RESUMO
The selective Bruton tyrosine kinase (BTK) inhibitor poseltinib has been shown to inhibit the BCR signal transduction pathway and cytokine production in B cells (Park et al. Arthritis Res. Ther. 18, 91, https://doi.org/10.1186/s13075-016-0988-z , 2016). This study describes the translation of nonclinical research studies to a phase I clinical trial in healthy volunteers in which pharmacokinetics (PKs) and pharmacodynamics (PDs) were evaluated for dose determination. The BTK protein kinase inhibitory effects of poseltinib in human peripheral blood mononuclear cells (PBMCs) and in rats with collagen-induced arthritis (CIA) were evaluated. High-dimensional phosphorylation analysis was conducted on human immune cells such as B cells, CD8 + memory cells, CD4 + memory cells, NK cells, neutrophils, and monocytes, to map the impact of poseltinib on BTK/PLC and AKT signaling pathways. PK and PD profiles were evaluated in a first-in-human study in healthy donors, and a PK/PD model was established based on BTK occupancy. Poseltinib bound to the BTK protein and modulated BTK phosphorylation in human PBMCs. High-dimensional phosphorylation analysis of 94 nodes showed that poseltinib had the highest impact on anti-IgM + CD40L stimulated B cells, however, lower impacts on anti-CD3/CD-28 stimulated T cells, IL-2 stimulated CD4 + T cells and NK cells, M-CSF stimulated monocytes, or LPS-induced granulocytes. In anti-IgM + CD40L stimulated B cells, poseltinib inhibited the phosphorylation of BTK, AKT, and PLCγ2. Moreover, poseltinib dose dependently improved arthritis disease severity in CIA rat model. In a clinical phase I trial for healthy volunteers, poseltinib exhibited dose-dependent and persistent BTK occupancy in PBMCs of all poseltinib-administrated patients in the study. More than 80% of BTK occupancy at 40 mg dosing was maintained for up to 48 h after the first dose. A first-in-human healthy volunteer study of poseltinib established target engagement with circulating BTK protein. Desirable PK and PD properties were observed, and a modeling approach was used for rational dose selection for subsequent trials. Poseltinib was confirmed as a potential BTK inhibitor for the treatment of autoimmune diseases.Trial registration: This article includes the results of a clinical intervention on human participants [NCT01765478].
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Compostos de Anilina/farmacologia , Modelos Biológicos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacocinética , Animais , Ensaios Clínicos Fase II como Assunto , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Simulação de Acoplamento Molecular , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , RatosRESUMO
Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter.
Assuntos
Aciclovir/análogos & derivados , Aminoácidos/metabolismo , Transportador 1 de Peptídeos/metabolismo , Pró-Fármacos/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Valina/análogos & derivados , Aciclovir/administração & dosagem , Aciclovir/sangue , Aciclovir/metabolismo , Aciclovir/urina , Adolescente , Adulto , Idoso , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Aminoácidos/urina , Transporte Biológico , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/urina , Óxidos S-Cíclicos/sangue , Óxidos S-Cíclicos/urina , Interações Medicamentosas , Feminino , Células HeLa , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Especificidade por Substrato , Valaciclovir , Valina/administração & dosagem , Valina/sangue , Valina/metabolismo , Valina/urina , Adulto JovemRESUMO
Pomaglumetad methionil (LY2140023) is the prodrug of a novel metabotropic glutamate 2/3 receptor agonist (LY404039) being investigated for the treatment of schizophrenia. Using accelerator mass spectrometry (AMS) and an intravenous (i.v.) radiolabeled tracer approach, the absolute bioavailability of the prodrug and the extent of its conversion to active moiety (LY404039) were estimated at presystemic (intestinal/first pass) and systemic sites after simultaneous oral and i.v. dosing in healthy subjects. The mean absolute bioavailability of prodrug (80 mg oral) was 0.68. On the basis of these data and a previous radiolabeled mass balance study in which no prodrug was recovered in feces, we concluded that 0.32 of the dose is converted to active drug in the intestinal tract. The fraction of prodrug converted to active moiety was approximately 1, indicating complete conversion of the prodrug that reaches the systemic circulation to the active moiety. Prodrug (80 mg oral and 100 µg i.v.) and active moiety (100 µg i.v.) were well tolerated in healthy subjects. Thus, the absolute bioavailability of prodrug LY2140023 and the fraction converted presystemically and systemically to active moiety LY404039 were estimated simultaneously using radiolabeled tracer microdosing and AMS.
