RESUMEN
PURPOSE: To evaluate the PK and safety of siponimod, a substrate of CYP2C9/3A4, in the presence or absence of a CYP3A4 inhibitor, itraconazole. METHODS: This was an open-label study in healthy subjects (aged 18-50 years; genotype: CYP2C9 *1*2 [cohort 1; n = 17] or *1*3 [cohort 2; n = 13]). Subjects received siponimod 0.25-mg single dose in treatment period 1 (days 1-14), itraconazole 100 mg twice daily in treatment period 2 (days 15-18), and siponimod 0.25-mg single dose (day 19) with itraconazole until day 31 (cohort 1) or day 35 (cohort 2) in treatment period 3. PK of siponimod alone and with itraconazole and safety were assessed. RESULTS: Overall, 29/30 subjects completed the study. In treatment period 1, geometric mean AUCinf, T1/2, and median Tmax were higher while systemic clearance was lower in cohort 2 than cohort 1. In treatment period 3, siponimod AUC decreased by 10% (geo-mean ratio [90% confidence intervals]: 0.90 [0.84; 0.96]) and 24% (0.76 [0.69; 0.82]) in cohorts 1 and 2, respectively. Siponimod Cmax was similar between treatment periods 1 and 3. In both cohorts, the Cmax and AUC of the metabolites (M17, M3, and M5) decreased in the presence of itraconazole. All adverse events were mild. CONCLUSIONS: The minor albeit significant reduction in plasma exposure of siponimod and its metabolites by itraconazole was unexpected. While the reason is unclear, the results suggest that coadministration of the two drugs would not cause a considerable increase of siponimod exposure independent of CYP2C9 genotype.
Asunto(s)
Azetidinas/farmacocinética , Compuestos de Bencilo/farmacocinética , Citocromo P-450 CYP2C9/genética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A , Itraconazol/farmacología , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Azetidinas/efectos adversos , Azetidinas/sangre , Compuestos de Bencilo/efectos adversos , Compuestos de Bencilo/sangre , Interacciones Farmacológicas , Electrocardiografía/efectos de los fármacos , Femenino , Genotipo , Voluntarios Sanos , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Moduladores de los Receptores de fosfatos y esfingosina 1/efectos adversos , Moduladores de los Receptores de fosfatos y esfingosina 1/sangre , Adulto JovenRESUMEN
Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [14C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine, and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (area under the concentration-time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 hours) and moderate distribution (Vz/F: 291 l). Siponimod was mainly cleared through biotransformation, predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 hours. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other cytochrome P450 enzymes.
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Azetidinas/metabolismo , Compuestos de Bencilo/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Receptores de Lisoesfingolípidos/agonistas , Adolescente , Adulto , Animales , Biotransformación/fisiología , Heces , Semivida , Voluntarios Sanos , Humanos , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Oxidación-Reducción , Estrés Oxidativo/fisiología , Adulto JovenRESUMEN
PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism. METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism. Primary PK parameters were generated using the SimCYP and WinNonlin software. RESULTS: Correlation analysis suggested that CYP2C9 is the main enzyme responsible for siponimod metabolism in humans. Compared with the CYP2C9*1/*1 genotype, HLM incubations from CYP2C9*3/*3 and CYP2C9*2/*2 donors showed ~ 10- and 3-fold decrease in siponimod metabolism, respectively. Simulations of enzyme contribution predicted that in the CYP2C9*1/*1 genotype, CYP2C9 is predominantly responsible for siponimod metabolism (~ 81%), whereas in the CYP2C9*3/*3 genotype, its contribution is reduced to 11%. The predicted exposure increase of siponimod with fluconazole 200 mg was 2.0-2.4-fold for CYP2C9*1/*1 genotype. In context of single dosing, the predicted mean area under the curve (AUC) is 2.7-, 3.0- and 4.5-fold higher in the CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, compared with the CYP2C9*1/*1 genotype. CONCLUSION: .Enzyme phenotyping with correlation analysis confirmed the predominant role of CYP2C9 in the biotransformation of siponimod and demonstrated the functional consequence of CYP2C9 genetic polymorphism on siponimod metabolism. Simulation of fluconazole inhibition closely predicted a 2-fold AUC change (ratio within ~ 20% deviation) to the observed value. In silico simulation predicted a significant reduction in siponimod clearance in the CYP2C9*2/*2 and CYP2C9*3/*3 genotypes based on the in vitro metabolism data; the predicted exposure was close (within 30%) to the observed results for the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes.
