RESUMEN
Migraine is a progressive neurological condition often accompanied by nausea and vomiting. Various drugs have recently been used in the treatment of migraine, including sumatriptan (SUT). However, SUT has poor pharmacological effects mainly due to its reduced permeability, blood brain barrier (BBB) effect, half-life and bioavailability. Herein, we developed SUT loaded nano-ethosomes (SUT-NEs) for intranasal (IN) delivery, after their incorporation into chitosan based mucoadhesive gel (SUT-NEsG). The observed mean particle size of SUT-NEs was 109.45 ± 4.03 nm with spherical morphology, mono dispersion (0.191 ± 0.001), negatively charged (-20.90 ± 1.98 mV) and with excellent entrapment efficiency (96.90 ± 1.85 %). Fourier-transform infrared (FTIR) spectra have depicted the compatibility of the components. Moreover, SUT-NEsG was homogeneous having suitable viscosity and mucoadhesive strength. In vitro release and ex vivo permeation analysis showed sustained release and improved permeation of the SUT-NEsG, respectively. Additionally, histopathological studies of nasal membrane affirmed the safety of SUT-NEsG after IN application. In vivo pharmacokinetic study demonstrated improved brain bioavailability of SUT-NEsG as compared to orally administered sumatriptan solution (SUT-SL). Furthermore, significantly enhanced pharmacological effect of SUT-NEsG was observed in behavioral and biochemical analysis, immunohistochemistry for NF-κB, and enzyme linked immuno assay (ELISA) for IL-1ß and TNF-α in Nitroglycerin (NTG) induced migraine model. It can be concluded that migraine may be successfully managed through IN application of SUT-NEsG owing to the direct targeted delivery to the brain.
Asunto(s)
Trastornos Migrañosos , Sumatriptán , Humanos , Sumatriptán/farmacocinética , Sumatriptán/uso terapéutico , Nitroglicerina/metabolismo , Nitroglicerina/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Administración Intranasal , Mucosa Nasal/metabolismoRESUMEN
Drug absorption is improved by the intranasal route's wide surface area and avoidance of first-pass metabolism. For the treatment of central nervous system diseases such as migraine, intranasal administration delivers the medication to the brain. The study's purpose was to develop an in situ nasal hydrogel that contained liposomes that were loaded with sumatriptan succinate (SS). A thin-film hydration approach was used to create liposomes, and a 32 factorial design was used to optimize them. The optimized liposomes had a spherical shape, a 171.31 nm particle size, a high drug encapsulation efficiency of 83.54%, and an 8-h drug release of 86.11%. To achieve in situ gel formation, SS-loaded liposomes were added to the liquid gelling system of poloxamer-407, poloxamer-188, and sodium alginate. The final product was tested for mucoadhesive strength, viscosity, drug content, gelation temperature, and gelation time. Following intranasal delivery, in vivo pharmacokinetic investigations showed a significant therapeutic concentration of the medication in the brain with a Cmax value of 167 ± 78 ng/mL and an area under the curve value of 502 ± 63 ng/min·mL. For SS-loaded liposomal thermosensitive nasal hydrogel, significantly higher values of the nose-to-brain targeting parameters, that is, drug targeting index (2.61) and nose-to-brain drug direct transport (57.01%), confirmed drug targeting to the brain through the nasal route. Liposomes containing thermosensitive in situ hydrogel demonstrated potential for intranasal administration of SS.
Asunto(s)
Liposomas , Sumatriptán , Sumatriptán/farmacocinética , Hidrogeles/metabolismo , Poloxámero/metabolismo , Encéfalo/metabolismoRESUMEN
Sumatriptan (ST) is a commonly prescribed drug for treating migraine. The efficiency of several routes of ST administration has been investigated. Recently, the intranasal route with different delivery systems has gained interest owing to its fast-acting and effectiveness. The present study is aimed at reviewing the available studies on novel delivery systems for intranasal ST administration. The oral route of ST administration is common but complicated with some problems. Gastroparesis in patients with migraine may reduce the absorption and effectiveness of ST upon oral use. Furthermore, the gastrointestinal (GI) system and hepatic metabolism can alter the pharmacokinetics and clinical effects of ST. The bioavailability of conventional nasal liquids is low due to the deposition of a large fraction of the delivered dose of a drug in the nasal cavity. Several delivery systems have been utilized in a wide range of preclinical and clinical studies to enhance the bioavailability of ST. The beneficial effects of the dry nasal powder of ST (AVP-825) have been proven in clinical studies. Moreover, other delivery systems based on microemulsions, microspheres, and nanoparticles have been introduced, and their higher bioavailability and efficacy were demonstrated in preclinical studies. Based on the extant findings, harnessing novel delivery systems can improve the bioavailability of ST and enhance its effectiveness against migraine attacks. However, further clinical studies are needed to approve the safety and efficacy of employing such systems in humans.
