RESUMO
Ligelizumab is a highly potent, humanized IgG1, anti-IgE monoclonal antibody. To explore its optimal subcutaneous delivery, the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of ligelizumab from two Phase 1 studies in healthy volunteers (HVs) and four Phase 2 and 3 studies in patients with chronic spontaneous urticaria (CSU) were assessed. Using different injection volumes or durations of a liquid-in-vial (LIVI) formulation or different formulations (LIVI vs. prefilled syringe (PFS)), single-dose ligelizumab showed comparable PK exposure in HVs. Steady-state exposure of ligelizumab was also comparable between LIVI and PFS following multiple dosing in CSU patients. The total IgE level (a PD marker) and tolerability were similar between the two formulations in both HVs and patients. Furthermore, the PK, total IgE, and tolerability were comparable for PFS administered either by patients or healthcare providers (HCPs). Collective evidence demonstrated that the injection duration or volume, formulation, or administrator had no apparent impact on the PK, PD, and tolerability of ligelizumab, supporting no clinically relevant difference between LIVI and PFS, and that PFS can be administered by patients or HCPs. This report provides a comprehensive assessment based on data of multiple clinical endpoints from both HVs and patients to inform formulation development and commercial use of a monoclonal antibody.
RESUMO
This open-label, randomized, 3-treatment, 3-period, 6-sequence, crossover study in healthy subjects compared the pharmacokinetic and pharmacodynamic properties of a lipid-based (soft gelatin capsule) prototype final market image (pFMI) formulation of tropifexor (90-µg) to its clinical service form (CSF) and assessed the food effect for the pFMI formulation. In the fasted state, drug exposure was higher for the pFMI. The geometric mean ratios for pFMI versus CSF of peak concentration and area under the concentration-time curve were 2.0 and 1.5, respectively. No food effect was apparent for the pFMI formulation, and the geometric mean ratios for pFMI fed versus pFMI fasted of peak concentration and area under concentration-time curve were 1.0 and 1.0 respectively. Despite having lower systemic exposure, the CSF formulation provided a higher pharmacological response for the gut biomarker fibroblast growth factor 19. Under fasted conditions, fibroblast growth factor 19 maximum change from baseline serum concentration after drug administration and area under the change from baseline serum concentration-time curve from time 0 to 24 hours were 36% for CSF and 12% for FMI. For a second biomarker, serum 7-alpha hydroxy-4-cholest-3-one, the pharmacological activity was comparable between CSF (fasted) and pFMI (both fasted and fed states). The pFMI offers advantages over the CSF in terms of insensitivity to food effect, lower intersubject variability, and overcoming solubility limitations.
Assuntos
Interações Alimento-Droga , Humanos , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Voluntários SaudáveisRESUMO
Tropifexor, a farnesoid X receptor agonist, is currently under clinical development for the treatment of nonalcoholic steatohepatitis. Tropifexor undergoes glucuronidation by uridine 5'-diphosphoglucuronosyltransferase (UGT) 1A1 and oxidation by cytochrome P450 (CYP) 3A4, as reported in in vitro studies. Here, we report the results from 2 drug-drug interaction studies. Study 1 enrolled 20 healthy subjects to investigate the effect of the UGT1A1 inhibitor atazanavir (ATZ) on tropifexor pharmacokinetics (PK). Study 2 had 2 cohorts with 16 healthy subjects each to investigate the effect of the strong CYP3A4 inhibitor itraconazole and strong CYP3A4 inducer rifampin on the PK of tropifexor. Coadministration of ATZ reduced the maximum plasma concentration (Cmax ) of tropifexor by 40%; however, it did not lead to increased exposure of tropifexor (both area under the plasma concentration-time curve [AUC] from time 0 to the last quantifiable concentration [AUClast ] and AUC from time 0 to infinity [AUCinf ] reduced by only 10%), suggesting minor relevance of the UGT1A1 pathway for clearance of tropifexor and no expected drug-drug interactions based on UGT1A1 inhibition. Inhibition of CYP3A4 by itraconazole increased the Cmax of tropifexor by only 9% and exposure (both AUClast and AUCinf ) by 47%, suggesting a weak effect of strong CYP3A4 inhibitors on tropifexor PK. Inducing CYP3A4 with rifampin decreased Cmax (55%) and AUC (AUClast by 79% and AUCinf by 77%). Coadministration of tropifexor with either ATZ, itraconazole, or rifampin was well tolerated.
