Uso de apomorfina
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El documento resume los resultados de varios estudios clínicos sobre el uso de la apomorfina para tratar los síntomas motores y no motores de la enfermedad de Parkinson. Se discuten opciones de administración como infusión subcutánea continua, inhalación, parches transdérmicos y liberación controlada desde implantes. Los estudios sugieren que la apomorfina puede mejorar los síntomas motores y neuropsiquiátricos de manera segura y rápida. Aún se necesita más investigación para establecer la seguridad y eficac
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Uso de apomorfina
- 1. Dr. Philippe Salles Gándara CETRAM Enero 2017
- 2. Estudio TOLEDO Multicéntico, doble-ciego, contra placebo. Fase III Eficacia y seguridad de la infusión de Apomorfina subcutánea en pacientes con EP con fluctuaciones motoras refractarias al tratamiento medico convencional Se espera gran reducción de los periodos off Interés en efecto sobre síntomas no motores
- 3. La via subcutanea ha sido el pilar: Infusión continua Lápiz de inyección Nódulos subcutaneos pueden complicar esta terapia Algunos pacientes tienen fobia a las agujas
- 4. VR04: Apomorfina inhalada Estudios Fase II han demostrado efectividad en el rescate del Off, rápidamente a manera dosis dependiente 0.5 mg “On” en 40 minutos 0.8 mg “On” 20 minutos Hasta 4mg “On” en 10 minutos
- 5. VR04:Apomorfina inhalada Estudios Fase II ClinicalTrials.gov Identifier:NCT01683292 Rápido rescate del Off Dosis de 0.2, 0.5, 0.8 mg estudiadas 0.5 mg “On” en 40 minutos 0.8 mg “On” 20 minutos Hasta 4mg “On” en 10 minutos
- 8. ND0701 ha sido desarrollada como apomorfina para el uso por esta vía de administración Alternativa a la infusión continua Aun se necesita establecer su seguridad y tolerabilidad
- 9. APL-130277 En desarrollo Para rescate de periodos Off 15 de 19 pacientes revirtieron el Off dentro de 30 minutos ~22 minutos Duración del On ~50 minutos Estudios en Fase III ClinicalTrials.gov Identifier: NCT02469090 Dosis 10-30 mg RN-101, Apotone En desarrollo Solución Buffer pH 7.6 cinética similar a una dosis s.c
- 10. El problema sigue siendo la absorción GI 2 Esteres de apomorfina Monolauroyl (MLA) y Dilauroyl (DLA) pueden ser transportados y DLA puede ser convertido a MLA para transporte Posibilidad para estudios clínicos en el futuro
- 12. Los polímeros PLGA pueden ayudar a una liberación lenta de apomorfina en humanos si es implantado Estudios experimentales demuestran protección contra la degradación de productos durante el almacenaje, remoción de solventes tóxicos y proveen una liberación controlada de la apomorfina a tasa constante Journal of Controlled Release 166 (2013) 256–267
- 14. Apomorfina se ha asociado a mejoría en la conducta Estudios observacionales sugieren seguridad y eficacia en EPI con psicosis y síntomas neuropsiquiátricos, también en el manejo de síntomas negativos de la esquizofrenia Incrementaría la respuesta estriatal pero reduce la activación del giro frontal suéropr durante la memoria de trabajo (DAT Scan)
- 16. 80% de pacientes con EPI desarrollan alteraciones cognitivas En estudios patológicos de modelos de alzheimer en roedores y bancos cerebrales de pacientes con EPI sugieren que la apomorfina tiene un rol modificador en el deposito amiloide, autofagia y anti-oxidación.
- 17. Descontrol de impulsos puede ser menor si se administran los AD en forma de liberación continua y no pulsatil Menor descontrol de impulsos con parche transdérmico de rotigotina 9.7% nuevos casos de descontrol de impulsos en un estudio observacional de 3 años con infusión continua de apomorfina
Notas del editor
- One such route is the pulmonary route inwhich apomorphine is administered by an inhaler device (Fig. 1). The pulmonary route bypasses the gastrointestinal tract and provides rapid delivery of the drug to the central nervous system. This is further aided by the fact that the pulmonary system is highly vascular. An inhaled version of apomorphine (VR040) has been developed and has been utilized in a phase 2, placebo-controlled, double-blind clinical trial at a single center in the UK (ClinicalTrials.gov Identifier: NCT01683292). The product is aimed at a quick rescue from“off” periods and, in the clinical trial, 3 doses (0.2, 0.5 and 0.8 mg) were studied. At 0.5 and 0.8 mg“off” was reversed and“on” state was achieved at 40 and 20 min respectively; the product was welltolerated [9]. A subsequent study, with higher doses up to 4 mg, showed good efficacy with a peak plasma level at 2e7 min after inhalation and“off” period reversal at a mean of 10 min. Long-term efficacy data and multicenter trials are still required, but inhalation may become a feasible delivery route for apomorphine rescue therapy in the future [10]. Pulmonary irritation on long term exposure and the ability of PD patients to handle the inhaler device during severe motor“off” periods remain concerns.
- The transdermal patch-pump is a technology where a minipump is attached to a skin patch and delivers the drug via the transdermal route (Fig. 2). The method has been utilized for levodopa delivery and an apomorphine product (ND0701) has been developed for use by this route in advanced PD as an alternative option to apomorphine infusion. The safety and tolerability of this delivery system needs to be further established.