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Azetidinas/farmacocinética , Compuestos de Bencilo/farmacocinética , Simulación por Computador , Inhibidores del Citocromo P-450 CYP2C9/farmacología , Citocromo P-450 CYP2C9/genética , Fluconazol/farmacología , Microsomas Hepáticos/enzimología , Modelos Biológicos , Variantes Farmacogenómicas , Polimorfismo Genético , Azetidinas/metabolismo , Compuestos de Bencilo/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Interacciones Farmacológicas , Genotipo , Humanos , Farmacogenética , Fenotipo , Programas InformáticosRESUMEN
PURPOSE: To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects. METHODS: This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18-45 years). In Period 1 (Days 1-12), siponimod was up-titrated from 0.25 to 2 mg over 5 days (Days 1-6) followed by 2 mg once daily on days 7-12. In Period 2, siponimod 2 mg qd was co-administered with rifampin 600 mg qd (Days 13-24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [Cmax,ss], median time to achieve Cmax,ss [Tmax, ss], and area under the curve at steady state [AUCtau,ss]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC). RESULTS: Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3 years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean Cmax,ss (28.6 ng/mL) was achieved in 4 h (median Tmax,ss; range, 1.58-8.00) and the geometric mean AUCtau,ss was 546 h × ng/mL. In Period 2, the siponimod geometric mean Cmax,ss and AUCtau,ss decreased to 15.7 ng/mL and 235 h × ng/mL, respectively; median Tmax remained unchanged (4 h). Rifampin co-administration increased M3 Cmax,ss by 53% while M5 Cmax,ss remained unchanged. The AUCtau,ss of M3 and M5 decreased by 10% and 37%, respectively. The majority of adverse events reported were mild, with a higher frequency during Period 2 (86.7%) versus Period 1 (50%). The mean ALC increased slightly under rifampin co-administration but remained below 1.0 × 109/L. CONCLUSIONS: The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in Cmax,ss (45%) and AUCtau,ss (57%) in healthy subjects.
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Azetidinas/farmacocinética , Compuestos de Bencilo/farmacocinética , Citocromo P-450 CYP2C9/biosíntesis , Receptores de Lisoesfingolípidos/efectos de los fármacos , Rifampin/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Azetidinas/efectos adversos , Compuestos de Bencilo/efectos adversos , Biotransformación , Interacciones Farmacológicas , Inducción Enzimática/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Recuento de Linfocitos , Masculino , Rifampin/efectos adversos , Adulto JovenRESUMEN
OBJECTIVE: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). METHODS: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI. All subjects received single oral doses of 0.25 mg siponimod on day 1; PK and safety data were collected during the 21-day follow-up. RESULTS: All subjects had similar baseline characteristics and completed the study. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in the mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2- to 5-fold increase, particularly in the moderate and severe HI groups vs HS. There were no clinically-relevant safety findings. CONCLUSIONS: Single oral doses of 0.25 mg siponimod were well tolerated, and HI did not significantly alter exposure to siponimod. Increase in the M3 and M5 metabolites requires further evaluation. These results do not warrant any dose adjustments of siponimod in subjects with HI.â©.
Asunto(s)
Azetidinas/efectos adversos , Azetidinas/farmacocinética , Compuestos de Bencilo/efectos adversos , Compuestos de Bencilo/farmacocinética , Insuficiencia Hepática/metabolismo , Hígado/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Azetidinas/sangre , Azetidinas/metabolismo , Compuestos de Bencilo/sangre , Compuestos de Bencilo/metabolismo , Femenino , Semivida , Insuficiencia Hepática/sangre , Insuficiencia Hepática/diagnóstico , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Lisoesfingolípidos/metabolismo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected inactive metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS). METHODS: The study enrolled subjects with severe RI (n = 8) and matched HS (n = 8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥ 50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects vs. HS. All subjects received a single oral dose of siponimod 0.25 mg on day 1; PK and safety were evaluated during the follow-up (~ 13 days). RESULTS: PK of siponimod was marginally affected in severe RI subjects vs. HS: Cmax decreased by 8%, and AUClast and AUCinf increased by 23% and 24%, respectively; half-life (37 vs. 26 hours) and systemic clearance (2.9 vs. 3.4 L/h) were comparable. Siponimod plasma unbound (u) fraction at 4 hours post-dose was similar between the two groups (range: 0.0172 - 0.0550%). Cmax(u) was comparable while AUClast(u) and AUCinf(u) were increased by 33% compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment (RI) compared with matched HS. No adverse events were reported during this study. CONCLUSIONS: Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further to severe RI, investigation of PK in subjects with mild and moderate RI was not warranted.â©.
Asunto(s)
Azetidinas/efectos adversos , Azetidinas/farmacocinética , Compuestos de Bencilo/efectos adversos , Compuestos de Bencilo/farmacocinética , Insuficiencia Renal/metabolismo , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Azetidinas/sangre , Azetidinas/metabolismo , Compuestos de Bencilo/sangre , Compuestos de Bencilo/metabolismo , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Receptores de Lisoesfingolípidos/metabolismo , Insuficiencia Renal/sangre , Insuficiencia Renal/diagnóstico , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: Examine the efficacy of a competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonist, selurampanel (BGG492), in the human photostimulation model. METHODS: Patients with epilepsy and a generalized epileptiform electroencephalography response to intermittent photic stimulation (photoparoxysmal response or PPR; diagnosed ≥ 6 months prior to initial study dosing) were enrolled in a phase II, multicenter, single-blind, within-subject, placebo-controlled proof-of-concept (PoC) study. PPR was used as a biomarker to assess the efficacy and safety of BGG492 in three cohorts (cohorts I-III received BGG492 50, 100, and 15 mg, respectively). Primary endpoints were to evaluate the efficacy of single oral BGG492 doses in abolishment of PPR or a relevant reduction of the standardized photoparoxysmal response (SPR), and to evaluate time of onset and duration of response. Secondary endpoints were to evaluate maximal SPR reduction, determine the pharmacokinetic profile of BGG492, explore the pharmacokinetic/pharmacodynamic relationship, and evaluate the safety and tolerability of BGG492. RESULTS: Ten patients were enrolled, with three participating twice, that is, in two cohorts (n = 13). Treatment with BGG492 resulted in abolition of PPR in seven of 13 patients in a dose-dependent manner: three, three, and one patient in cohorts I-III, respectively. All patients showed treatment-related reductions of SPR range of at least three steps in at least one eye condition (eye closure, eyes closed, or eyes open). Generally, onset of the suppressive effect appeared to be within 1-2 h post-BGG492 dose and continued in three patients at the 50- and 100-mg doses for 29-33 h. Most common adverse events across the BGG492-treated groups were headache and nasopharyngitis (three patients each), followed by dizziness, fatigue, and diarrhea (two patients each). SIGNIFICANCE: The dose-dependent positive effect of BGG492 on the PPR and SPR in patients with photosensitive epilepsy in this proof-of-concept study supports further investigation of AMPA receptor antagonists in large-scale phase III trials.
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Anticonvulsivantes/uso terapéutico , Epilepsia Refleja/tratamiento farmacológico , Estimulación Luminosa/efectos adversos , Quinazolinonas/uso terapéutico , Adolescente , Adulto , Anciano , Anticonvulsivantes/farmacocinética , Área Bajo la Curva , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Electroencefalografía , Epilepsia Refleja/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinazolinonas/farmacocinética , Método Simple Ciego , Adulto JovenRESUMEN
AIM: Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects. METHODS: Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25-10 mg over 9-10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. RESULTS: Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1-12 vs. the non-titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non-titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non-titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3-7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min⻹; P ≤ 0.0001). From days 9-12, HRs in both titration regimens were comparable with placebo. CONCLUSION: Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg.
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Azetidinas/administración & dosificación , Compuestos de Bencilo/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Receptores de Lisoesfingolípidos/metabolismo , Adolescente , Adulto , Azetidinas/farmacocinética , Azetidinas/farmacología , Compuestos de Bencilo/farmacocinética , Compuestos de Bencilo/farmacología , Bradicardia/prevención & control , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Abuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.