Assuntos
Citocromo P-450 CYP3A , Itraconazol , Humanos , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Voluntários Saudáveis , RifampinaRESUMO
PURPOSE: Pharmacokinetic drug-drug interactions (DDIs) are investigated to ensure safety for patients receiving concomitant medications. Here, we present a strategy to characterise the DDI potential of remibrutinib, as an inhibitor of drug-metabolising enzymes and drug transporters, and as an inducer. Initial in vitro studies were performed, followed by a biomarker-based assessment of induction in a first in human study, concluded by a clinical study to verify initial results. Remibrutinib is a covalent inhibitor of Bruton's Tyrosine kinase (BTKi) carrying a reactive acrylamide moiety (warhead), thus the potential contribution of covalent binding (off-target) to observed interactions was investigated as this could lead to prolonged and more potent drug interactions. METHODS: DDI assessment was focused on the putative inhibition of key metabolic enzymes (Cytochrome P450, CYP), drug transporters and a potential effect on oral contraceptives (OC) by induction of enzymes that are involved in their clearance (CYP3A4). The impact of covalent binding was assessed by synthesising an identical reference molecule but with an inactivated warhead. RESULTS: An interaction potential of limited clinical relevance was revealed for remibrutinib for CYP enzymes and drug transporters. The reactive warhead of remibrutinib had no impact on CYP enzyme and transporter inhibition, including time-dependent inhibition of CYP3A4, but may increase the induction potential of remibrutinib. CONCLUSIONS: Observed inhibition of metabolic enzymes indicated that remibrutinib is a weak inhibitor of CYP3A4 and CYP2C9 and is not a clinically relevant inhibitor of uptake and efflux transporters, except for intestinal P-glycoprotein and breast cancer resistance protein inhibition. OC may be safely administered and are effective when given with pharmacologically relevant doses of remibrutinib.
Assuntos
Proteínas de Neoplasias , Inibidores de Proteínas Quinases , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Humanos , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacocinéticaRESUMO
Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200-µg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf,u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf,u , 1.64 [90%CI, 1.25-2.16]; Cmax,u , 1.30 [90%CI, 0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf,u (1.61 [90%CI, 1.04-2.49]) and comparable Cmax,u (1.02 [90%CI, 0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment.
Assuntos
Isoxazóis , Hepatopatias , Área Sob a Curva , Benzotiazóis , Humanos , Hepatopatias/metabolismoRESUMO
Remibrutinib, a novel oral Bruton's Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first-pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady-state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27-fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically-based pharmacokinetic (PBPK) model, which well-described the therapeutic dose range of 25-100 mg. Simulations of untested scenarios revealed an absence of drug-drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration-time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.
