed to explore additional features regarding CD-LD ER use in clinical practice. Methods. A survey consisting of 21 multiple-choice questions was developed and administered to experts in the use of CD-LD ER, based on prescription volume. Results. Of the 394 HCPs who were invited to participate, 90 (23%) HCPs completed the survey. All respondents were aware of the dose conversion table; the largest group did not find the table to be helpful and did not use it to convert patients to CD-LD ER. The most common strategy in calculating the CD-LD ER dose was based on the total daily LD IR dose, with the majority of that group initiating dose conversion by doubling the total daily LD dose from CD-LD IR and administering CD-LD ER one less time per day. Conclusion. Overall, most survey respondents agreed that a good starting point for CD-LD ER conversion could be doubling the daily LD IR dose and administering it one time less frequently. Moreover, rapid patient follow-up after initial dose conversion to allow for further dose adjustments plays a critical role in achieving success. Gaining experience over time is important for satisfactory conversion

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

Introduction: IPX203 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. Methods: IPX203 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. Results: Pharmacokinetic 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. Conclusion: These data confirm that the unique design of IPX203 addresses some of the limitations of oral LD delivery

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease: The RISE-PD Randomized Clinical Trial

IMPORTANCE: Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations. OBJECTIVE: To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial. INTERVENTIONS: Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks. MAIN OUTCOME AND MEASURES: The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period. RESULTS: A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P \u3c .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%). CONCLUSIONS AND RELEVANCE: In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03670953