Asunto(s)
Trastornos Migrañosos , Sumatriptán , Administración Intranasal , Administración Oral , Sistemas de Liberación de Medicamentos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT1/farmacocinética , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Sumatriptán/farmacocinética , Sumatriptán/uso terapéutico , Resultado del TratamientoRESUMEN
Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration-time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80-1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69-0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80-1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.
We evaluated the possibility of interactions between atogepant, a new drug for the prevention of migraine, and sumatriptan, a commonly used drug to treat active migraines. A group of 30 healthy adults received atogepant alone, sumatriptan alone or the two drugs taken together, and we measured how the body absorbed, distributed and got rid of the two drugs when given together compared with each drug given alone. There was no indication of any clinically important interactions between atogepant and sumatriptan.
Asunto(s)
Sumatriptán , Adulto , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Humanos , Piperidinas , Piridinas , Pirroles , Compuestos de Espiro , Sumatriptán/farmacocinéticaRESUMEN
Hepatic clearance may be uptake rate limited by organic anion transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1). While comparison of OATP activity has been investigated across species, little has been reported for OCT1. Additionally, while data on interspecies transporter expression in the liver exist, quantitative comparison of these transporters in multiple tissues is lacking. In the current research, the pharmacokinetics of OCT1 substrates (sumatriptan and metformin) were assessed in Oct knockout rats for comparison with previous Oct1/2-/- mice data and OCT1 pharmacogenetics in humans. Effect of OCT1 inhibitors verapamil and erlotinib on OCT1 substrate liver partitioning was also evaluated in rats. Expression of 18 transporters, including Oatps and Octs, in 9 tissues from mice and rats was quantitated using nanoLC/MS-MS, along with uptake transporters in hepatocytes from 5 species. Interspecies differences in OCT1 activity were further evaluated via uptake of OCT1 substrates in hepatocytes with corresponding in vivo liver partitioning in rodents and monkey. In Oct1-/- rats, sumatriptan hepatic clearance and liver partitioning decreased; however, metformin pharmacokinetics were unaffected. OCT1 inhibitor coadministration decreased sumatriptan liver partitioning. In rodents, Oatp expression was highest in the liver, although comparable expression of Oatps in other tissues was determined. Expression of Octs was highest in the kidney, with liver Oct1 expression comparably lower than Oatps. Liver partitioning of OCT1 substrates was lower in rodents than in monkey, in agreement with the highest OCT1 expression and uptake of OCT1 substrates in monkey hepatocytes. Species-dependent OCT1 activity requires consideration when translating preclinical data to the clinic.
Asunto(s)
Eliminación Hepatobiliar/fisiología , Transportador 1 de Catión Orgánico/metabolismo , Animales , Perros , Clorhidrato de Erlotinib/farmacología , Femenino , Células HEK293 , Haplorrinos , Eliminación Hepatobiliar/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Riñón/metabolismo , Hígado/metabolismo , Masculino , Metformina/administración & dosificación , Metformina/farmacocinética , Ratones , Ratones Noqueados , Transportador 1 de Catión Orgánico/antagonistas & inhibidores , Transportador 1 de Catión Orgánico/genética , Ratas , Ratas Transgénicas , Especificidad de la Especie , Sumatriptán/administración & dosificación , Sumatriptán/farmacocinética , Verapamilo/farmacologíaRESUMEN
OBJECTIVES: Migraine is a neurological disorder with unilateral pulsatile headache which can affect the functions of sufferers. Migraineurs experience some undesirable symptoms such as pain, nausea, vomiting and in some cases auras which make the oral delivery non-selective. The lipid nanoparticles are considered as good carriers for nose-to-brain drug delivery. The present study aimed to formulate and evaluate a sumatriptan-loaded nanostructured lipid carrier (NLC). METHODS: A drug-loaded NLC was optimized using D-optimal design of experiment and then the characterization of the formulated NLC including particle size, zeta potential, electron microscopy, thermal analysis, drug loading efficiency and release kinetics were carried out. Pharmacokinetic evaluations were also performed during an in-vivo study on Sprague-Dawley rats and neuropharmacokinetic parameters such as drug targeting efficiency (DTE) and direct transport percentage (DTP) were calculated. KEY FINDINGS: The optimization of experiments led to nanoparticles with 101 nm mean diameter and polydispersity index (PDI) of 0.27. The drug entrapment efficiency (EE) for optimized nanoparticle was found to be 91.00%. DTE and DTP of intranasal-administered NLC were calculated 258.02% and 61.23%, respectively. CONCLUSIONS: Neuropharmacokinetic evaluation of intranasal NLC dispersion represents a suitable brain delivery system. The DTP of NLC formulation suggests the desirable entrance of sumatriptan into the brain.
