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AIMS: Osimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events. METHODS: Comprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUCss) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis. RESULTS: E-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUCss; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control. CONCLUSIONS: E-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit.
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AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL-6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non-small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose-dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W.
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The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied, in vitro and in clinic. Cytokine-mediated suppression of CYPs or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The FDA recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures (AUCss) of CYP-sensitive substrates co-administered with cytokine modulators as reported in the UW DIDB were extracted and examined for each of the CYPs. Co-administration of CYP3A (midazolam/simvastatin), CYP2C19 (omeprazole), or CYP1A2 (caffeine/tizanidine) substrates with anti-IL-6 and with anti-IL-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ -58% to ~35%; no significant trends were observed for CYP2D6 (dextromethorphan) and CYP2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when co-administered with tocilizumab, suggest a ~6-7 fold increase in midazolam clearance suggesting potential implications of cytokine- CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of non-clinical and clinical assessments of cytokine-CYP drug interactions, in drug discovery and development. Significance Statement Significance statement: There has been significant progress in understanding cytokine-mediated drug interactions for CYP-sensitive substrates. This article provides an overview of the progress in this field, including a trend analysis of systemic exposures of CYP-sensitive substrates co-administered with anti-IL-x therapeutics. In addition, the review also provides a perspective of current methods used to assess these drug interactions during drug development, and a focus on individualized medicine, particularly in acute care settings.
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This exploratory, post hoc analysis aimed to model circulating tumor DNA (ctDNA) dynamics and predict disease progression in patients with treatment-naïve locally advanced/metastatic epidermal growth factor receptor mutation (EGFRm)-positive non-small cell lung cancer, from the FLAURA trial (NCT02296125). Patients were randomized 1:1 and received osimertinib 80 mg once daily (q.d.) or comparator EGFR-TKIs (gefitinib 250 mg q.d. or erlotinib 150 mg q.d.). Plasma was collected at baseline and multiple timepoints until treatment discontinuation. Patients with Response Evaluation Criteria in Solid Tumors (RECIST) imaging data and detectable EGFR mutations (Ex19del/L858R) at baseline and ≥ 3 additional timepoints were evaluable. Joint modeling was conducted to characterize the relationship between longitudinal changes in ctDNA and probability of progression-free survival (PFS). A Bayesian joint model of ctDNA and PFS was developed solving differential equations with the ctDNA dynamics and the PFS time-to-event probability. Of 556 patients, 353 had detectable ctDNA at baseline. Evaluable patients (with available imaging and ≥ 3 additional timepoints, n = 320; ctDNA set) were divided into training (n = 259) and validation (n = 61) sets. In the validation set, the model predicted a median PFS of 17.7 months (95% confidence interval (CI): 11.9-28.3) for osimertinib (n = 23) and 9.1 months (95% CI: 6.3-14.8) for comparator (n = 38), consistent with observed RECIST PFS (16.4 months and 9.7, respectively). The model demonstrates that EGFRm ctDNA dynamics can predict the risk of disease progression in this patient population and could be used to predict RECIST-defined disease progression.
