RESUMO
Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interações Medicamentosas , Monitoramento de Medicamentos , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Sulfonamidas/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Masculino , Adulto Jovem , Pessoa de Meia-Idade , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Feminino , Citocromo P-450 CYP3A/metabolismo , Ciclosporina/administração & dosagem , Triazóis/administração & dosagem , Antineoplásicos/administração & dosagemRESUMO
PURPOSE: The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. METHODS: LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. RESULTS: In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid. CONCLUSIONS: OAT1- mediated DDIs can be predicted using in vitro measured IC50 and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.
Assuntos
Aminoácidos , Compostos Bicíclicos Heterocíclicos com Pontes , Óxidos S-Cíclicos , Interações Medicamentosas , Aminoácidos/metabolismo , Óxidos S-Cíclicos/sangue , Óxidos S-Cíclicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Modelos Biológicos , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-IdadeRESUMO
This work presents an end-to-end approach for assessing the absolute bioavailability of highly hydrophobic, poorly water-soluble compounds that exhibit high nonspecific binding using venetoclax as a model drug. The approach utilizes a stable labeled i.v. microdose and requires fewer resources compared with traditional approaches that use radioactive 14 C-labeled compounds. The stable labeled venetoclax and internal standard were synthesized, then an i.v. formulation was developed. In the clinical study, female subjects received a single oral dose of venetoclax 100 mg followed by a 100-µg i.v. dose of cold-labeled 13 C-venetoclax at the oral time of maximum concentration (Tmax ). The i.v. microdose was prepared as an extemporaneous, sterile compounded solution on the dosing day by pharmacists at the clinical site. Several measures were taken to ensure the sterility and safety of the i.v. preparation. A sensitive liquid chromatography-tandem mass spectrometry method was developed to allow the detection of plasma levels from the i.v. microdose. Plasma samples were collected through 72 h, and pharmacokinetic parameters were estimated using noncompartmental methods. Postdosing sample analysis demonstrated the consistency of the preparations and allowed the precise calculation of the pharmacokinetic parameters based on the actual injected dose. The absolute bioavailability of venetoclax was estimated at 5.4% under fasting conditions. Venetoclax extraction ratio was estimated to be 0.06 suggesting that the fraction transferred from the enterocytes into the liver is limiting venetoclax bioavailability. The proposed framework can be applied to other highly hydrophobic, poorly water-soluble compounds that exhibit high nonspecific binding to support the understanding of their absorption and disposition mechanisms and guide formulation development.
Assuntos
Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Adulto , Pesquisa Biomédica , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Sulfonamidas/sangueRESUMO
For the first time, synthesis of bifunctional [2.2.2]-cryptands (CRYPT) and demonstration of radiolabeling with lead(II) (Pb2+) isotopes are disclosed herein. The synthesis is convenient and high-yielding and gives access to three distinct bifunctional handles (azide (-N3), isothiocyanate (-NCS), and tetrazine (-Tz)) that can enable the construction of radioimmunoconjugates for targeted and pretargeted therapy. Proof-of-principle CRYPT radiolabeling was successful with lead-203 ([203Pb]Pb2+) and demonstrated complexation efficiency superior to that of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and efficiency comparable to that of the current industry standard TCMC (1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane). In vitro human serum stability assays demonstrated excellent [203Pb]Pb-CRYPT stability over 72 h (91.7 ± 0.56%; n = 3). [203Pb]Pb-CRYPT-radioimmunoconjugates were synthesized from the corresponding CRYPT-immunoconjugate or by conjugating [203Pb]Pb-Tz-CRYPT to transcyclooctene modified trastuzumab (TCO-trastuzumab) via the inverse electron-demand Diels-Alder (IEEDA) reaction. This investigation reveals the potential for CRYPT ligands to become new industry standards for therapeutic and diagnostic radiometals in radiopharmaceutical elaboration.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Medicina Nuclear , Compostos Radiofarmacêuticos/química , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Humanos , Estrutura Molecular , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/síntese químicaRESUMO