Asunto(s)
Encéfalo/metabolismo , Portadores de Fármacos/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Nanoestructuras , Mucosa Nasal/metabolismo , Sumatriptán/farmacocinética , Administración Intranasal , Animales , Encéfalo/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Lípidos , Masculino , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Mucosa Nasal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sumatriptán/administración & dosificación , Sumatriptán/síntesis químicaRESUMEN
OBJECTIVE: To evaluate the potential for pharmacokinetic interaction and the safety and tolerability when ubrogepant and sumatriptan are coadministered in a Phase 1 study in healthy participants, and to inform the safety and tolerability of ubrogepant alone and in combination with triptans in Phase 3 trials in participants with migraine. BACKGROUND: Calcitonin gene-related peptide is a potent vasodilatory neurotransmitter believed to play a key role in the pathophysiology of migraine. Ubrogepant (UBRELVY™) is a potent and selective antagonist of the human calcitonin gene-related peptide receptor approved for the acute treatment of migraine. Sumatriptan is a serotonin receptor agonist and the most commonly used triptan for the acute treatment of migraine. Ubrogepant could be prescribed with triptans. DESIGN: The Phase 1 study was a single-center, open-label, randomized, 3-way crossover, single-dose, pharmacokinetic interaction study, where participants received each of 3 oral treatments with a 7-day washout period between treatments: single dose of ubrogepant 100 mg, single dose of sumatriptan 100 mg, and ubrogepant 100 mg plus sumatriptan 100 mg. Pharmacokinetic parameters were calculated using a model-independent approach. The ACHIEVE I and II trials were 2 multicenter, single-attack, randomized, Phase 3 trials in adults with a history of migraine with or without aura. Participants had the option to take a second dose of study medication or rescue medication to treat a nonresponding migraine or a migraine recurrence from 2 to 48 hours after the initial dose of study medication. Rescue medication options included acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, anti-emetics, or triptans. Treatment-emergent adverse events were evaluated up to 30 days after the last dose in the Phase 1 and Phase 3 studies. RESULTS: Ubrogepant median time to maximum plasma concentration was delayed (3 hours [range: 1-5 hours] vs 1.5 hours [range: 1-4 hours]), mean maximum plasma concentration was reduced by 24% (coefficient of variation: 37.4%) when ubrogepant was coadministered with sumatriptan (n = 29) compared with ubrogepant administered alone (N = 30). No significant effect was observed on the area under the plasma concentration-time curve of ubrogepant. Sumatriptan area under the curve and maximum plasma concentration showed no significant change when sumatriptan was coadministered with ubrogepant (n = 29), but the sumatriptan time to maximum plasma concentration was delayed (1 hour [range: 0.5-5 hours] vs 3 hours [range: 0.5-6 hours]. No treatment-emergent adverse events were reported with the coadministration of ubrogepant 100 mg and sumatriptan 100 mg in the Phase 1 study. The pooled safety data from ACHIEVE trials (N = 1938) showed similar rates of treatment-related treatment-emergent adverse events between participants who took ubrogepant alone and participants who took ubrogepant and a triptan as a rescue medication (14.9% [53/355] vs 12.8% [5/39] in the ubrogepant 100 mg treatment group, respectively). CONCLUSIONS: Although there were slight alterations in ubrogepant pharmacokinetic parameters when coadministered with sumatriptan, such changes are expected to have minimal clinical relevance, especially because no changes were seen in sumatriptan area under the curve and maximum plasma concentration when coadministered with ubrogepant. Coadministration of ubrogepant with sumatriptan was well tolerated in healthy participants in the Phase 1 study, and coadministration of ubrogepant with triptans was well tolerated in participants with migraine in the Phase 3 trials. No new safety concerns for ubrogepant were identified across all trials.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos/tratamiento farmacológico , Piridinas , Pirroles , Sumatriptán , Triptaminas , Adulto , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacocinética , Estudios Cruzados , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Masculino , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacocinética , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/farmacocinética , Sumatriptán/administración & dosificación , Sumatriptán/efectos adversos , Sumatriptán/farmacocinética , Triptaminas/administración & dosificación , Triptaminas/efectos adversos , Triptaminas/farmacocinéticaRESUMEN
A mechanistic model was developed and tested to predict the release of sumatriptan succinate from dissolving microneedles and its permeation across the epidermal skin layers. Material balance equations were written to describe molecular transport followed by absorption into the systemic circulation. The solid drug particles were encapsulated in pyramid-shaped, polyvinylpyrrolidone-based water-soluble microneedles. Plots, generated from literature values and designed to simulate concentration distributions in the epidermal layers, agreed with optical coherence tomography (OCT)images captured at early stages of the experiments. Simulations showed that an increase in the pitch width led to a faster release of the medication. By modifying the governing equations to include a microneedle baseplate, the model was able to estimate short- and long-term release behaviors from in vitro Franz cellexperiments. These studies were performed using three distinct dissolving microneedle formulations and minipig skin as the biological membrane. The calculated diffusion coefficients were one order of magnitude greater than the value estimated when the drug was directly applied to the skin surface. The dissolution rate constant was affected by the concentration of the polymer matrix.
Asunto(s)
Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Modelos Biológicos , Povidona/química , Sumatriptán/farmacocinética , Administración Cutánea , Animales , Liberación de Fármacos , Agujas , Piel/metabolismo , Absorción Cutánea , Sumatriptán/administración & dosificación , Porcinos , Porcinos EnanosRESUMEN
BACKGROUND: Sumatriptan succinate (SUT) is a potent drug used for relieving or ending migraine and cluster headaches. SUT bioavailability is low (15%) when it is taken orally owing to its gastric breakdown and bloodstream before reaching the target arteries. AIM: The aim of the study was to enhance SUT bioavailability through developing an intranasal transferosomal mucoadhesive gel. METHODS: SUT-loaded nanotransferosomes were prepared by thin film hydration method and characterized for various parameters such as vesicle diameter, percent entrapment efficiency (%EE), in vitro release and ex vivo permeation studies. The in-situ gels were prepared using various ratios of poloxamer 407, poloxamer 188, and carrageenan and characterized for gelation temperature, mucoadhesive strength, and rheological properties. RESULTS: The prepared transferosomes exhibited percent entrapment efficiencies (%EE) of 40.41±3.02 to 77.47±2.85%, mean diameters of 97.25 to 245.01 nm, sustained drug release over 6 hours, and acceptable ex vivo permeation findings. The optimum formulae were incorporated into poloxamer 407 and poloxamer 188-based thermosensitive in-situ gel using carrageenan as a mucoadhesive polymer. Pharmacokinetic evaluation showed that the prepared in-situ gel of SUT-loaded nano-transferosomes gave enhanced bioavailability, 4.09-fold, as compared to oral drug solution. CONCLUSION: Based on enhancing the bioavailability and sustaining the drug release, it can be concluded that the in-situ gel of SUT-loaded nano-transferosomes were developed as a promising non-invasive drug delivery system for treating migraine.
Asunto(s)
Diseño de Fármacos , Nanopartículas/química , Sumatriptán/farmacocinética , Administración Intranasal , Animales , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Geles , Liposomas/química , Liposomas/metabolismo , Nanopartículas/metabolismo , Tamaño de la Partícula , Conejos , Sumatriptán/administración & dosificación , Sumatriptán/síntesis química , Propiedades de SuperficieRESUMEN
Cortical spreading depression (CSD) in the CNS is suggested as a common mechanism contributing to headache. Despite strong evidence for CNS involvement in headache disorders, drug development for headache disorders remains focused on peripheral targets. Difficulty in delivering drugs across the blood-brain barrier (BBB) may partially account for this disparity. It is known, however, that BBB permeability is increased during several CNS pathologies. In this study, we investigated BBB changes in response to KCl-induced CSD events and subsequent allodynia in rats. Cortical KCl injection in awake, freely moving rats produced facial allodynia with peak intensity between 1.5 and 3 h and CSD induction within 0.5-2 h postinjection. Brain perfusion of 14C-sucrose as a marker of BBB paracellular permeability revealed increased leak in the cortex, but not brainstem, beginning 0.5 h post-KCl injection and resolving within 6 h; no changes in tight junction (TJ) proteins occludin or claudin-5 expression were observed. Acute pretreatment with topiramate to inhibit CSD did not prevent the increased BBB paracellular permeability. CNS delivery of the abortive anti-migraine agent sumatriptan was increased in the cortex 1.5 h post-KCl injection. Surprisingly, sumatriptan uptake was also increased in the brainstem following CSD induction, suggesting regulation of active transport mechanisms at the BBB. Together, these results demonstrate the ability of CSD events to produce transient, time-dependent changes in BBB permeability when allodynia is present and to mediate access of clinically relevant therapeutics (i.e., sumatriptan) to the CNS.