Assuntos
Inibidores do Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/farmacocinética , Algoritmos , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Humanos , Fígado/enzimologia , Fígado/metabolismo , Taxa de Depuração Metabólica , Proteínas Tirosina Quinases/administração & dosagem , SegurançaRESUMO
Tropifexor (NVP-LJN452) is a highly potent, selective, nonsteroidal, non-bile acid farnesoid X receptor agonist for the treatment of nonalcoholic steatohepatitis. Its absorption, metabolism, and excretion were studied after a 1-mg oral dose of [14C]tropifexor was given to four healthy male subjects. Mass balance was achieved with â¼94% of the administered dose recovered in excreta through a 312-hour collection period. Fecal excretion of tropifexor-related radioactivity played a major role (â¼65% of the total dose). Tropifexor reached a maximum blood concentration (Cmax) of 33.5 ng/ml with a median time to reach Cmax of 4 hours and was eliminated with a plasma elimination half-life of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (â¼92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metabolism appeared to be the major clearance pathway of tropifexor. Metabolites containing multiple oxidative modifications and combined oxidation and glucuronidation were also observed in human excreta. The involvement of direct glucuronidation could not be ruled out based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Because of these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study. SIGNIFICANCE STATEMENT: Tropifexor was found to be primarily cleared from the human body via oxidative metabolism. In vitro metabolism experiments revealed that the relative contribution of oxidation and glucuronidation was concentration-dependent, with glucuronidation as the predominant pathway at higher concentrations and the oxidative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development.
Assuntos
Benzotiazóis/farmacocinética , Isoxazóis/farmacocinética , Administração Oral , Adolescente , Adulto , Benzotiazóis/administração & dosagem , Absorção Gastrointestinal , Voluntários Saudáveis , Humanos , Isoxazóis/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: Ligelizumab is a humanised IgG1 anti-IgE antibody that binds IgE with higher affinity than omalizumab. Ligelizumab had greater efficacy than omalizumab on inhaled and skin allergen provocation responses in mild allergic asthma. This multi-centre, randomised, double-blind study was designed to test ligelizumab in severe asthma patients not adequately controlled with high-dose inhaled corticoids plus long-acting ß2-agonist. METHODS: Patients received 16 weeks ligelizumab (240 mg q2w), omalizumab or placebo subcutaneously, and ACQ-7 was measured as primary outcome at Week 16. In addition, the study generated dose-ranging data of ligelizumab and safety data. RESULTS: A total of 471 patients, age 47.4 ± 13.36 years, were included in the study. Treatment with ligelizumab did not significantly improve asthma control (ACQ-7) and exacerbation rates compared to omalizumab and placebo. Therefore, primary and secondary objectives of the study were not met. The compound was well tolerated, and the safety profile showed no new safety findings. Pharmacokinetic data demonstrated faster clearance and lower serum concentrations of ligelizumab than historical omalizumab data, and exploratory in vitro data showed differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. CONCLUSION: Ligelizumab failed to demonstrate superiority over placebo or omalizumab. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high-affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. Therefore, the data suggest that different anti-IgE antibodies might be selectively efficacious for different IgE-mediated diseases.
RESUMO
AIMS: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. METHODS: A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration-time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1-mL prefilled syringe or 1 × 2-mL prefilled syringe. RESULTS: Mean serum concentration-time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1-year phase 3 study in patients confirmed PK results observed in the phase 1 study. CONCLUSION: Collective evidence from both studies demonstrated that 2-mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.
Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Anticorpos Monoclonais Humanizados/uso terapêutico , Voluntários Saudáveis , Humanos , Injeções Subcutâneas , Psoríase/tratamento farmacológicoRESUMO
This open-label disease-drug-drug interaction study assessed whether blockade of the interleukin (IL)-17A pathway by secukinumab and subsequent downregulation of inflammatory cytokines like IL-6 or high-sensitivity C-reactive protein affects the pharmacokinetics (PKs) of a sensitive probe substrate of the cytochrome P450 3A4 isoform (CYP3A4). The PKs of midazolam, metabolized by CYP3A4, was evaluated before and after 7 and 35 days of treatment initiation of subcutaneous secukinumab at a dose of 300 mg weekly in 24 patients with moderate-to-severe psoriasis. Although demonstrating the expected decrease in downstream inflammatory cytokines, secukinumab had no clinically relevant effects on the PKs of midazolam, provided substantial clinical benefit, and was generally well tolerated. In summary, blockade of IL-17A signaling in patients with moderate-to-severe psoriasis does not significantly affect CYP3A4 enzyme activities and, therefore, the use of secukinumab is unlikely to influence the PKs of CYP3A4 substrates.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Hipnóticos e Sedativos/farmacocinética , Midazolam/farmacocinética , Psoríase/tratamento farmacológico , Adolescente , Adulto , Idoso , Interações Medicamentosas , Feminino , Humanos , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto JovemRESUMO
Fevipiprant, a prostaglandin D2 receptor 2 antagonist, is in clinical development as a treatment for asthma. The goal of this study was to assess the potential of fevipiprant to cause drug-drug interactions (DDI) as a perpetrator, that is, by altering the pharmacokinetics (PK) of co-medications. In vitro drug interaction studies of clinically relevant drug metabolizing enzymes and transporters were conducted for fevipiprant and its acyl glucuronide (AG) metabolite. Comparison of Ki values with unbound systemic or portal vein steady-state plasma exposure of fevipiprant and its AG metabolite revealed the potential for inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) transporters (R-value of 5.99), while other targets including cytochrome P450 enzymes were not, or only marginally, inhibited. Consequently, an open-label, two-part, two-period, single-sequence clinical study assessed the effect of fevipiprant 450â¯mg QD on the pharmacokinetics of simvastatin 20â¯mg and rosuvastatin 20â¯mg, two statins with different dependency in OATP1B1-mediated hepatic uptake, in healthy adult volunteers. The study also assessed the pharmacogenetics of the SLCO1B1 gene, which encodes OATP1B1. Clinically, fevipiprant 450â¯mg QD showed a low potential for interaction and increased the peak concentrations of simvastatin acid and rosuvastatin by 2.23- and 1.87-fold, respectively, with little or no impact on total exposure. Genotype analysis confirmed that SLCO1B1 genotype influences statin pharmacokinetics to a similar extent either with or without fevipiprant co-administration. In summary, fevipiprant at 450â¯mg QD has only minor liabilities as a perpetrator for DDI.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Ácidos Indolacéticos/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Piridinas/farmacologia , Rosuvastatina Cálcica/farmacocinética , Sinvastatina/farmacocinética , Adulto , Interações Medicamentosas , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos , Farmacogenética , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidoresRESUMO
This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P-gp, the potential interaction with quinidine, a strong inhibitor of P-gp but not CYP3A, was studied as well. Using a fixed-sequence, 3-way crossover design, 20 healthy male subjects received single oral doses of 10 mg leniolisib during three phases separated by a washout: (1) leniolisib alone, (2) 200 mg itraconazole once daily for 9 days plus leniolisib on day 5, and (3) 300 mg quinidine administered 1 h before and 3 h after leniolisib. Itraconazole increased the leniolisib oral drug exposure (AUCinf ) by on average 2.1-fold, whereas the peak drug concentration (Cmax ) was less impacted (1.25-fold). The terminal elimination half-life (T1/2 ) of leniolisib was also increased by ~2-fold. Neither oral AUCinf nor Cmax or T1/2 was found to be altered by quinidine. These findings suggest that the interaction with itraconazole occurred mainly systemically through inhibition of CYP3A, and corroborate our in vitro findings that leniolisib is neither a sensitive CYP3A substrate nor a relevant in vivo substrate for intestinal or hepatic P-gp. Assuming itraconazole levels achieved complete inhibition of CYP3A, the fractional contribution of CYP3A to the overall disposition of leniolisib is estimated to be about 50%. The concomitant use of leniolisib with strong inhibitors of CYP3A as well as strong and moderate inducers of CYP3A is best avoided.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/farmacologia , Humanos , Itraconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Quinidina/farmacologia , Adulto JovemRESUMO
Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.