Model-informed drug development (MIDD) is critical in all stages of the drug-development process and almost all regulatory submissions for new agents incorporate some form of modeling and simulation. This review describes the MIDD approaches used in the end-to-end development of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes mellitus. Approaches included (1) quantitative systems pharmacology modeling to predict dose-response relationships, (2) dose-response modeling and model-based meta-analysis for dose selection and efficacy comparisons, (3) population pharmacokinetics (PKs) modeling to characterize PKs and quantify population variability in PK parameters, (4) regression modeling to evaluate ertugliflozin dose-proportionality and the impact of uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 genotype on ertugliflozin PKs, and (5) physiologically-based PK modeling to assess the risk of UGT-mediated drug-drug interactions. These end-to-end MIDD approaches for ertugliflozin facilitated decision making, resulted in time/cost savings, and supported registration and labeling.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Biológicos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Humanos , Farmacologia em Rede , Análise de Regressão , Inibidores do Transportador 2 de Sódio-Glicose/sangueRESUMO
OBJECTIVE: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. MATERIALS AND METHODS: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 µg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 µg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. RESULTS: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. CONCLUSION: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug-drug interaction should be paid attention to when the drugs were used in combination.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Dexmedetomidina/sangue , Midazolam/análogos & derivados , Midazolam/sangue , Tetra-Hidronaftalenos/sangue , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão , Dexmedetomidina/metabolismo , Dexmedetomidina/farmacocinética , Cães , Feminino , Masculino , Midazolam/metabolismo , Midazolam/farmacocinética , Espectrometria de Massas em Tandem , Tetra-Hidronaftalenos/metabolismo , Tetra-Hidronaftalenos/farmacocinéticaRESUMO
Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.
Assuntos
Antineoplásicos/sangue , Inibidores do Citocromo P-450 CYP3A/sangue , Aprovação de Drogas , Interações Medicamentosas/fisiologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Humanos , Síndrome do QT Longo/sangue , Síndrome do QT Longo/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Estaurosporina/sangue , Sulfonamidas/efeitos adversos , Sulfonamidas/sangueRESUMO
A rapid and sensitive analytical method was developed to quantify venetoclax, an oral BH3-mimetic that blocks the anti-apoptotic protein BCL-2, in mouse plasma using ultra-high-performance liquid chromatography with electrospray ionization tandem mass spectrometric detection. Plasma protein precipitation was performed on 5 µL samples, and separation of the analytes was accomplished on an Accucore aQ column using gradient elution at a flow rate of 0.4 mL/min. The calibration curve was linear (R2 ≥ 0.99) over the concentration range of 5-1,000 ng/mL, and the lower limit of quantitation was 5 ng/mL. The intra-day and inter-day precisions (RSD%) were < 10.5%, and accuracies ranged from 94.4 to 106%. The developed method was successfully applied to pharmacokinetic studies involving serial 30 µL blood sampling from male and female mice after oral administration of venetoclax (10 mg/kg) alone or 30 min after oral administration of ketoconazole (50 mg/kg) or vehicle (PEG400). The observed pharmacokinetic profiles suggest venetoclax undergoes sexually dimorphic disposition in mice. However, regardless of sex, pharmacokinetic studies demonstrated that venetoclax AUC(0-6h) was increased greater than 2-fold with prior administration of ketoconazole. Overall, our pharmacokinetic studies suggest that mice could be a translationally relevant model for the characterization of venetoclax pharmacokinetics. We have developed an analytical method suitable for such murine pharmacokinetic studies.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/química , Interações Medicamentosas , Feminino , Cetoconazol/administração & dosagem , Cetoconazol/farmacocinética , Modelos Lineares , Masculino , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double-blind, vehicle-controlled phase 3 studies showed that twice-daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady-state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss ] and maximum concentration [Cmax,ss ]). PK data were available from 244 participants across 6 clinical studies (AUCss , N = 239; Cmax,ss , N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5-fold higher AUCss and Cmax,ss values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUCss and Cmax,ss . Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUCss and Cmax,ss for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2-17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.