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Acrilamidas , Compuestos de Anilina , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Indoles , Neoplasias Pulmonares , Pirimidinas , Humanos , Antineoplásicos/uso terapéutico , Teorema de Bayes , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/uso terapéutico , Progresión de la Enfermedad , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas QuinasasRESUMEN
Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [11 C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [11 C]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (IDmax[brain] ) 22 min (median, Tmax[brain] ) after injection. Total volume of distribution (VT ) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in VT in whole brain or BMs. After greater than or equal to 21 days' daily treatment, VT in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [11 C]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Inhibidores de Proteínas Quinasas , Mutación , Encéfalo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Tomografía de Emisión de Positrones , Imagen por Resonancia MagnéticaRESUMEN
Savolitinib is an oral MET (hepatocyte growth factor receptor) tyrosine kinase inhibitor, with demonstrated preliminary efficacy in several cancer types. Previous pharmacokinetics assessments showed that savolitinib is rapidly absorbed but there are limited data on the absolute bioavailability and absorption, distribution, metabolism, and excretion (ADME) of savolitinib. This open-label, two-part, phase 1 clinical study (NCT04675021) used a radiolabeled micro-tracer approach to evaluate absolute bioavailability and a traditional approach to determine the ADME of savolitinib in healthy male adult volunteers (N = 8). Pharmacokinetics, safety, and metabolic profiling and structural identification from plasma, urine, and fecal samples were also assessed. Volunteers received a single oral savolitinib 600 mg dose followed by intravenous 100 µg of [14 C]savolitinib in Part 1 and a single oral 300 mg [14 C]savolitinib dose (≤4.1 MBq [megabecquerel] [14 C]) in Part 2. Following Part 1, absolute oral bioavailability was 69%, the median time of maximum observed concentration was 3.5 hours, and the mean terminal half-life was 6.1 hours. Following Part 2, 94% of the radioactivity administered was recovered, with 56% and 38% in urine and feces, respectively. Exposure to savolitinib and metabolites M8, M44, M2, and M3 accounted for 22%, 36%, 13%, 7%, and 2%, respectively, of plasma total radioactivity. Approximately 3% of the dose was excreted as unchanged savolitinib in urine. Most savolitinib elimination occurred via metabolism by several different pathways. No new safety signals were observed. Our data show that the oral bioavailability of savolitinib is high and the majority of savolitinib elimination occurs via metabolism and is excreted in the urine.
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Pirazinas , Triazinas , Adulto , Humanos , Masculino , Disponibilidad Biológica , Pirazinas/efectos adversos , VoluntariosRESUMEN
AIMS: Clinical drug interaction studies with itraconazole and rifampicin have demonstrated that acalabrutinib is a sensitive substrate of CYP3A. A physiologically based pharmacokinetic (PBPK) model was developed based on the data of these studies. One of the active CYP3A metabolites, ACP-5862, was identified but never studied in a drug interaction scenario. This study aims to evaluate both parent and metabolite exposure change with coadministration of moderate CYP3A inhibitors and its impact on safety and efficacy. METHODS: In an open label, randomized, 2-period study, we investigated the effect of coadministration of fluconazole or isavuconazole on the pharmacokinetics of acalabrutinib. Bruton tyrosine kinase receptor occupancy and safety were compared between different treatments. Experimental data were compared to PBPK simulation results. RESULTS: Least square means of acalabrutinib maximum plasma concentration and area under the curve increased 1.37 (1.14-1.64) and 1.60 (1.45-1.77)-fold in the presence of isavuconazole and 1.48 (1.10-1.98) and 2.16 (1.94-2.40)-fold in the presence of fluconazole, respectively. For ACP-5862, these values are 0.72 (0.63-0.82) and 0.91 (0.86-0.97) fold for isavuconazole and 0.65 (0.49-0.87) and 0.95 (0.91-0.99) fold for fluconazole coadministration. The PBPK model was able to recover acalabrutinib and ACP-5862 PK profiles in the study. Bruton tyrosine kinase receptor occupancy change was minimal in the presence of isavuconazole. There were no deaths, serious adverse events (AEs), or subject discontinuation due to AEs in this study. Only mild (Grade 1) AEs were reported during the study, by 17% of the study population. CONCLUSION: Our results demonstrate the impact of fluconazole and isavuconazole on the pharmacokinetics of acalabrutinib and ACP-5862, and suggest that no dose adjustment is needed for concomitant administration with moderate CYP3A inhibitors. the current PBPK model can be used to propose dose adjustment for drug interactions via CYP3A.