Assuntos
Hepatócitos/metabolismo , Ácidos Indolacéticos/farmacocinética , Microssomos Hepáticos/metabolismo , Piridinas/farmacocinética , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Biotransformação , Fezes/química , Voluntários Saudáveis , Humanos , Técnicas In Vitro , Ácidos Indolacéticos/sangue , Ácidos Indolacéticos/urina , Masculino , Taxa de Depuração Metabólica , Metaboloma , Pessoa de Meia-Idade , Ligação Proteica , Piridinas/sangue , Piridinas/urina , Eliminação Renal , Distribuição Tecidual , Adulto JovemRESUMO
OBJECTIVE: Indacaterol/glycopyrronium (IND/GLY) is a once-daily fixed-dose combination of two long-acting bronchodilators: indacaterol 110 µg (long-acting ß2-adrenergic agonist, LABA) and glycopyrronium 50 µg (long-acting muscarinic antagonist, LAMA). This study assessed the pharmacokinetics of IND/GLY 110/50 µg following multiple once-daily inhaled administrations in healthy Chinese subjects. METHODS: This was a single-centre, open-label, multiple-dose study of inhaled IND/GLY delivered via the Breezhaler® device. Pharmacokinetic samples were collected on day 1 after first dose, on days 5, 7, 10, and 12 (predose (trough)) and on day 14 (steady state) after last dose for pharmacokinetic analysis using non-compartmental analysis. RESULTS: Both IND and GLY were absorbed rapidly after inhalation of IND/GLY (tmax: IND, 15 minutes; GLY, 5 minutes). Accumulation through systemic exposure of both IND and GLY from day 1 to day 14 was observed (mean accumulation ratio (Racc) of AUC0-24h (day 14/day 1): IND, 3.02; GLY 2.94; estimated accumulation ratio of Cmax: IND 1.56; GLY 1.33). Mean effective half-life (t1/2,acc) was 41.3 h and 40.0 h for IND and GLY, respectively. Pharmacokinetic steady states were reached after 12 and 10 days of daily dosing for IND and GLY, respectively. There was one mild adverse event (AE) not related to the study drug. No discontinuations due to treatment related AEs/SAEs (adverse event/serious adverse event) were reported. CONCLUSIONS: In healthy Chinese subjects, multiple once-daily inhaled doses of IND/GLY 110/50 µg were rapidly absorbed and were safe and well tolerated. The comparison of systemic exposure data following inhalation of IND/GLY 110/50 µg in Chinese vs. the non-Chinese populations did not indicate any clinically relevant differences across ethnicities.â©.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Glicopirrolato/administração & dosagem , Glicopirrolato/farmacocinética , Indanos/administração & dosagem , Indanos/farmacocinética , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacocinética , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Área Sob a Curva , Povo Asiático , Broncodilatadores/efeitos adversos , China , Esquema de Medicação , Combinação de Medicamentos , Feminino , Glicopirrolato/efeitos adversos , Meia-Vida , Voluntários Saudáveis , Humanos , Indanos/efeitos adversos , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Antagonistas Muscarínicos/efeitos adversos , Nebulizadores e Vaporizadores , Quinolonas/efeitos adversos , Absorção pelo Trato Respiratório , Adulto JovemRESUMO
PURPOSE: The conduct of thorough QTc (TQT) studies is often challenging with compounds that are characterized by limited tolerability in healthy individuals. This is applicable to several central nervous system drugs, including mavoglurant acting as a selective allosteric modulator of metabotropic glutamate receptor 5. This TQT study describes the use of a single intravenous dosing regimen as an alternate approach allowing for sufficiently high Cmax values while controlling tolerability. METHODS: This study was a randomized, placebo- and active-controlled, 4-period, crossover, TQT study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg). FINDINGS: Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic Cmax values were achieved that were approximately 2-fold higher than at the multiple maximum tolerated dose and more than 3-fold higher relative to therapeutic plasma concentrations. The upper bound of the 2-sided 90% CI of Fridericia-corrected placebo- and baseline-adjusted QTc intervals (QTcFs) did not exceed 10 milliseconds at any postdose time point for both mavoglurant doses. The pharmacokinetic and pharmacodynamic analysis confirmed the lack of an association between mavoglurant plasma concentrations and ΔΔQTcF data over the entire range of plasma concentration data at 25 and 50 mg of mavoglurant. An outlier analysis revealed no individuals with newly identified QTcF intervals >480 milliseconds or any QTcF prolongations >60 milliseconds compared with baseline in any of the treatment groups. Hence, the lack of any clinically relevant QTc prolongation was found for therapeutic and supratherapeutic single intravenous doses of 25 and 50 mg of mavoglurant. IMPLICATIONS: This TQT study describes the use of single intravenous dosing as an alternate approach to achieve supratherapeutic plasma concentrations as required per the International Council for Harmonisation E14 guideline with compounds characterized by exposure related tolerability limitations. The increased Cmax/AUC ratio compared with conventional oral dosing may contribute to a reduced incidence of adverse events that appear more related to overall exposure.