Asunto(s)
Barrera Hematoencefálica/fisiopatología , Tronco Encefálico/efectos de los fármacos , Fármacos del Sistema Nervioso Central/farmacología , Corteza Cerebral/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Cefalea/tratamiento farmacológico , Hiperalgesia/fisiopatología , Sumatriptán/farmacología , Animales , Fármacos del Sistema Nervioso Central/farmacocinética , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Femenino , Cefalea/fisiopatología , Hiperalgesia/inducido químicamente , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Sumatriptán/farmacocinética , Topiramato/farmacologíaRESUMEN
INTRODUCTION: Migraine is a common, disabling disorder, and many patients remain dissatisfied with existing treatments. AVP-825 (ONZETRA® Xsail®) is a Breath Powered® exhalation delivery system for low-dose sumatriptan nasal powder (22 mg) that has been recently approved for use in the treatment of acute migraine with or without aura in adults. AVP-825 takes advantage of unique features of nasal anatomy and physiology to avoid limitations typically seen with other types of intranasal medication delivery. Areas covered: This review provides a summary of the pharmacology, clinical efficacy and tolerability of AVP-825 in clinical studies to date and also provides an overview of the unique aspects of the delivery system. Expert commentary: AVP-825 represents an improvement in nasal delivery of sumatriptan for migraine. PK studies indicate a distinct advantage of AVP-825 over traditional liquid nasal sprays in terms of absorption time, which may underlie the early efficacy observed with AVP-825. It offers the benefits of non-oral medications at a comparatively low sumatriptan dose, without the limitations associated with more invasive approaches. AVP-825 is suitable for use across multiple phases of a migraine attack from use as an early intervention to use in a more advanced migraine with nausea, given the non-oral application.
Asunto(s)
Sistemas de Liberación de Medicamentos , Trastornos Migrañosos/tratamiento farmacológico , Sumatriptán/administración & dosificación , Administración Intranasal , Adulto , Relación Dosis-Respuesta a Droga , Humanos , Satisfacción del Paciente , Polvos , Agonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Agonistas del Receptor de Serotonina 5-HT1/efectos adversos , Agonistas del Receptor de Serotonina 5-HT1/farmacocinética , Sumatriptán/efectos adversos , Sumatriptán/farmacocinéticaRESUMEN
This 3-way, single-dose, randomized crossover study evaluated the pharmacokinetics (PK) and dose proportionality of 5-, 10-, and 15-mg doses of intranasal sumatriptan (DFN-02) coformulated with a permeation enhancer (DDM) in 18 healthy adults. The objective was to determine which DFN-02 dose approximates the PK of a 6-mg dose of sumatriptan delivered via subcutaneous injection in the deltoid muscle of the arm. Sumatriptan plasma concentrations peaked with DFN-02 between 10 and 15 minutes postdose, declining thereafter, with a t1/2 of about 2.5 hours; mean Cmax and AUC0-∞ values increased linearly across doses. After DFN-02 doses of 5, 10, and 15 mg, mean Cmax was 40.7 ± 14.2, 71.2 â± â22.1, and 101.0 â± â49.5 ng/mL, and mean AUC0-∞ was 49.9 â± â20.6, 87.1 â± 31.2, and 120.5 â± 53.3 ng·h/mL, respectively. The increase in sumatriptan bioavailability was less than dose-proportional among the DFN-02 doses studied. Based on the established PK of a 6-mg subcutaneous sumatriptan injection (mean Tmax , â12 minutes; mean Cmax , â74 â± 15 ng/mL in the deltoid area of the arm) and the peak and time to peak sumatriptan concentrations of the DFN-02 doses tested, a 10-mg dose of DFN-02 was found to be the closest match. Overall, DFN-02 was well tolerated at doses of 5 to 15 mg, and no new safety concerns were identified.