Assuntos
Absorção Fisiológica , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Fármacos Dermatológicos/farmacocinética , Fármacos Dermatológicos/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/uso terapêutico , Administração Tópica , Adolescente , Adulto , Idoso , Área Sob a Curva , Compostos de Boro/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Criança , Pré-Escolar , Ensaios Clínicos Fase I como Assunto , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/sangue , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Dinâmica não Linear , Pomadas , Inibidores da Fosfodiesterase 4/sangue , Psoríase/tratamento farmacológico , Análise de Regressão , Adulto JovemRESUMO
Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, prevents renal glucose reabsorption resulting in urinary glucose excretion. This open-label, parallel cohort, randomized study conducted in healthy Chinese adults residing in China assessed the pharmacokinetics, tolerability, and safety of 5 mg and 15 mg of ertugliflozin following single (fasted condition) and multiple-dose (fed condition) administration. Sixteen subjects were randomized and completed the study. Ertugliflozin absorption was rapid, with maximum plasma concentrations observed 1 hour after dosing under fasted conditions and 2 to 4 hours after dosing under fed conditions. Following single- and multiple-dose administration, ertugliflozin exhibited dose-proportional exposures with an apparent mean terminal half-life of approximately 9.5 to 11.9 hours. Steady state was reached after 4 once-daily doses. The accumulation ratio based on the area under the plasma concentration-time curve after multiple-dose administration was approximately 1.3 and 1.2 for ertugliflozin 5 mg and 15 mg, respectively. Ertugliflozin was generally well tolerated following administration of single and multiple oral doses of 5 mg and 15 mg in healthy Chinese subjects. Pharmacokinetic comparison with non-Asian subjects indicated that there are no clinically meaningful racial differences and no dose modification of ertugliflozin is required based on race or body weight.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Adulto , Área Sob a Curva , Povo Asiático , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/sangue , Adulto JovemRESUMO
BACKGROUND: Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus. METHODS: Serial pharmacokinetic and lymphocyte count data from 73 women enrolled in a phase I study of venetoclax (single doses of 10-500 mg or two cycles of 30-600 mg or placebo once daily for 7 days followed by a 21-day washout) were analyzed using a sequential population pharmacokinetic/pharmacodynamic modeling approach. Simulations to evaluate changes in B-lymphocyte and total lymphocyte counts following different venetoclax dosing scenarios were conducted. RESULTS: Effect of venetoclax plasma exposures on B lymphocytes was described using an indirect linear response model and on total lymphocytes using a maximal response (Emax) with an effect site compartment. Baseline lymphocyte counts were significant covariates on the slope and half maximal inhibitory concentration parameter estimates for the respective models; with higher baseline counts associated with a greater reduction upon treatment with venetoclax. Model simulations showed that continuous dosing with lower doses of venetoclax (e.g., 150 mg daily) are predicted to achieve similar maximal effects on B-lymphocyte counts compared to cyclic dosing with higher doses (e.g., 400 mg 1 week on/3 weeks off); with better recovery of total lymphocyte counts during off-treatment weeks for the cyclic regimens. CONCLUSIONS: Venetoclax treatment in women with systemic lupus erythematosus was associated with exposure-dependent reductions in B lymphocytes, and to a lesser extent, total lymphocyte counts. Results from this study support evaluation of B-cell lymphoma-2 inhibitors as potential therapies for the treatment of systemic lupus erythematosus. CLINICALTRIALS.GOV: NCT01686555.