Assuntos
Coração/efeitos dos fármacos , Indóis/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Administração Intravenosa , Adulto , Regulação Alostérica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Fluoroquinolonas/farmacologia , Coração/fisiologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Humanos , Indóis/farmacocinética , Masculino , Moxifloxacina , Projetos PilotoRESUMO
PURPOSE: QMF149 is a fixed-dose combination of the long-acting ß2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler(®) device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. METHODS: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 µg, mometasone furoate 320 µg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 µg/mometasone furoate 320 µg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. RESULTS: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. CONCLUSIONS: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.
Assuntos
Corticosteroides/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Indanos/farmacocinética , Pregnadienodiois/farmacocinética , Quinolonas/farmacocinética , Administração por Inalação , Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Adulto , Área Sob a Curva , Estudos Cross-Over , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Indanos/administração & dosagem , Masculino , Furoato de Mometasona/administração & dosagem , Furoato de Mometasona/farmacocinética , Pregnadienodiois/administração & dosagem , Quinolonas/administração & dosagemAssuntos
Anticorpos Monoclonais/farmacocinética , Líquidos Corporais/metabolismo , Psoríase/metabolismo , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Peso Corporal , Avaliação Pré-Clínica de Medicamentos , Humanos , Injeções Subcutâneas , Interleucina-17/imunologia , Perfusão , Fatores de TempoRESUMO
OBJECTIVE: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). METHODS: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18-40 years. In period 1, a single oral dose of an OC containing 30 µg ethinyl estradiol (EE)/150 µg levonorgestrel (LNG) was administered alone. In period 2, the OC was administered with a clinically relevant multiple dose of mavoglurant 100 mg b.i.d. under steady-state conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration, and the PK parameters Cmax and AUClast were estimated using noncompartmental methods. RESULTS: The geometric mean ratios of EE Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval (CI): 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63-0.73), respectively. CONCLUSIONS: In conclusion, EE PK was unchanged, whereas Cmax and AUClast of LNG were 19% and 32% lower, respectively, when given with mavoglurant Further investigation regarding the impact on contraceptive efficacy is warranted.