Asunto(s)
Esclerosis Múltiple , Moduladores de los Receptores de fosfatos y esfingosina 1 , Animales , Humanos , Lisofosfolípidos , Esclerosis Múltiple/tratamiento farmacológico , Esfingosina/análogos & derivadosRESUMEN
BACKGROUND: Siponimod (BAF312), a selective S1P1/S1P5 agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P1/S1P5-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells. OBJECTIVE: Generate preclinical evidence confirming siponimod's CNS penetration and activity. METHODS: Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using 14C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated 123I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P1 receptor quantification in brain homogenates. RESULTS: In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (Brain/BloodDER) of 6-7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P1 levels. QWBA distribution analysis in rats indicated that [14C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a brain/bloodDER of â¼6, as in rodents. CONCLUSION: Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.
RESUMEN
PURPOSE: The goal of this study was to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of intravenous (IV) siponimod in healthy subjects. METHODS: This randomized, open-label study was conducted in 2 parts. In Part 1, a total of 16 eligible subjects received either a single oral dose of siponimod (0.25 mg) followed by a single IV infusion (0.25 mg/3 h) in Sequence 1, or vice versa in Sequence 2. In Part 2, a total of 17 eligible subjects received single IV infusions of siponimod (1 mg/24 h). FINDINGS: No clinically relevant effect on mean 5-minute or hourly average heart rate was observed following the siponimod IV dosing regimens and both remained above 50 beats/min. Observed atrioventricular blocks and sinus pauses were asymptomatic. The mean change in absolute lymphocyte count from baseline was comparable for the siponimod 0.25 mg oral regimen and the two IV siponimod regimens. Oral siponimod displayed a good absolute bioavailability of 84%. The mean peak exposure of oral siponimod was approximately 48% lower than that of IV siponimod. The M17 metabolite was found to be the most prominent systemic metabolite of siponimod in humans. IMPLICATIONS: Siponimod IV infusions were well tolerated, with safety and PD (absolute lymphocyte count) profiles similar to those of oral siponimod. The PD/PK findings supported the development of an innovative rapid IV titration regimen for patients with intracerebral hemorrhage.
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Azetidinas/administración & dosificación , Compuestos de Bencilo/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Administración Oral , Adulto , Azetidinas/efectos adversos , Azetidinas/farmacocinética , Compuestos de Bencilo/efectos adversos , Compuestos de Bencilo/farmacocinética , Disponibilidad Biológica , Femenino , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Moduladores de los Receptores de fosfatos y esfingosina 1/efectos adversos , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacocinética , Adulto JovenRESUMEN
Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB(1) and CB(2) receptors. This phase I study aimed to evaluate the pharmacokinetics, safety, and tolerability of single oral doses of CRA13. Sixty-three of 69 healthy adult males were randomized in seven cohorts (n = 9) to receive 1 to 80 mg of CRA13 or placebo orally in fasted condition. To investigate the diet effect, an independent group (n = 6) was randomized to receive 40 mg of CRA13 after high-fat and high-calorie breakfast in crossover design with a 2-week washout period. Peak plasma concentration (C(max)) ranged from 7.8 to 467.6 ng/ml (1-80 mg). CRA13 was rapidly absorbed and demonstrated linear pharmacokinetics (1-80 mg). Time to reach C(max) (t(max)) was 1.5 to 2 h for all doses in both fasted and fed groups. Administration of 40 mg of CRA13 with food induced approximately 2-fold increase in the C(max) and the area under the concentration-time curve, AUC(0 - tz). The apparent elimination half-life (t(1/2)) was 21 to 36 h and 30 to 41 h for fasted and fed groups, respectively. Dizziness, headache, and nausea were the most frequently reported adverse events (AEs), predominantly at the 40- and 80-mg doses. The incidence of AEs was dose-dependent and mild to moderate. No deaths and serious adverse events were reported. In conclusion, CRA13 was reasonably well tolerated and demonstrated a linear pharmacokinetics over the studied dose range (1-80 mg). Food intake increased CRA13 C(max) and AUC(0 - tz) by approximately 2-fold, whereas t(max) was unaffected.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Naftalenos/efectos adversos , Naftalenos/farmacocinética , Área Bajo la Curva , Estudios de Cohortes , Método Doble Ciego , Semivida , Humanos , Masculino , Naftalenos/farmacología , PlacebosRESUMEN
PURPOSE: To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. METHODS: Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. RESULTS: Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in AUC(0 - infinity)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. CONCLUSIONS: The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.