Assuntos
Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Doenças Autoimunes/imunologia , Linfócitos B/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Contagem de Linfócitos , Pessoa de Meia-Idade , Modelos Teóricos , Placebos/administração & dosagem , Segurança , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Resultado do TratamentoRESUMO
A fixed-dose combination (FDC) of ertugliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and immediate-release metformin is approved for the treatment of type 2 diabetes mellitus in the United States and European Union. Four open-label, randomized, 2-period, single-dose, crossover studies were conducted under fasted conditions in healthy subjects to demonstrate bioequivalence of the ertugliflozin/metformin FDC tablets and coadministration of the individual components at respective strengths. In each study, 32 or 34 subjects received an ertugliflozin/metformin FDC tablet (2.5 mg/500 mg, 7.5 mg/850 mg, or 7.5 mg/1000 mg) and the respective doses of individual components (ertugliflozin with US- or EU-sourced metformin [Glucophage]). Plasma samples for ertugliflozin and metformin concentrations were collected for 72 hours in each period. For both ertugliflozin and metformin, the 90% confidence intervals for the adjusted geometric mean ratio (FDC : coadministration) for area under the plasma concentration-time profile from time zero extrapolated to infinity and maximum observed plasma concentration were within acceptance criteria for bioequivalence. The majority of adverse events were mild in intensity. The studies demonstrated that each strength of FDC tablet is bioequivalent to respective doses of coadministered individual components, supporting that safety and efficacy can be bridged to the individual components used in phase 3 studies evaluating ertugliflozin in combination with metformin.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Adolescente , Adulto , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Estudos Cross-Over , Combinação de Medicamentos , Jejum/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Metformina/sangue , Pessoa de Meia-Idade , Comprimidos , Equivalência Terapêutica , Adulto JovemRESUMO
Ertugliflozin (ERTU) is a novel, potent, and highly selective sodium glucose cotransporter 2 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. We describe a novel bioanalytical method using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for quantitative determination of ERTU in rat plasma. Acetonitrile-based protein precipitation method was used for sample preparation, and chromatographic separation was performed on a Kinetex® C18 column with an isocratic mobile phase comprising acetonitrile and 10â¯mM potassium phosphate buffer (pHâ¯6.0). The eluent was monitored by a fluorescence detector at an optimized excitation/emission wavelength pair of 277/320â¯nm. The method was validated to demonstrate the selectivity, linearity (ranging from 4 to 2000â¯ng/mL), precision, accuracy, recovery, matrix effect, and stability in line with the current FDA guidelines. The newly developed method was successfully applied to investigate the pharmacokinetic interactions of ERTU with mefenamic acid (MEF) and ketoconazole (KET). The findings of the present study revealed that the pharmacokinetics of ERTU may be altered by concurrent administration of MEF and KET in rats. To our knowledge, the present study is the first to develop a validated bioanalytical method for quantification of ERTU using HPLC coupled with fluorescence detection and to assess the drug interaction potential of ERTU with non-steroidal anti-inflammatory (MEF) and azole antifungal (KET) drugs.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Cetoconazol/farmacocinética , Ácido Mefenâmico/farmacocinética , Espectrometria de Fluorescência/métodos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Interações Medicamentosas , Cetoconazol/sangue , Cetoconazol/química , Limite de Detecção , Modelos Lineares , Masculino , Ácido Mefenâmico/sangue , Ácido Mefenâmico/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
In this study, we present the synthesis and characterization of the octadentate bispidine ligand, H2bispox2 and its complexes with medicinally useful radiometal nuclides (111In3+ and 177Lu3+), including their X-ray diffraction single crystal structures with the stable isotopes. 111InCl3 radiolabels the ligand quantitatively at ambient conditions ([L] = 10-5 M, room temperature, pH 7 and 15 min) and the in vitro human serum stability assays demonstrated high stability of the [111In(bispox2)]+ complex over 5 days. Moreover, the ß - emitter 177Lu radiolabels the ligand at 37 °C in 30 min (pH 8). These initial investigations reveal the potential of the octadentate bispidine ligand H2bispox2 as a useful chelator for 111In and 177Lu-based radiopharmaceuticals.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Complexos de Coordenação/química , Oxiquinolina/análogos & derivados , Compostos Radiofarmacêuticos/química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Quelantes/síntese química , Quelantes/química , Complexos de Coordenação/sangue , Complexos de Coordenação/síntese química , Estabilidade de Medicamentos , Humanos , Radioisótopos de Índio , Ligantes , Lutécio , Camundongos , Estrutura Molecular , Oxiquinolina/sangue , Oxiquinolina/síntese química , Oxiquinolina/química , Radioisótopos , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/síntese químicaRESUMO
INTRODUCTION: Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. METHODS: A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS: No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.