Asunto(s)
Sumatriptán/análogos & derivados , Sumatriptán/administración & dosificación , Sumatriptán/farmacocinética , Administración Intranasal , Adulto , Área Bajo la Curva , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Subcutáneas/métodos , Masculino , Rociadores Nasales , Adulto JovenRESUMEN
The P-glycoprotein (Pgp) transporter reduces the penetration of a chemically diverse range of neurotherapeutics at the blood-brain barrier, but the molecular features of drugs and drug-Pgp interactions that drive transport remain to be clarified. In particular, the triptan neurotherapeutics, eletriptan (ETT) and sumatriptan (STT), were identified to have a >10-fold difference in transport rates despite being from the same drug class. Consistent with these transport differences, ETT activated Pgp-mediated ATP hydrolysis â¼2-fold, whereas STT slightly inhibited Pgp-mediated ATP hydrolysis by â¼10%. The interactions between them were also noncompetitive, suggesting that they occupy different binding sites on the transporter. Despite these differences, protein fluorescence spectroscopy revealed that the drugs have similar affinity to the transporter. NMR with Pgp and the drugs showed that they have distinct interactions with the transporter. Tertiary conformational changes probed by acrylamide quenching of Pgp tryptophan fluorescence with the drugs and a nonhydrolyzable ATP analog implied that the STT-bound Pgp must undergo larger conformational changes to hydrolyze ATP than ETT-bound Pgp. These results and previous transport studies were used to build a conformationally driven model for triptan transport with Pgp where STT presents a higher conformational barrier for ATP hydrolysis and transport than ETT.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Pirrolidinas/farmacocinética , Agonistas de Receptores de Serotonina/farmacocinética , Sumatriptán/farmacocinética , Triptaminas/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Adenosina Trifosfato/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Hidrólisis , Ratones , Conformación Proteica/efectos de los fármacos , Pirrolidinas/metabolismo , Agonistas de Receptores de Serotonina/metabolismo , Sumatriptán/metabolismo , Triptaminas/metabolismoRESUMEN
The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 µg sulfasalazine, 250 µg rosuvastatin, 300 µg glibenclamide, 1200 µg celiprolol, and 600 µg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Atorvastatina/farmacocinética , Citrus paradisi/metabolismo , Transportadores de Anión Orgánico/metabolismo , Farmacogenética/métodos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adulto , Atorvastatina/química , Atorvastatina/metabolismo , Celiprolol/química , Celiprolol/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Interacciones Alimento-Droga , Genotipo , Gliburida/química , Gliburida/farmacocinética , Humanos , Absorción Intestinal , Masculino , Proteínas de Neoplasias/metabolismo , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Sulfasalazina/química , Sulfasalazina/farmacocinética , Sumatriptán/química , Sumatriptán/farmacocinéticaRESUMEN
OBJECTIVE/BACKGROUND: Intranasal sumatriptan (Imitrex® ) may be an alternative for patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting an unmet need for an effective non-oral migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of 1-O-n-Dodecyl-ß-D-Maltopyranoside (DDM, Intravail A-3™), a permeation enhancer, on sumatriptan's pharmacokinetic profile by comparing the pharmacokinetic characteristics of two commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults, with DFN-02 - a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We also determined the pharmacokinetic characteristics of DDM and evaluated its safety and tolerability. METHODS: We conducted two studies: a randomized, three-way crossover study comparing monodose and multidose devices for delivery of single doses of DFN-02 with commercially available intranasal sumatriptan 20 mg in 18 healthy, fasted adults, and an open-label, randomized, single-dose, three-way crossover bioavailability study comparing DFN-02 with 4 mg and 6 mg subcutaneous