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Agonistas de Receptores de Cannabinoides , Mucosa Intestinal/metabolismo , Sistema Linfático/metabolismo , Naftalenos/farmacología , Administración Oral , Adolescente , Adulto , Animales , Disponibilidad Biológica , Transporte Biológico , Perros , Ayuno , Humanos , Masculino , Persona de Mediana Edad , Periodo Posprandial , Triglicéridos/sangre , Adulto JovenRESUMEN
We predicted the drug-drug interaction (DDI) potential of siponimod in presence of cytochrome P450 (CYP)2C9/CYP3A4 inhibitors/inducers in subjects with different CYP2C9 genotypes by physiologically-based pharmacokinetic (PK) modeling. The model was established using in vitro and clinical PK data and verified by adequately predicting siponimod PK when coadministered with rifampin. With strong and moderate CYP3A4 inhibitors, an increased DDI risk for siponimod was predicted for CYP2C9*3/*3 genotype vs. other genotypes area under the curve ratio (AUCR): 3.03-4.20 vs. ≤ 1.49 for strong; 2.42 vs. 1.14-1.30 for moderate. AUCRs increased with moderate (2.13-2.49) and weak (1.12-1.42) CYP3A4/CYP2C9 inhibitors to the same extent for all genotypes. With strong CYP3A4/moderate CYP2C9 inducers and moderate CYP3A4 inducers, predicted AUCRs were 0.21-0.32 and 0.35-0.71, respectively. This complementary analysis to the clinical PK-DDI studies confirmed the relevant influence of CYP2C9 polymorphism on the DDI behavior of siponimod and represented the basis for the DDI labeling recommendations.
Asunto(s)
Azetidinas/farmacocinética , Compuestos de Bencilo/farmacocinética , Inductores de las Enzimas del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Modelos Biológicos , Rifampin/farmacología , Área Bajo la Curva , Simulación por Computador , Citocromo P-450 CYP2C9/genética , Inhibidores del Citocromo P-450 CYP2C9/farmacología , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Interacciones Farmacológicas , Genotipo , Semivida , HumanosRESUMEN
OBJECTIVES: The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B). METHODS: Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1-2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (Cmax; from 31.2 to 34.0 ng/mL) and elimination half-life (T½; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in Cmax versus the CYP2C9*1/*1 genotype. The mean T½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies. CONCLUSIONS: Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans.
Asunto(s)
Azetidinas/farmacocinética , Compuestos de Bencilo/farmacocinética , Inhibidores del Citocromo P-450 CYP2C9/administración & dosificación , Citocromo P-450 CYP2C9/efectos de los fármacos , Fluconazol/administración & dosificación , Voluntarios Sanos/estadística & datos numéricos , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacocinética , Adolescente , Adulto , Azetidinas/administración & dosificación , Compuestos de Bencilo/administración & dosificación , Citocromo P-450 CYP2C9/metabolismo , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/uso terapéutico , Interacciones Farmacológicas , Quimioterapia Combinada/métodos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Adulto JovenRESUMEN
Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After multiple dosing, geometric mean (%CV) Cmax ss, Cmin ss, and AUCtau were 77.6 micromol/L (18), 45.3 micromol/L (25), and 747 h.mol/L (19), respectively, with a tmax of 2 hours. Mean half-lives were 9.3 and 11.3 hours for single and multiple dosing, respectively. Food had no clinically significant effect on single-dose pharmacokinetics. Half-life ( approximately 10 hours) and low intersubject variability in main pharmacokinetic parameters were similar under fasted and fed conditions. Median tmax increased from 1.5 to 2.5 hours with food. Licarbazepine is well tolerated and has predictable pharmacokinetics.
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Dibenzazepinas/farmacocinética , Interacciones Alimento-Droga , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Dibenzazepinas/administración & dosificación , Dibenzazepinas/sangre , Relación Dosis-Respuesta a Droga , Ayuno , Femenino , Alimentos , Semivida , Humanos , MasculinoRESUMEN
Receptor tyrosine kinases have a single transmembrane (TM) segment that is usually assumed to play a passive role in ligand-induced dimerization and activation of the receptor. However, mutations within some of these receptors, and recent studies with the epidermal growth factor (EGF) and ErbB2 receptors have indicated that interactions between TM domains do contribute to stabilization of ligand-independent and/or ligand-induced receptor dimerization and activation. One consequence of the importance of these interactions is that short hydrophobic peptides corresponding to these domains should act as specific inhibitors. To test this hypothesis, we constructed expression vectors encoding short fusion peptides encompassing native or mutated TM domains of the EGF, ErbB2, and insulin receptors. In human cell lines overexpressing the wild-type EGF receptor or ErbB2, we observed that the peptides are expressed at the cell surface and that they inhibit specifically the autophosphorylation and signaling pathway of their cognate receptor. Identical results were obtained with peptides chemically synthesized. Mechanism of action involves inhibition of dimerization of the receptors as shown by the lack of effects of mutant nondimerizing sequences, completed by density centrifugation and covalent cross-linking experiments. Our findings stress the role of TM domain interactions in ErbB receptor function, and possibly for other single-spanning membrane proteins.
Asunto(s)
Péptidos/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptores de Superficie Celular/química , Transducción de Señal , Línea Celular , Dimerización , Receptores ErbB/análisis , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Péptidos/química , Péptidos/genética , Fosforilación , Receptor ErbB-2/genéticaRESUMEN
OBJECTIVE: To evaluate effects of siponimod on response to T-cell-dependent (influenza) and T-cell-independent (pneumococcal polysaccharide vaccine [PPV-23]) vaccinations in healthy participants. METHODS: In this double-blind, placebo-controlled, parallel-group study, each participant underwent a 7-week treatment period and received intramuscular injections of influenza and PPV-23 vaccines (day 21). Participants were randomized to 4 treatment groups (N = 30 each) and received placebo or siponimod 2 mg once daily in concomitant, interrupted, or preceding fashion. Individual response to vaccination was defined by a ≥4-fold (influenza) antibody titer increase and by a ≥2-fold increase in serotype-specific immunoglobulin (Ig) G concentrations (PPV-23) on day 28 vs baseline. Responder rates were compared using noninferiority analysis. RESULTS: Mean influenza titers were similar to placebo in the preceding and interrupted groups but lower in the concomitant group. The proportion of participants with influenza titers ≥40 four weeks after vaccination (seroprotection) was similar to placebo across all groups and antigens. In each treatment group, response criteria were met for 3 of 4 antigens including H1N1 and H3N2. A noninferior response was determined in the context of preceding treatment but not interrupted or concomitant treatment. Regarding PPV-23, approximately 90%-100% of participants exhibited a ≥2-fold increase in IgG concentrations vs baseline. Noninferior responder rates were determined for each siponimod treatment group. CONCLUSIONS: Siponimod treatment had no relevant effect on antibody response to PPV-23. European Medicines Agency response criteria were essentially met for influenza, but titers were lower on concomitant treatment. Overall, these data suggest that siponimod has limited effect on the efficacy of vaccinations with neoantigens. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in healthy persons, siponimod had limited effect on the immune response following influenza or pneumococcal vaccinations.
RESUMEN
Receptor tyrosine kinases (RTKs) are the main mediators of the signaling network that transmit extracellular signals into the cell, and control cellular differentiation and proliferation. Recent and rapid advances in our understanding of cellular signaling by receptor tyrosine kinases, in normal and malignant cells, have brought to light the potential of RTKs as selective anti-cancer targets. Their activity is normally tightly controlled and regulated. Overexpression of RTK proteins or functional alterations caused by mutations in the corresponding genes or abnormal stimulation by autocrine growth factor loops contribute to constitutive RTK signaling, resulting in dysregulated cell growth and cancer. The mechanisms of uncontrolled RTK signaling that leads to cancer has provided the rationale for anti-RTK drug development. Herceptin, Gleevec, and Iressa are the first examples of drugs which have successfully translated basic research on oncogenes into cancer therapeutics. RTKs can be viewed as multifunctional targets, and strategies towards the prevention and inhibition of RTK signaling include antibodies, antagonist ligands, small molecule inhibitors of protein kinase activity, and inhibitors of protein-protein interactions. Progresses in the field of rational drug design and computational chemistry will vastly benefit from the availability of increasing structural knowledge of both the kinase domains and the ligand-binding sites of these receptors.
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Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Sistemas de Liberación de Medicamentos , Humanos , Ligandos , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.