Assuntos
Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Insuficiência Hepática/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacocinética , Administração Oral , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Estudos de Casos e Controles , Feminino , Meia-Vida , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pessoa de Meia-Idade , Segurança , Sulfonamidas/administração & dosagem , Sulfonamidas/sangueRESUMO
Equilibrium dialysis has been widely used for the measurement of the fraction of unbound drug (fu) in plasma, but it suffers from the accuracy and reliability for low fu values. To address this concern, an orthogonal approach, called the bidirectional equilibrium dialysis, is described to simultaneously measure a pair of fu values for each drug based on equilibration in 2 opposite dialysis directions: from plasma to buffer (fu,p/b) and from buffer to plasma (fu,b/p). Hypothetically, if true equilibrium is attained in both dialysis directions, the measured fu,b/p and fu,p/b values for a given drug should converge, and thus, the ratio of fu,b/p to fu,p/b becomes unity (1.0). Thus, the ratio can be used as a tangible readout for data reliability. This methodology has been extensively tested in the present study using various drugs with distinct plasma binding characteristics. Our results clearly showed that low fu values (<0.01) could be reliably determined and verified using either the standard or dilution bidirectional equilibrium dialysis method for some known highly bound drugs; for extensively bound drugs with high logD7.4, such as montelukast, bedaquiline, and venetoclax, only a range of fu can be reported with confidence because of uncertainty in the true equilibrium.
Assuntos
Monitoramento de Medicamentos/métodos , Acetatos/sangue , Acetatos/farmacocinética , Proteínas Sanguíneas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Soluções Tampão , Cromatografia Líquida de Alta Pressão , Ciclopropanos , Diálise/métodos , Diarilquinolinas/sangue , Diarilquinolinas/farmacocinética , Estudos de Viabilidade , Meia-Vida , Humanos , Estudo de Prova de Conceito , Ligação Proteica , Quinolinas/sangue , Quinolinas/farmacocinética , Reprodutibilidade dos Testes , Sulfetos , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
Ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed-dose combination (FDC) therapies with either sitagliptin or immediate-release metformin. The effect of a standard, high-fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15-/100-mg), and ertugliflozin/metformin FDC (7.5-/1000-mg) tablets was evaluated. In 3 separate open-label, 2-period, 2-sequence, single-dose, crossover studies, 14 healthy subjects per study were randomized to receive either ertugliflozin monotherapy or FDC tablets comprising ertugliflozin and sitagliptin or ertugliflozin and metformin under fasted and fed (or vice versa) conditions. Food did not meaningfully affect the pharmacokinetics of ertugliflozin, sitagliptin, or metformin. For FDCs, the effect of food was consistent with that described for individual components. All treatments were well tolerated. Ertugliflozin and ertugliflozin/sitagliptin FDC tablets can be administered without regard to meals. As metformin is administered with meals because of its gastrointestinal side effects, the ertugliflozin/metformin FDC should also be administered with meals.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Gorduras na Dieta/administração & dosagem , Interações Alimento-Droga , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Fosfato de Sitagliptina/farmacocinética , Adulto , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Estudos Cross-Over , Combinação de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Metformina/efeitos adversos , Metformina/sangue , Pessoa de Meia-Idade , Fosfato de Sitagliptina/efeitos adversos , Fosfato de Sitagliptina/sangue , Adulto JovemRESUMO
In the present study, an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach was designed to concurrently measure the levels of ertugliflozin and sitagliptin in rat plasma with diazepam as the internal standard (IS). Acetonitrile-based protein precipitation was applied for sample preparation, then analytes (ertugliflozin and sitagliptin) were subjected to gradient elution chromatography with a mobile phase composed of acetonitrile (A) and 0.1% formic acid in water (B). Ertugliflozin was monitored by m/z 437.2â¯ââ¯329.0 transition for quantification and m/z 437.2â¯ââ¯207.5 transition for qualification, and sitagliptin was determined by m/z 408.2â¯ââ¯235.0 transition for quantification and m/z 408.2â¯ââ¯174.0 transition for qualification by multiple reaction monitoring (MRM) in positive ion electrospray ionization (ESI) source. When the concentration of ertugliflozin ranged from 1 to 1000â¯ng/mL and sitagliptin ranged from 2 to 2500â¯ng/mL, the method exhibited good linearity. For both ertugliflozin and sitagliptin, the intra- and inter-day precision were determined with the values of 1.6-10.9% and 0.8-13.3%, respectively; and the accuracy ranged from -5.7% to 14.6%. Matrix effect, extraction recovery, and stability data were in line with the stipulated FDA guidelines for validating a bioanalytical method. The validity of the designed method was confirmed through the pharmacokinetic experiments.