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Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Área Bajo la Curva , Benzamidas , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Interacciones Farmacológicas , Fluconazol/efectos adversos , Humanos , Modelos Biológicos , Pirazinas , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Acalabrutinib received approval for the treatment of adult patients with mantle cell lymphoma who received at least 1 prior therapy and adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. This study investigated the impact of hepatic impairment (HI) on acalabrutinib pharmacokinetics (PK) and safety at a single 50-mg dose in fasted subjects. This study was divided into 2 parts: study 1, an open-label, parallel-group study in Child-Pugh class A or B subjects and healthy subjects; and study 2, an open-label, parallel-group study in Child-Pugh class C subjects and healthy subjects. Baseline characteristics and safety profiles were similar across groups. Acalabrutinib exposure (area under the plasma concentration-time curve) increased slightly (1.90- and 1.48-fold) in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment compared with healthy subjects. In severe hepatic impairment (Child-Pugh class C), acalabrutinib exposure (area under the plasma concentration-time curve and maximum plasma concentration) increased ≈5.0- and 3.6-fold, respectively. Results were consistent across total and unbound exposures. Severe hepatic impairment did not impact total/unbound metabolite (ACP-5862) exposures; the metabolite-to-parent ratio decreased to 0.6 to 0.8 (vs 3.1-3.6 in healthy subjects). In summary, single oral dose of 50-mg acalabrutinib was safe and well tolerated in subjects with mild, moderate, and severe hepatic impairment and in healthy control subjects. In subjects with severe hepatic impairment, mean acalabrutinib exposure increased by up to 5-fold and should be avoided. Acalabrutinib does not require dose adjustment in patients with mild or moderate hepatic impairment.
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Hepatopatías , Adulto , Área Bajo la Curva , Benzamidas/efectos adversos , Humanos , Hepatopatías/metabolismo , Pirazinas/efectos adversosRESUMEN
AIMS: Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP-5862) vs. efficacy and safety responses in patients with B-cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab. METHODS: For exposure-efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression-free survival and tumour regression. For exposure-safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B-cell malignancies. Acalabrutinib and ACP-5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP-5862 to overall efficacy/safety. RESULTS: A total of 573 patients were included (exposure-efficacy analyses, n = 274; exposure-safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration-time curve (AUC24h,ss ) and total active maximal concentration at steady-state (Cmax,ss ) were similar for patients who received acalabrutinib as monotherapy or in combination with obinutuzumab, and for responders and nonresponders. No relationship was observed between AUC24h,ss /Cmax,ss and progression-free survival or tumour regression. Acalabrutinib AUC24h,ss and Cmax,ss were generally comparable across groups regardless of AE incidence. CONCLUSION: No clinically meaningful correlations between acalabrutinib PK exposure and efficacy and safety outcomes were observed. These data support the fixed acalabrutinib dose of 100 mg twice daily in the treatment of patients with B-cell malignancies.
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Leucemia Linfocítica Crónica de Células B , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , PirazinasRESUMEN
AIMS: We investigated savolitinib pharmacokinetics (PK) when administered alone or in combination with rifampicin, itraconazole or famotidine, and investigated midazolam PK when administered with or without savolitinib in healthy males. METHODS: Savolitinib PK was evaluated before/after: rifampicin (600 mg once daily [QD] for 5 days); itraconazole (200 mg QD for 5 days); a single dose of famotidine (40 mg QD) 2 hours before savolitinib. Midazolam PK was evaluated before/after midazolam (1 mg QD) with or without savolitinib (600 mg QD). Each study enrolled 20, 16, 16 and 14 volunteers, respectively. Plasma samples were collected to determine the effect on PK. RESULTS: The geometric mean ratios (GMR, %) (90% confidence intervals [CIs]) for savolitinib alone and in combination for Cmax , AUC respectively, were 45.4 (41.4-49.9), 38.5 (34.2-43.3) in the rifampicin study (n = 18); 105.2 (87.7-126.3), 108.4 (96.3-122.1) in the itraconazole study (n = 16); and 78.8 (67.7-91.7), 87.4 (81.2-94.2) in the famotidine study (n = 16). The GMRs (90% CIs) for midazolam alone and in combination with savolitinib for Cmax , AUC respectively, were 84.1 (70.0-101.0), 96.7 (92.4-101.1) (n = 14). Savolitinib alone or in combination was well tolerated. CONCLUSIONS: Co-dosing of rifampicin significantly reduced exposure to savolitinib vs savolitinib alone; co-dosing of itraconazole or midazolam with savolitinib had no clinically significant effect on savolitinib or midazolam PK, respectively. Co-dosing of famotidine with savolitinib reduced exposure to savolitinib, although this was not considered clinically meaningful. No new savolitinib-related safety findings were observed.
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Itraconazol , Midazolam , Área Bajo la Curva , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Famotidina , Humanos , Itraconazol/efectos adversos , Masculino , Midazolam/efectos adversos , Pirazinas , Rifampin/efectos adversos , TriazinasRESUMEN
This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP-5862 samples from 304 subjects from 12 clinical studies in patients with B-cell malignancies and healthy subjects were analysed by nonlinear mixed-effects modelling. Acalabrutinib PK was characterized by a 2-compartment model with first-order elimination. The large variability in absorption was adequately described by transit compartment chain and first-order absorption, with between-occasion variability on the mean transit time and relative bioavailability. The PK of ACP-5862 was characterized by a 2-compartment model with first-order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and coadministration of proton-pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.
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Benzamidas , Neoplasias , Benzamidas/farmacocinética , Voluntarios Sanos , Humanos , Modelos Biológicos , Pirazinas/farmacocinéticaRESUMEN
Selumetinib (ARRY-142886), an oral, potent and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor, is approved by the US Food and Drug Administration for the treatment of pediatric patients aged ≥2 years with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. A physiologically based pharmacokinetic (PBPK) model was constructed to predict plasma concentration-time profiles of selumetinib, and to evaluate the impact of coadministering moderate cytochrome P450 (CYP) 3A4/2C19 inhibitors/inducers. The model was also used to extrapolate pharmacokinetic exposures from older children with different body surface area to guide dosing in younger children. This model was built based on physiochemical data and clinical in vivo drug-drug interaction (DDI) studies with itraconazole and fluconazole, and verified against data from an in vivo rifampicin DDI study and an absolute bioavailability study. The pediatric model was updated by changing system-specific input parameters using the Simcyp pediatric module. The model captured the observed selumetinib pharmacokinetic profiles and the interactions with CYP inhibitors/inducers. The predictions from the PBPK model showed a DDI effect of 30% to 40% increase or decrease in selumetinib exposure when coadministered with moderate CYP inhibitors or inducers, respectively, which was used to inform dose management and adjustments. The pediatric PBPK model was applied to simulate exposures in specific body surface area brackets that matched those achieved with a 25 mg/m2 dose in SPRINT clinical trials. The pediatric PBPK model was used to guide the dose for younger patients in a planned pediatric clinical study.
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Bencimidazoles/farmacocinética , Inductores de las Enzimas del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Adolescente , Factores de Edad , Área Bajo la Curva , Superficie Corporal , Niño , Preescolar , Cálculo de Dosificación de Drogas , Interacciones Farmacológicas , Fluconazol/farmacología , Humanos , Itraconazol/farmacología , Tasa de Depuración Metabólica , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Rifampin/farmacologíaRESUMEN
PURPOSE: Limited information is available regarding the drug-drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. METHODS: A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. RESULTS: While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration-time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. CONCLUSION: Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Modelos Biológicos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Vincristina/administración & dosificación , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Células CACO-2 , Simulación por Computador , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/farmacocinética , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prednisona/farmacocinética , Rituximab/administración & dosificación , Rituximab/efectos adversos , Rituximab/farmacocinética , Distribución Tisular , Vincristina/efectos adversos , Vincristina/farmacocinética , Adulto JovenRESUMEN
PURPOSE: Selumetinib (ARRY-142886) is a potent, selective, MEK1/2 inhibitor approved in the US for the treatment of children (≥ 2 years) with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We characterized population pharmacokinetics (PK) of selumetinib and its active N-desmethyl metabolite, evaluated exposure-safety/efficacy relationships, and assessed the proposed therapeutic dose of 25 mg/m2 bid based on body surface area (BSA) in this patient population. METHODS: Population PK modeling and covariate analysis (demographics, formulation, liver enzymes, BSA, patients/healthy volunteers) were based on pooled PK data from adult healthy volunteers (n = 391), adult oncology patients (n = 83) and pediatric patients with NF1-PN (n = 68). Longitudinal selumetinib/metabolite exposures were predicted with the final model. Exposure-safety/efficacy analyses were applied to pediatric patients (dose levels: 20, 25, 30 mg/m2 bid). RESULTS: Selumetinib and metabolite concentration-time courses were modeled using a joint compartmental model. Typical selumetinib plasma clearance was 11.6 L/h (95% CI 11.0-12.2 L/ h). Only BSA had a clinically relevant (> 20%) impact on exposure, supporting BSA-based administration in children. Selumetinib and metabolite exposures in responders (≥ 20% PN volume decrease from baseline) and non-responders were largely overlapping, with medians numerically higher in responders. No clear relationships between exposure and safety events were established; exposure was not associated with key adverse events (AEs) including rash acneiform, diarrhea, vomiting, and nausea. CONCLUSION: Findings support continuous selumetinib 25 mg/m2 bid in pediatric patients. Importantly, the updated dosing nomogram ensures that patients will receive a clinically active, yet tolerable, dose regardless of differences in BSA and allows dose reductions, if necessary.
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Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Neurofibroma Plexiforme/tratamiento farmacológico , Neurofibromatosis 1/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Femenino , Voluntarios Sanos , Humanos , Estudios Longitudinales , Masculino , Neurofibroma Plexiforme/metabolismo , Neurofibromatosis 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto JovenRESUMEN
Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically. The activity of the SPTs was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure-activity relationships including those around a target binding model. Compounds with favorable pharmacokinetic parameters were identified, and two compounds demonstrated cidality in a mouse model of Staphylococcus aureus infection.
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Antibacterianos/farmacología , Girasa de ADN/metabolismo , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Azoles/química , Azoles/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Isoxazoles/química , Isoxazoles/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/farmacología , Ratas , Ratas Wistar , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on Cmax and area under the plasma concentration-time curve, was 1.19-fold (90% CI: 0.6, 2.0) and 1.85-fold (90% CI: 0.9, 3.6), respectively, higher for patients with SRI vs patients with NRF, with no clear correlation between CrCL and exposure. No new safety signals were identified after 12 weeks of osimertinib 80 mg continuous dosing. PK parameters pooled across this study and other phase I, II, and III osimertinib clinical studies (exploratory population PK analysis), showed minimal correlation between CrCL and total clearance. In conclusion, no dose adjustment is required for osimertinib for patients with SRI.
Asunto(s)
Acrilamidas/farmacocinética , Compuestos de Anilina/farmacocinética , Insuficiencia Hepática/complicaciones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Acrilamidas/administración & dosificación , Administración Oral , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Área Bajo la Curva , Femenino , Insuficiencia Hepática/fisiopatología , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Osimertinib has shown promising activity in patients with leptomeningeal metastases (LMs) of EGFR-positive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib (80 mg qd) in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17, and AURA3). METHODS: Patients with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-tyrosine kinase inhibitor therapy received osimertinib (80 mg qd). Patients with central nervous system (CNS) metastases (including LMs) were eligible if the lesions were neurologically asymptomatic and stable. Patients with evidence of LMs at the study entry were retrospectively included for the analysis; brain scans were assessed for radiologic LM response by neuroradiologically blinded, independent central review per the modified Response Assessment in Neuro-Oncology LM criteria. LM objective response rate, duration of response, progression-free survival, and overall survival were assessed. A longitudinal analysis was performed to investigate the relationship between changes from the baseline in non-CNS tumor sizes and LM responses at each visit of patients in AURA LM and BLOOM studies. RESULTS: For the 22 patients included in the analysis, LM objective response rate was 55% (95% confidence interval [CI]: 32-76). Median LM duration of response was not reached (95% CI: 2.8-not calculable [NC]). Median LM progression-free survival and overall survival were 11.1 months (95% CI: 4.6-NC) and 18.8 months (95% CI: 6.3-NC), respectively. The longitudinal analysis revealed similar non-CNS and LM responses between the patients in AURA LM and BLOOM programs. CONCLUSIONS: Patients with EGFR T790M-positive NSCLC and radiologically detected LM obtained clinical benefit from osimertinib (80 mg qd).
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Acrilamidas , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios RetrospectivosRESUMEN
PURPOSE: In this phase I study (BLOOM), osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was evaluated in patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy. PATIENTS AND METHODS: Patients with cytologically confirmed LM received osimertinib 160 mg once daily. Objectives were to assess confirmed objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Additional efficacy evaluations included changes from baseline in CSF cytology and neurologic examination. Measurable lesions were assessed by investigator according to RECIST version 1.1. LMs were assessed by neuroradiologic blinded central independent review (BICR) according to Response Assessment in Neuro-Oncology LM radiologic criteria and by investigator. RESULTS: Forty-one patients were enrolled. LM ORR and DoR by neuroradiologic BICR were 62% (95% CI, 45% to 78%) and 15.2 months (95% CI, 7.5 to 17.5 months), respectively. Overall, ORR by investigator was 41% (95% CI, 26% to 58%), and median DoR was 8.3 months (95% CI, 5.6 to 16.5 months). Median investigator-assessed PFS was 8.6 months (95% CI, 5.4 to 13.7 months) with 78% maturity; median OS was 11.0 months (95% CI, 8.0 to 18.0 months) with 68% maturity. CSF tumor cell clearance was confirmed in 11 (28%; 95% CI, 15% to 44%) of 40 patients. Neurologic function was improved in 12 (57%) of 21 patients with an abnormal assessment at baseline. The adverse event and PK profiles were consistent with previous reports for osimertinib. CONCLUSION: Osimertinib showed meaningful therapeutic efficacy in the CNS and a manageable safety profile at 160 mg once daily in patients with EGFRm NSCLC and LM.
Asunto(s)
Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinomatosis Meníngea/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/secundario , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Carcinomatosis Meníngea/secundario , Persona de Mediana Edad , MutaciónRESUMEN
Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of 11C-labelled osimertinib administered intravenously in subjects with an intact blood-brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax(brain) (standardized uptake value), Tmax(brain) and AUC0-90 minbrain/blood ratio were calculated. The outcome measure for 11C-osimertinib brain exposure was the total distribution volume (VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in grey than in white matter. Mean Cmax, Tmax and AUC0-90 minbrain/blood ratio were 1.5 (range 1-1.8), 13 min (range 5-30 min), and 3.8 (range 3.3-4.1). Whole brain and white matter VT were 14 mL×cm-3 (range 11-18) and 7 mL×cm-3 (range 5-12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood-brain barrier. The approach used further illustrates the role of molecular imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.
Asunto(s)
Acrilamidas/farmacocinética , Compuestos de Anilina/farmacocinética , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Encéfalo/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Acrilamidas/administración & dosificación , Adulto , Compuestos de Anilina/administración & dosificación , Antineoplásicos/administración & dosificación , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/secundario , Radioisótopos de Carbono , Carcinoma de Pulmón de Células no Pequeñas/patología , Voluntarios Sanos , Humanos , Inyecciones Intravenosas , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Distribución TisularRESUMEN
A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer and disease progression post-EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3-32. At baseline, both patients had abnormal liver function tests (LFTs; Child-Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10-fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax )) and LFTs, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.