sumatriptan in 78 healthy, fasted adults. In the study comparing DFN-02 with IN sumatriptan, subjects received a single dose of DFN-02 (sumatriptan 10 mg plus DDM 0.20%) via monodose and multidose delivery systems with at least 5 days between treatments. In the comparison with SC sumatriptan, subjects received a single dose of each treatment with at least 3 days between treatments. In both studies, blood was sampled for pharmacokinetic evaluation of sumatriptan and DDM through 24 hours post-dose; safety and tolerability were monitored throughout. RESULTS: In the comparison with commercially available intranasal sumatriptan 20 mg, DFN-02 had a more rapid absorption profile; tmax was 15 minutes for DFN-02 monodose, 10.2 minutes for DFN-02 multidose, and 2.0 hours for commercially available intranasal sumatriptan 20 mg. Compared with 4 and 6 mg subcutaneous sumatriptan, DFN-02's median tmax (10 minutes) was significantly earlier (15 minutes; P < .0001). Mean sumatriptan exposure metrics were similar for DFN-02 and 4 mg sumatriptan: AUC0-2 : 35.12 and 44.82 ng*hour/mL, respectively; AUC0-∞ : 60.70 and 69.21 ng*hour/mL, respectively; Cmax : 51.79 and 49.07 ng/mL, respectively. With 6 mg subcutaneous sumatriptan, these exposure metrics were about 50% larger (AUC0-2 : 67.17 ng*hour/mL; AUC0-∞ : 103.78 ng*hour/mL; Cmax : 72.75 ng/mL). Inter-subject variability of AUC0-2 , AUC0-∞ , and Cmax was 42-58% for DFN-02, 15-22% for 4 mg subcutaneous sumatriptan, and 15-25% for 6 mg subcutaneous sumatriptan. DDM exposure was low (mean Cmax : 1.63 ng/mL), tmax was 30 minutes, and it was undetectable by 4 hours. There were no serious adverse events, discontinuations due to adverse events, or remarkable findings for vital signs, physical examinations (including nasal and injection site examinations), or clinical laboratory assessments. The overall incidence of adverse events was comparable across treatments, and all treatment-related events were mild in severity. Adverse events occurring in ≥10% of subjects were dysgeusia (19%), headache (18%), nausea (15%), paresthesia (15%), and dizziness (12%). CONCLUSIONS: In healthy subjects, DFN-02, an intranasal spray containing 10 mg sumatriptan plus DDM, had a more rapid absorption profile than commercially available intranasal sumatriptan 20 mg, and systemic exposure from a single-dose administration of DFN-02 was similar to 4 mg SC sumatriptan and two-thirds that of 6 mg SC sumatriptan. With DFN-02, plasma sumatriptan peaked 5 minutes earlier than with both subcutaneous formulations. Systemic exposure to sumatriptan was similar with DFN-02 and 4 mg subcutaneous sumatriptan; both yielded lower systemic exposure than 6 mg subcutaneous sumatriptan. Systemic exposure to DFN-02's excipient DDM was short-lived. DFN-02's safety and tolerability appear to be comparable to subcutaneous sumatriptan. Addition of a permeation enhancer improved the absorption profile compared with commercially available intranasal sumatriptan 20 mg.
Asunto(s)
Sumatriptán/análogos & derivados , Sumatriptán/efectos adversos , Sumatriptán/farmacocinética , Vasoconstrictores/efectos adversos , Vasoconstrictores/farmacocinética , Administración Intranasal , Adulto , Área Bajo la Curva , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Trastornos Migrañosos/tratamiento farmacológico , Proyectos Piloto , Sumatriptán/administración & dosificación , Equivalencia Terapéutica , Vasoconstrictores/administración & dosificaciónAsunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Sumatriptán/administración & dosificación , Vasoconstrictores/administración & dosificación , Administración Intranasal , Aerosoles , Esquema de Medicación , Interacciones Farmacológicas , Humanos , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/fisiopatología , Polvos , Agonistas del Receptor de Serotonina 5-HT1/efectos adversos , Agonistas del Receptor de Serotonina 5-HT1/farmacocinética , Sumatriptán/efectos adversos , Sumatriptán/farmacocinética , Resultado del Tratamiento , Vasoconstrictores/efectos adversos , Vasoconstrictores/farmacocinéticaRESUMEN
OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.
Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Sumatriptán/administración & dosificación , Vasoconstrictores/administración & dosificación , Administración Cutánea , Adolescente , Adulto , Área Bajo la Curva , Niño , Estudios Cruzados , Femenino , Humanos , Iontoforesis/efectos adversos , Iontoforesis/métodos , Masculino , Trastornos Migrañosos/sangre , Sumatriptán/efectos adversos , Sumatriptán/farmacocinética , Vasoconstrictores/efectos adversos , Vasoconstrictores/farmacocinéticaRESUMEN
Buccal administration of sumatriptan succinate might be an interesting alternative to the present administration routes, due to its non-invasiveness and rapid onset of action, but because of its low permeability, a permeation enhancement strategy is required. The aim of this work was then to study, in-vitro, buccal iontophoresis of sumatriptan succinate. Permeation experiments were performed in-vitro across pig esophageal epithelium, a recently proposed model of human buccal mucosa, using vertical diffusion cells. The iontophoretic behavior of the tissue was characterized by measuring its isoelectric point (Na(+) transport number and the electroosmotic flow of acetaminophen determination) and by evaluating tissue integrity after current application. The results obtained confirm the usefulness of pig esophageal epithelium as an in-vitro model membrane for buccal drug delivery. The application of iontophoresis increased sumatriptan transport, proportionally to the current density applied, without tissue damage: electrotransport was the predominant mechanism. Integrating the results of the present work with literature data on the transport of other molecules across the buccal mucosa and across the skin, we can draw a general conclusion: the difference in passive transport across buccal mucosa and across the skin is influenced by permeant lipophilicity and by the penetration pathway. Finally, buccal iontophoretic administration of sumatriptan allows to administer 6mg of the drug in 1h, representing a promising alternative to the current administration routes.
Asunto(s)
Iontoforesis , Mucosa Bucal/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Sumatriptán/administración & dosificación , Acetaminofén/farmacocinética , Administración Bucal , Animales , Transporte Biológico , Sistemas de Liberación de Medicamentos , Punto Isoeléctrico , Modelos Animales , Permeabilidad , Agonistas del Receptor de Serotonina 5-HT1/farmacocinética , Absorción Cutánea , Sumatriptán/farmacocinética , PorcinosRESUMEN
A sensitive and fast liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the simultaneous quantification of naproxen and sumatriptan in human plasma. A simple liquid-liquid extraction procedure, with a mixture of ethyl acetate, methyl tert-butyl ether, and dichloromethane (4:3:3, v/v), was used for the cleanup of plasma. Naratriptan and aceclofenac were employed as internal standards. The analyses were carried out using an ACE C18 column (50 × 4.6 mm i.d.; particle size 5 µm) and a mobile phase consisting of 2 mM aqueous ammonium acetate with 0.025 % formic acid and methanol (38:62, v/v). A triple-quadrupole mass spectrometer equipped with an electrospray source in the positive mode was set up in the selective reaction monitoring mode to detect the ion transitions m/z 231.67 â m/z 185.07, m/z 296.70 â m/z 157.30, m/z 354.80 â m/z 215.00, and m/z 336.80 â m/z 97.94 for naproxen, sumatriptan, aceclofenac, and naratriptan, respectively. The method was validated and proved to be linear, accurate, precise, and selective over the ranges of 2.5-130 µg mL(-1) for naproxen and 1-50 ng mL(-1) for sumatriptan. The validated method was successfully applied to a pharmacokinetic study with simultaneous administration of naproxen sodium and sumatriptan succinate tablet formulations in healthy volunteers.
Asunto(s)
Cromatografía Liquida/métodos , Naproxeno/sangre , Sumatriptán/sangre , Espectrometría de Masas en Tándem/métodos , Humanos , Naproxeno/farmacocinética , Plasma/química , Sumatriptán/farmacocinéticaRESUMEN
Available formulations of sumatriptan succinate (SS) have low bioavailability or are associated with site reactions. We developed various types of self-dissolving microneedle arrays (MNs) fabricated from sodium hyaluronate as a new delivery system for SS and evaluated their skin permeation and irritation in terms of clinical application. In vitro permeation studies with human skin, physicochemical properties (needle length, thickness and density), and penetration enhancers (glycerin, sodium dodecyl sulfate and lauric acid diethanolamide) were investigated. SS-loaded high-density MNs of 800 µm in length were the optimal formulation and met clinical therapeutic requirements. Penetration enhancers did not significantly affect permeation of SS from MNs. Optical coherence tomography images demonstrated that SS-loaded high-density MNs (800 µm) uniformly created drug permeation pathways for the delivery of SS into the skin. SS-loaded high-density MNs induced moderate primary skin irritations in rats, but the skin recovered within 72 h of removal of the MNs. These findings suggest that high-density MNs of 800 µm in length are an effective and promising formulation for transdermal delivery of SS. To our knowledge, this is the first report of SS permeation across human skin using self-dissolving MNs.