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Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Fosfato de Sitagliptina/sangue , Administração Oral , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão , Meia-Vida , Limite de Detecção , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/farmacocinética , Espectrometria de Massas em TandemRESUMO
PURPOSE: Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin. METHODS: Twelve healthy adult subjects were enrolled in this open-label, 2-period, fixed-sequence study and received ertugliflozin 15mg on day 1 of period 1, followed by rifampin 600mg once daily on days 1 to 10 in period 2. On day 8 of period 2, ertugliflozin 15mg was coadministered with rifampin 600mg. Plasma samples for ertugliflozin pharmacokinetic analysis were collected during 72hours after dosing on day 1 of period 1 and day 8 of period 2 and analyzed using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental analysis of concentration-time data. Natural log transformed AUC0-∞ and Cmax of ertugliflozin were analyzed using a mixed-effects model with treatment as a fixed effect and subject as a random effect. FINDINGS: After administration of ertugliflozin 15mg alone or with rifampin, the Tmax was 1hour. The mean t½ was 12.3hours for ertugliflozin alone and 9.2hours with steady-state rifampin. Geometric mean ratios for AUC0-∞ and Cmax were 61.2% (90% CI, 57.2%-65.4%) and 84.6% (90% CI, 74.2%-96.5%), respectively. Ertugliflozin was well tolerated when administered alone or with rifampin. IMPLICATIONS: Coadministration of ertugliflozin with rifampin decreased ertugliflozin AUC0-∞ and Cmax by 39% and 15%, respectively. The effect of the reduced exposure was evaluated using the ertugliflozin dose-response model. The model predicted that a 5-mg ertugliflozin dose after coadministration with rifampin is expected to maintain clinically meaningful glycemic efficacy. Therefore, no dose adjustment of ertugliflozin is recommended when ertugliflozin is coadministered with a UGT and CYP inducer, such as rifampin.
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Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Rifampina/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/sangue , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE. METHODS: Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice). The multiple-dose evaluation consisted of two cycles, each with once-daily dosing for 7 days followed by a 21-day washout. Non-compartmental and population pharmacokinetic analyses of venetoclax serial plasma concentrations were conducted. RESULTS: Venetoclax exhibited approximately dose-proportional exposures, with peak concentrations observed 4-8 h post-dose. Venetoclax steady-state exposures were achieved by day 4 of dosing, and the median area under the plasma concentration-time curve (AUC) accumulation ratio ranged from 1.1 to 1.5. A two-compartment model with first-order absorption and elimination described venetoclax pharmacokinetics. The estimates (95% bootstrap confidence interval) for venetoclax apparent clearance, central and peripheral volumes of distribution, intercompartmental clearance, absorption rate constant, and lag time were 16.3 L/h (14.6-17.9), 37 L (26-57), 122 L (98-183), 3.7 L/h (2.6-5.0), 0.13 h-1 (0.11-0.17), and 1.6 h (1.6-1.7), respectively. The population estimate for venetoclax terminal-phase elimination half-life was approximately 28 h. CONCLUSIONS: In female subjects with SLE, venetoclax displayed pharmacokinetic characteristics consistent with previous observations in subjects with hematologic malignancies. CLINICALTRIALS. GOV IDENTIFIER: NCT01686555.