Assuntos
Aminoácidos/farmacocinética , Antipsicóticos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Óxidos S-Cíclicos/farmacocinética , Modelos Biológicos , Peptídeo Hidrolases/metabolismo , Pró-Fármacos/farmacocinética , Ativação Metabólica , Administração Oral , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/efeitos adversos , Aminoácidos/análise , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/análise , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/análise , Radioisótopos de Carbono , Estudos Cross-Over , Óxidos S-Cíclicos/administração & dosagem , Óxidos S-Cíclicos/efeitos adversos , Óxidos S-Cíclicos/análise , Relação Dose-Resposta a Droga , Fezes/química , Humanos , Infusões Intravenosas , Mucosa Intestinal/enzimologia , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/análise , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Adulto JovemRESUMO
The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed.
Assuntos
Injúria Renal Aguda/terapia , Cálculos da Dosagem de Medicamento , Nefrologia/normas , Preparações Farmacêuticas/metabolismo , Farmacocinética , Terapia de Substituição Renal , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/metabolismo , Estado Terminal , Humanos , Nefrologia/métodos , Preparações Farmacêuticas/administração & dosagem , Terapia de Substituição Renal/efeitos adversosRESUMO
BACKGROUND: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology. METHODS: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans. RESULTS: In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10mg). CONCLUSIONS: We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.
Assuntos
Benzamidas/farmacologia , Antagonistas de Entorpecentes/farmacologia , Pupila/efeitos dos fármacos , Pirrolidinas/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Adolescente , Adulto , Animais , Benzamidas/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fentanila/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Miose/induzido quimicamente , Miose/tratamento farmacológico , Morfina/farmacologia , Midríase/induzido quimicamente , Midríase/tratamento farmacológico , Naltrexona/farmacologia , Antagonistas de Entorpecentes/sangue , Entorpecentes/farmacologia , Pupila/fisiologia , Pirrolidinas/sangue , Ratos Sprague-Dawley , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Adulto JovemRESUMO
To determine whether physicians can adequately titrate atomoxetine without knowing genotype status for hepatic cytochrome P450 2D6, we pooled data from two open-label studies of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder. Patients were assessed weekly up to 10 weeks and doses titrated for efficacy and tolerability at the discretion of investigators (max. 1.8 mg/kg/d). Mean dose was 0.1 mg/kg/d lower in poor metabolizer (PM) patients (n=87) than extensive metabolizers (EMs, n=1239). PMs demonstrated marginally better efficacy on the ADHDRS-IV-Parent:Inv and had comparable safety profiles, except for a 4.0-bpm greater increase in mean pulse rate and a 1.0-kg greater weight loss. Changes from baseline in Fridericia QTc did not differ between groups or correlate with dose in PMs. Results suggest genotyping is unnecessary during routine clinical management, because investigators were able to dose atomoxetine to comparable efficacy and safety levels in EMs and PMs without knowledge of genotype metabolizer status.
Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade , Citocromo P-450 CYP2D6/genética , Propilaminas/uso terapêutico , Adolescente , Inibidores da Captação Adrenérgica/farmacocinética , Cloridrato de Atomoxetina , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Criança , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Feminino , Humanos , Masculino , Propilaminas/farmacocinética , Fatores de TempoRESUMO
Atomoxetine (Strattera, a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine. The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1-2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.
Assuntos
Inibidores da Captação Adrenérgica/efeitos adversos , Inibidores da Captação Adrenérgica/farmacocinética , Inibidores da Captação Adrenérgica/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Propilaminas/efeitos adversos , Propilaminas/farmacocinética , Propilaminas/uso terapêutico , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/farmacologia , Cloridrato de Atomoxetina , Fenômenos Químicos , Físico-Química , Criança , Interações Medicamentosas , Humanos , Propilaminas/administração & dosagem , Propilaminas/farmacologiaRESUMO
In the studies reported here, the ability of atomoxetine hydrochloride (Strattera) to inhibit or induce the metabolic capabilities of selected human isoforms of cytochrome P450 was evaluated. Initially, the potential of atomoxetine and its two metabolites, N-desmethylatomoxetine and 4-hydroxyatomoxetine, to inhibit the metabolism of probe substrates for CYP1A2, CYP2C9, CYP2D6, and CYP3A was evaluated in human hepatic microsomes. Although little inhibition of CYP1A2 and CYP2C9 activity was observed, inhibition was predicted for CYP3A (56% predicted inhibition) and CYP2D6 (60% predicted inhibition) at concentrations representative of high therapeutic doses of atomoxetine. The ability of atomoxetine to induce the catalytic activities of CYP1A2 and CYP3A in human hepatocytes was also evaluated; however, atomoxetine did not induce either isoenzyme. Based on the potential of interaction from the in vitro experiments, drug interaction studies in healthy subjects were conducted using probe substrates for CYP2D6 (desipramine) in CYP2D6 extensive metabolizer subjects and CYP3A (midazolam) in CYP2D6 poor metabolizer subjects. Single-dose pharmacokinetic parameters of desipramine (single dose of 50 mg) were not altered when coadministered with atomoxetine (40 or 60 mg b.i.d. for 13 days). Only modest changes (approximately 16%) were observed in the plasma pharmacokinetics of midazolam (single dose of 5 mg) when coadministered with atomoxetine (60 mg b.i.d. for 12 days). Although at high therapeutic doses of atomoxetine inhibition of CYP2D6 and CYP3A was predicted, definitive in vivo studies clearly indicate that atomoxetine administration with substrates of CYP2D6 and CYP3A does not result in clinically significant drug interactions.