- A buccal formulation of apomorphine (APL-130277) is being developed for use as a rescue medication in overcoming“off” periods (Fig. 3). The product is a thin-film strip containing apomorphine in a bilayer (to avoid oral irritation) and patients are instructed to keep thefilm under the tongue for the drug to be absorbed through the oral cavity for rapid delivery. In initial studies,15 of 19 patients studied experienced reversal of their“off” periods within 30 min (average time to full“on” was 22 min) with the “on” lasting for a mean duration of 50 min [11]. No major adverse events have been reported and there is no report as yet of anyproblematicmucosalirritationinthemouth.Phase3trialswith APL-130277 are now under way in doses ranging from 10 to 30 mg in what promises to be an important new development for rescue therapy in PD (ClinicalTrials.gov Identifier: NCT02469090). Another sublingual device, delivering a buffered solution of apomorphine (RN-101, Apotone) is also being developed. Using buffered solutions at a pH of 7.6 in an early trial the product, which is delivered by a dual chambered device, has shown time toT-max and C-max being comparable to a single dose of subcutaneous apomorphine.
- Oral therapy with apomorphine could avoid many of the problems associated with a needle based subcutaneous therapy, but intestinal absorption of apomorphine remains a key problem. Borkar et al. [12] used a Caco-2 monolayer that is grown on afilter support and is known to be a good model for assessing intestinal permeability and have shown that of two apomorphine esters, monolauroyl apomorphine (MLA) and dilauroyl apomorphine (DLA), MLA can be transported and DLA needs to be converted to MLA for transport. Another study has described the beneficial motor effects of the orally active compound, R-(-)-11-O-valeryl-Nn-propylnoraporphine, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, levodopa-primed dyskinetic common marmosets [13]. Reversal of motor disability and improvement of dyskinesia in these preclinical studies is described as paving the way for future clinical trials of apomorphine esters as oral prodrugs for PD patients
- Controlled release drug delivery systems: poly(lactic-coglycolic acid) (PLGA) copolymers the PLGA polymers could help in promoting slow release of apomorphine in humans if implanted. Experimental studies by Regnier-Delplace et al. [14] suggest that novel types of PLGA copolymers, which either bear free or esterified -COOH groups in the side chains, provide efficient protection against degradation of products during storage, remove toxic solvents, and provide controlled release of apomorphine at a constant rate, thus offering the potential for future therapeutic approaches.
- Apomorphine has been linked to improvement in behavior in previous studies and open-label observations suggest its safety and efficacy in PD patients with psychosis and neuropsychiatric symptoms and in managing the negative symptoms of schizophrenia [15e17]. Passamonti et al. [18] reported that individual differences in striatal dopamine transporter (DAT) levels and levels of nigrostriatal degeneration, measured with DaTscan, drove striatal neural activity during working memory exercises in PD, via a D2-receptor-mediated mechanism. The data suggest that apomorphinechallengeincreasedthe striatalresponsebut reduced activation of the superior frontal gyrus during working memory in these patients (Fig. 4). It is possible that thesefindings could be translated to clinical paradigms to address the behavioral effects of apomorphine using a combination of functional magnetic resonance imaging (f MRI) and quantitative DAT imaging studies.
- Passamonti et al. [18] reported that individual differences in striatal dopamine transporter (DAT) levels and levels of nigrostriatal degeneration, measured with DaTscan, drove striatal neural activity during working memory exercises in PD, via a D2-receptor-mediated mechanism. The data suggest that apomorphinechallengeincreasedthe striatalresponsebut reduced activation of the superior frontal gyrus during working memory in these patients (Fig. 4). It is possible that thesefindings could be translated to clinical paradigms to address the behavioral effects of apomorphine using a combination of functional magnetic resonance imaging (f MRI) and quantitative DAT imaging studies.
- Up to 80% of patients with PD develop functionally significant cognitive impairment [19,20]. Studies in rodent models of Alzheimer's pathology and neuropathological studies based on brain bank studiesinPD patientssuggestthatapomorphinemighthavea role as a potential modifier of amyloid deposition as well as autophagy and anti-oxidation [21,22]. In 3xTg-AD mice, apomorphine infusion appears to improve memory function with a decrease in intraneuronal amyloid deposition [21]. A retrospective brain bankbased study of non-demented PD cases suggested a potential antiamyloid effect of apomorphine [23]. Whether these observations may translate into a clinical therapeuticoptionforapomorphine astherapyforcognitiveimpairment inAlzheimer'sdiseaseorPDremainstobeestablishedvialargescale controlled clinical trials, perhaps with surrogate amyloid imaging
- Impulsecontroldisorders(ICD)haveemergedasakeychallenge to dopaminergic treatment in PD, particularly the use of dopamine agonist therapy, which also is complicated by the potential for dopamine agonist withdrawal syndrome [24]. Recent evidence suggests that ICD rates may be lower when dopamine agonists are administered in a continuous drug delivery strategy rather than as pulsatile therapy. Evidence for this has emerged with low rates of ICD being reported with rotigotine transdermalpatch therapy in an open-label, observational, multicenter study compared with oral dopamine agonists [25]. A 3-year clinical observational study that screened a cohort of patients receiving apomorphine infusion and intrajejunal levodopa infusion for specific development of ICD reports a relatively low rate (9.7%) of new cases on apomorphine infusionwith clinically relevant ICD. However, apomorphine had to be discontinuedin only1 casebecause ofICD [26].It is intriguingto consider whether apomorphine infusion in suitably selected cases of patients with ICD may be a feasible option to consider, as has been suggested in a review of management of ICD in PD