Assuntos
Anticoncepcionais Orais Combinados/farmacocinética , Anticoncepcionais Orais Hormonais/farmacocinética , Etinilestradiol/farmacocinética , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Indóis/administração & dosagem , Levanogestrel/farmacocinética , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Combinados/sangue , Anticoncepcionais Orais Hormonais/administração & dosagem , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepcionais Orais Hormonais/sangue , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Etinilestradiol/sangue , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Voluntários Saudáveis , Humanos , Indóis/efeitos adversos , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Levanogestrel/sangue , Taxa de Depuração Metabólica , Modelos Biológicos , Adulto JovemRESUMO
OBJECTIVES: This study aimed to evaluate influence of ethnic factors on the pharmacokinetics of orally inhaled QMF149, a novel combination of an approved longacting ß2-agonist, indacaterol (Onbrez® Breezhaler® for COPD), and an approved inhaled corticosteroid, mometasone furoate (MF), (Asmanex® Twisthaler® for asthma), following multiple dose administration of QMF149 (indacaterol acetate/MF) 150/80 µg and 150/320 µg via the Breezhaler® device in healthy Japanese and Caucasian subjects. METHODS: This was a single-center, openlabel, multiple-dose, two-period, complete crossover study that randomized healthy Japanese and, age and weight matched Caucasian subjects to QMF149 150/80 µg or 150/320 µg once daily (o.d.) for 14 days in each period. Pharmacokinetics (PK) were assessed up to 24 hours on days 1 and 14. RESULTS: 24 Japanese and 24 Caucasian healthy subjects were enrolled. Indacaterol and MF had similar PK profiles across both the doses and both ethnic groups. The maximum geometric mean ratios (90% confidence interval (CI)) for Japanese vs. Caucasian subjects for Cmax were 1.23 (1.11 - 1.38) and 1.24 (1.11 - 1.38) for indacaterol and MF, respectively. For AUC, the maximum ratios were 1.22 (1.09 - 1.36) and 1.30 (1.18 - 1.44) for indacaterol and MF, respectively. The mild trend towards higher exposure in Japanese subjects could be explained by the fact that the mean body weight was 14% higher for Caucasians compared to their Japanese counterparts. No serious adverse events or discontinuations related to study medication were reported. CONCLUSION: The study demonstrated increase of mean exposure parameters in Japanese subjects vs. Caucasian subjects, which ranged between 19 - 23% and 17 - 30%, for indacaterol and MF components, respectively. Multiple doses of both the QMF149 dose levels were safe and well-tolerated in all subjects. Body weight was considered a key contributory factor for the observed difference in exposure. These results suggest no dose adjustment for QMF149 is required in Asian populations.
Assuntos
Antiasmáticos/farmacocinética , Povo Asiático , Indanos/farmacocinética , Pregnadienodiois/farmacocinética , Quinolonas/farmacocinética , População Branca , Administração por Inalação , Adulto , Antiasmáticos/administração & dosagem , Antiasmáticos/efeitos adversos , Antiasmáticos/sangue , Área Sob a Curva , Estudos Cross-Over , Combinação de Medicamentos , Monitoramento de Medicamentos , Humanos , Indanos/administração & dosagem , Indanos/efeitos adversos , Indanos/sangue , Japão , Masculino , Nebulizadores e Vaporizadores , Pregnadienodiois/administração & dosagem , Pregnadienodiois/efeitos adversos , Pregnadienodiois/sangue , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/sangue , Adulto JovemRESUMO
PURPOSE: To compare the pharmacokinetics of intravenous (IV), oral immediate-release (IR) and oral modified-release (MR) formulations of mavoglurant in healthy subjects, and to assess the food effect on the MR formulation's input characteristics. METHODS: Plasma concentration-time data from two clinical studies in healthy volunteers were pooled and analysed using NONMEM®. Drug entry into the systemic circulation was modelled using a sum of inverse Gaussian (IG) functions as an input rate function, which was estimated specifically for each formulation and food state. RESULTS: Mavoglurant pharmacokinetics was best described by a two-compartment model with a sum of either two or three IG functions as input function. The mean absolute bioavailability from the MR formulation (0.387) was less than from the IR formulation (0.436). The MR formulation pharmacokinetics were significantly impacted by food: bioavailability was higher (0.508) and the input process was shorter (complete in approximately 36 versus 12 h for the fasted and fed states, respectively). CONCLUSIONS: Modelling and simulation of mavoglurant pharmacokinetics indicate that the MR formulation might provide a slightly lower steady-state concentration range with lower peaks (possibly better drug tolerance) than the IR formulation, and that the MR formulation's input properties strongly depend on the food conditions at drug administration.