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Microssomos Hepáticos/metabolismo , Propilaminas/metabolismo , Cloridrato de Atomoxetina , Citocromo P-450 CYP2C9 , Diclofenaco/metabolismo , Interações Medicamentosas , Etanolaminas/metabolismo , Humanos , Hidroxilação , Microssomos Hepáticos/enzimologia , Midazolam/metabolismo , Fenacetina/metabolismoRESUMO
OBJECTIVE: Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder in children, adolescents, and adults. This study was conducted, in part, to evaluate the single-dose and steady-state pharmacokinetics of atomoxetine in pediatric patients. METHODS: This was an open-label, dose-titration study in pediatric patients with attention deficit hyperactivity disorder. Eligible patients could elect to participate in a single-dose or steady-state discontinuation pharmacokinetic evaluation including serial plasma sample collection over 24 hours. Plasma concentrations of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine were determined using an atmospheric pressure chemical ionization liquid chromatography/mass spectrometry/mass spectrometry assay. Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS: Twenty-one cytochrome P450 2D6 extensive metabolizer patients participated in these single-dose and steady-state pharmacokinetic evaluations. Atomoxetine was rapidly absorbed, with peak plasma concentrations occurring 1 to 2 hours after dosing. Half-life averaged 3.12 and 3.28 hours after a single dose and at steady state, respectively. Minimal accumulation occurred in plasma after multiple twice-daily dosing in extensive metabolizer pediatric patients, as expected based on single-dose pharmacokinetics. As the dose (in mg/kg) increased, proportional increases in area under the curve were observed. CONCLUSIONS: The pharmacokinetics of atomoxetine in extensive metabolizer patients were well characterized over a wide range of doses in this study. Atomoxetine pharmacokinetics in pediatric patients and adult subjects were similar after adjustment for body weight.
Assuntos
Antidepressivos/farmacocinética , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Propilaminas/farmacocinética , Adolescente , Adulto , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Área Sob a Curva , Cloridrato de Atomoxetina , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Citocromo P-450 CYP2D6/genética , Esquema de Medicação , Feminino , Humanos , Masculino , Propilaminas/administração & dosagem , Propilaminas/uso terapêutico , Resultado do TratamentoRESUMO
The role of the polymorphic cytochrome p450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented following both single and multiple doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the overall disposition and metabolism of a 20-mg dose of (14)C-atomoxetine was evaluated in CYP2D6 extensive metabolizer (EM; n = 4) and poor metabolizer (PM; n = 3) subjects under steady-state conditions. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the preponderance of radioactivity being excreted into the urine. In EM subjects, the majority of the radioactive dose was excreted within 24 h, whereas in PM subjects the majority of the dose was excreted by 72 h. The biotransformation of atomoxetine was similar in all subjects undergoing aromatic ring hydroxylation, benzylic oxidation, and N-demethylation with no CYP2D6 phenotype-specific metabolites. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged in PM subjects (t(1/2) = 62 h) compared with EM subjects (t(1/2) = 18 h). In EM subjects, atomoxetine (t(1/2) = 5 h) and 4-hydroxyatomoxetine-O-glucuronide (t(1/2) = 7 h) were the principle circulating species, whereas atomoxetine (t(1/2) = 20 h) and N-desmethylatomoxetine (t(1/2) = 33 h) were the principle circulating species in PM subjects. Although differences were observed in the excretion and relative amounts of metabolites formed, the primary difference observed between EM and PM subjects was the rate at which atomoxetine was biotransformed to 4-hydroxyatomoxetine.
Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Propilaminas/metabolismo , Adulto , Cloridrato de Atomoxetina , Biotransformação/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Propilaminas/sangue , Propilaminas/química , Propilaminas/urinaRESUMO
The purpose of this study was to characterize the effect of potent CYP2D6 inhibition byparoxetine on atomoxetine disposition in extensive metabolizers. This was a single-blind, two-period, sequential studyin 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased C(ss,max), AUC0-12, and t1/2 of atomoxetine by approximately 3.5-, 6.5-, and 2.5-fold, respectively. After coadministration with paroxetine, increases in N-desmethylatomoxetine and decreases in 4-hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates.