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BACKGROUND: This analysis evaluated aqueous humour (AH) interleukin (IL)-6 concentrations and the association between AH IL-6 and visual outcomes in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DMO) receiving anti-vascular endothelial growth factor (VEGF) monotherapy. METHODS: Post hoc analysis of the multicentre, double-masked, randomised HARBOR (NCT00891735) and READ-3 (NCT01077401) trials. HARBOR enrolled treatment-naïve nAMD patients. READ-3 enrolled treatment-naïve/previously treated DMO patients. HARBOR patients received ranibizumab 0.5 or 2.0 mg monthly or as needed; AH samples were collected at month 2, after two previous intravitreal injections. READ-3 patients received ranibizumab 0.5 or 2.0 mg as needed; AH samples were collected at baseline and months 3, 6, 9, and 12. MAIN OUTCOME MEASURE: association between AH IL-6 concentrations and month 24 best-corrected visual acuity (BCVA). RESULTS: In both trials (HARBOR, N = 36; READ-3, N = 137), patients with higher AH IL-6 concentrations had worse visual outcomes. HARBOR patients with low AH IL-6 concentrations at month 2 had a mean (95% CI) BCVA change at month 24 of +2.9 (-2.6, 8.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of -9.0 (-22.7, 4.7) letters. READ-3 patients with low AH concentrations at baseline had a mean (95% CI) BCVA change at month 12 of +9.3 (7.4, 11.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of +5.6 (2.2, 9.1) letters. CONCLUSIONS: Higher IL-6 AH concentrations may predict suboptimal visual responses to anti-VEGF monotherapy in patients with nAMD/DMO.
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Inibidores da Angiogênese , Humor Aquoso , Retinopatia Diabética , Interleucina-6 , Injeções Intravítreas , Edema Macular , Ranibizumab , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Humanos , Ranibizumab/administração & dosagem , Ranibizumab/uso terapêutico , Interleucina-6/metabolismo , Acuidade Visual/fisiologia , Humor Aquoso/metabolismo , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Masculino , Feminino , Método Duplo-Cego , Idoso , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Edema Macular/tratamento farmacológico , Edema Macular/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Retinopatia Diabética/fisiopatologia , Pessoa de Meia-Idade , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/metabolismo , Degeneração Macular Exsudativa/fisiopatologia , Idoso de 80 Anos ou maisRESUMO
BACKGROUND/AIMS: We characterised the relationships between monitoring frequency, ranibizumab injection need and vision in patients receiving as-needed (pro re nata; PRN) ranibizumab for macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in this post-hoc analysis of SHORE and HORIZON. METHODS: Patients aged 18 years and older with macular oedema due to BRVO/CRVO were included in this analysis. Injection frequency and best-corrected visual acuity (BCVA) were evaluated by PRN injection frequency in the PRN dosing phase (months (M) 7-15) of SHORE and through 12 months of HORIZON. Prespecified PRN re-treatment criteria for each trial were based on protocol-prespecified BCVA and optical coherence tomography outcomes. RESULTS: After the initial 7 monthly ranibizumab injections, patients in SHORE gained a mean of 18.3 letters from baseline. Patients randomised to PRN, on average, maintained these gains. However, some patients experienced additional mean gains, whereas others suffered losses (range 4.0 (95% CI 0.7 to 7.3) to -4.6 (95% CI -11.8 to 2.6) letters in patients who received 0 and 6-7 PRN injections, respectively). In BRAVO and CRUISE (lead-in trials), patients experienced mean gains from baseline to M6 (monthly dosing) of 19.3 and 15.0 letters, respectively, with gains maintained with PRN from M6 to M12. However, mean BCVA changes from baseline to M12 varied in HORIZON (range -0.4 (95% CI -2.5 to 1.6) to -3.6 (95% CI -6.2 to -1.0) letters in patients who received zero and six injections, respectively, during the preceding PRN phase of BRAVO and CRUISE). CONCLUSION: The BRVO/CRVO population is heterogenous with a varied response to ranibizumab treatment.
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Objective: To evaluate correlations between variability in central foveal thickness (CFT) and vision with ranibizumab in a HARBOR post hoc analysis. Methods and analysis: Patients with neovascular age-related macular degeneration (nAMD; N=1097) received monthly or as-needed (PRN) ranibizumab (0.5 or 2.0 mg) for 24 months. Fluctuation scores were used to assess CFT variability; every time CFT increased and then decreased (or vice versa), numeric value of the change was added to the score. Magnitude of change <50 µm was considered clinically insignificant and did not count towards the score. Fluctuation scores were grouped into quartiles. Least squares mean (LSM) changes in best-corrected visual acuity (BCVA) were plotted against fluctuation score quartiles for CFT, subretinal fluid (SRF) height, neurosensory retina and neurosensory retina + subretinal hyper-reflective material. Results: Patients with lower fluctuations scores (quartiles 1-3) had greatest vision gains at month 24, with LSM changes from baseline of 9.0-10.8 and 8.7-10.6 letters in the monthly and PRN arms, respectively. Corresponding changes for quartile 4 were 6.7 and 6.5 letters, respectively. There were no differences between quartiles for association between fluctuations in SRF height and BCVA gains. There were inverse correlations between magnitude of fluctuations in neurosensory and inner retina thickness and BCVA gains for quartile 4 vs quartiles 1-3. Patients in quartiles 1 and 2 showed rapid, robust BCVA gains, whereas those in quartiles 3 and 4 had lesser responses. Conclusions: Fluctuations in retinal thickening with ranibizumab may be associated with treatment response in patients with nAMD. Trial registration number: NCT00891735.
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Ranibizumab , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/uso terapêutico , Humanos , Injeções Intravítreas , Ranibizumab/uso terapêutico , Tomografia de Coerência Óptica , Resultado do Tratamento , Fatores de Crescimento do Endotélio Vascular , Acuidade VisualRESUMO
PURPOSE: To characterize relationships between Consensus on Neovascular Age-Related Macular Degeneration Nomenclature (CONAN) Study Group classifications of macular neovascularization (MNV) and visual responses to ranibizumab in patients with neovascular age-related macular degeneration (nAMD). METHODS: This was a post hoc analysis of the phase 3 HARBOR trial of ranibizumab in nAMD. Analyses included ranibizumab-treated eyes with baseline multimodal imaging data; baseline MNV; subretinal and/or intraretinal fluid at screening, baseline, or week 1; and spectral-domain optical coherence tomography images through month 24 (n = 700). Mean best-corrected visual acuity (BCVA) over time and mean BCVA change at months 12 and 24 were compared between eyes with type 1, type 2/mixed type 1 and 2 (type 2/M), and any type 3 MNV at baseline. RESULTS: At baseline, 263 (37.6%), 287 (41.0%), and 150 (21.4%) eyes had type 1, type 2/M, and any type 3 lesions, respectively. Type 1 eyes had the best mean BCVA at baseline (59.0 [95% CI: 57.7-60.3] letters) and month 24 (67.7 [65.8-69.6] letters), whereas type 2/M eyes had the worst (50.0 [48.6-51.4] letters and 60.8 [58.7-62.9] letters, respectively). Mean BCVA gains at month 24 were most pronounced for type 2/M eyes (10.8 [8.9-12.7] letters) and similar for type 1 (8.7 [6.9-10.5] letters) and any type 3 eyes (8.3 [6.3-10.3] letters). CONCLUSION: Differences in BCVA outcomes between CONAN lesion type subgroups support the use of an anatomic classification system to characterize MNV and prognosticate visual responses to anti-vascular endothelial growth factor therapy for nAMD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00891735. Date of registration: April 29, 2009.
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Neovascularização de Coroide , Degeneração Macular , Degeneração Macular Exsudativa , Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/tratamento farmacológico , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Ranibizumab/uso terapêutico , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Acuidade Visual , Degeneração Macular Exsudativa/complicações , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011.
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Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , para-Aminobenzoatos/farmacologia , para-Aminobenzoatos/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , para-Aminobenzoatos/efeitos adversos , para-Aminobenzoatos/farmacocinéticaRESUMO
The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine. The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Pirrolidinas/administração & dosagem , Indução de Remissão , Distribuição Tecidual , Adulto Jovem , para-Aminobenzoatos/administração & dosagemRESUMO
In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.
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Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Proteínas Proto-Oncogênicas c-mdm2/sangue , Pirrolidinas/efeitos adversos , Pirrolidinas/sangue , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Adulto Jovem , para-Aminobenzoatos/efeitos adversos , para-Aminobenzoatos/sangue , para-Aminobenzoatos/metabolismo , para-Aminobenzoatos/farmacocinéticaRESUMO
Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for intravenous administration. On cleavage by plasma esterases, the active principle (AP = idasanutlin) is released. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day dosing schedule every 28 days. Dose escalation used the Bayesian new continual reassessment model. Accelerated dose titration was permitted until grade ≥2 drug-related AEs were observed. The target DLT rate to define the MTD was 16-25%. p53 activation was assessed by measuring macrophage inhibitory cytokine-1 (MIC-1). Results Forty-one patients received 14-120 mg AP; 39 were DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug to AP and an approximately linear and dose-proportional dose-exposure relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. MIC-1 increases were exposure dependent. Stable disease was observed in 14 patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development.
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Antineoplásicos/administração & dosagem , Pró-Fármacos/administração & dosagem , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/metabolismo , para-Aminobenzoatos/metabolismo , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Pró-Fármacos/efeitos adversos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Resultado do Tratamento , Proteína Supressora de Tumor p53/metabolismoRESUMO
PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic p53 activator with oral administration. To determine the need to conduct dedicated trial(s) for organ impairment on pharmacokinetic (PK) exposure and/or drug-drug interactions, a single dose of [14C]- and [13C]-labeled idasanutlin was evaluated. METHODS: This study was an open-label, non-randomized, single-center trial of idasanutlin to investigate the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an IV tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors. After completing cycle 1 assessments, patients could have participated in an optional treatment extension of idasanutlin. Clinical endpoints were PK, and safety/tolerability. RESULTS: Co-administration of an oral dose of idasanutlin with an IV tracer dose revealed low systemic CL, a moderate Vd, and a moderate (40.1%) absolute bioavailability of idasanutlin. Idasanutlin and its major inactive metabolite, M4, were the major circulating moieties in plasma, and excretion of idasanutlin-associated radioactivity was primarily via the fecal route (91.5% of the dose), with negligible amounts recovered in urine, following oral administration. CONCLUSION: The clinical implications of this study support the conclusion that renal impairment is unlikely to significantly impact exposure to idasanutlin and M4 metabolite, whereas a significant hepatic impairment may potentially alter exposure to the parent drug and/or metabolite(s). The potential for drug-drug interactions is low.
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Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Estudos de Coortes , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/farmacocinética , para-Aminobenzoatos/farmacocinéticaRESUMO
BACKGROUND: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer. METHODS: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141. FINDINGS: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths. INTERPRETATION: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer. FUNDING: F Hoffmann-La Roche/Genentech.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Amplificação de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/antagonistas & inibidores , Resultado do TratamentoRESUMO
PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval. METHOD: Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed. RESULTS: A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation. CONCLUSION: The concentration-QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.
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Leucemia Mieloide/tratamento farmacológico , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/uso terapêutico , para-Aminobenzoatos/uso terapêutico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Leucemia Mieloide/patologia , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Pirrolidinas/efeitos adversos , Pirrolidinas/sangue , Adulto Jovem , para-Aminobenzoatos/efeitos adversos , para-Aminobenzoatos/sangueRESUMO
PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors. METHOD: This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability. RESULTS: The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in Cmax and a modest increase (31%) in AUC for idasanutlin, a marked reduction in Cmax (~ 60%) and AUC0 (~ 50%) for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. Cmax and AUC were both 45% higher for the SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI values just outside the upper end of the equivalence criteria (80-125%), the high-fat meal reached bioequivalence with dosing under fasting. CONCLUSION: In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect.
Assuntos
Neoplasias/tratamento farmacológico , Pirrolidinas , Triazóis , para-Aminobenzoatos , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Composição de Medicamentos/métodos , Interações Medicamentosas , Jejum , Feminino , Interações Alimento-Droga , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/classificação , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Comprimidos , Equivalência Terapêutica , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética , para-Aminobenzoatos/administração & dosagem , para-Aminobenzoatos/efeitos adversos , para-Aminobenzoatos/farmacocinéticaRESUMO
Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2-treatment (A, fasted conditions; B, following a high-fat meal), 2-sequence (AB or BA) crossover assessment, separated by a 10-day washout. In group 2 (n = 24), subjects were enrolled in a 2-period, fixed-sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high-fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%-393%) and 311% (90%CI, 273%-355%) for Cmax and AUC0-∞ , respectively, versus fasted conditions. Coadministration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4. Alectinib should be administered under fed conditions to maximize its bioavailability, whereas no restrictions are required with antisecretory agents.
Assuntos
Carbazóis/farmacocinética , Esomeprazol/administração & dosagem , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Adulto , Área Sob a Curva , Carbazóis/administração & dosagem , Estudos Cross-Over , Dieta Hiperlipídica , Interações Medicamentosas , Esomeprazol/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Distribuição Aleatória , Adulto JovemAssuntos
Crise Blástica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Pirrolidinas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Crise Blástica/sangue , Crise Blástica/tratamento farmacológico , Crise Blástica/mortalidade , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pirrolidinas/efeitos adversos , para-Aminobenzoatos/efeitos adversosRESUMO
PURPOSE: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted. EXPERIMENTAL DESIGN: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. RESULTS: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. CONCLUSIONS: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.
Assuntos
Antineoplásicos/uso terapêutico , Imidazolinas/uso terapêutico , Leucemia Linfoide/tratamento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose , Análise Mutacional de DNA , Esquema de Medicação , Expressão Gênica , Humanos , Imidazolinas/farmacocinética , Imidazolinas/toxicidade , Leucemia Linfoide/genética , Dose Máxima Tolerável , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Danoprevir, a potent, selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is metabolized by cytochrome P450 (CYP) 3A. Clinical studies in HCV patients have shown a potential need for a high danoprevir daily dose and/or dosing frequency. Ritonavir, an HIV-1 protease inhibitor (PI) and potent CYP3A inhibitor, is used as a pharmacokinetic enhancer at subtherapeutic doses in combination with other HIV PIs. Coadministering danoprevir with ritonavir as a pharmacokinetic enhancer could allow reduced danoprevir doses and/or dosing frequency. Here we evaluate the impact of ritonavir on danoprevir pharmacokinetics. METHODS: The effects of low-dose ritonavir on danoprevir pharmacokinetics were simulated using Simcyp, a population-based simulator. Following results from this drug-drug interaction (DDI) model, a crossover study was performed in healthy volunteers to investigate the effects of acute and repeat dosing of low-dose ritonavir on danoprevir single-dose pharmacokinetics. Volunteers received a single oral dose of danoprevir 100 mg in a fixed sequence as follows: alone, and on the first day and the last day of 10-day dosing with ritonavir 100 mg every 12 hours. RESULTS: The initial DDI model predicted that following multiple dosing of ritonavir 100 mg every 12 hours for 10 days, the danoprevir area under the plasma concentration-time curve (AUC) from time zero to 24 hours and maximum plasma drug concentration (C(max)) would increase by about 3.9- and 3.2-fold, respectively. The clinical results at day 10 of ritonavir dosing showed that the plasma drug concentration at 12 hours postdose, AUC from time zero to infinity and C(max) of danoprevir increased by approximately 42-fold, 5.5-fold and 3.2-fold, respectively, compared with danoprevir alone. The DDI model was refined with the clinical data and sensitivity analyses were performed to better understand factors impacting the ritonavir-danoprevir interaction. CONCLUSION: DDI model simulations predicted that danoprevir exposures could be successfully enhanced with ritonavir coadministration, and that a clinical study confirming this result was warranted. The clinical results demonstrate that low-dose ritonavir enhances the pharmacokinetic profile of low-dose danoprevir such that overall danoprevir exposures can be reduced while sustaining danoprevir trough concentrations.
Assuntos
Lactamas/farmacocinética , Inibidores de Proteases/farmacologia , Inibidores de Proteases/farmacocinética , Ritonavir/farmacologia , Sulfonamidas/farmacocinética , Adulto , Simulação por Computador , Estudos Cross-Over , Ciclopropanos , Interações Medicamentosas , Feminino , Humanos , Isoindóis , Lactamas/sangue , Lactamas Macrocíclicas , Masculino , Modelos Biológicos , Prolina/análogos & derivados , Inibidores de Proteases/sangue , Sulfonamidas/sangue , Proteínas não Estruturais Virais/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND & AIMS: Orlistat is a weight management agent that selectively inhibits gastrointestinal lipase activity. Because of orlistat's mode of action, increased fecal fat is presented to the colonic mucosa, and fecal bile acid and free fatty acid composition may be altered during treatment. Our aim was to assess the effect of treatment of obese subjects with orlistat 120 mg 3 times a day for 6 weeks on fecal lipid and bile acid parameters and colonic mucosal cell proliferation. METHODS: Twenty-four obese (body mass index, 30-40 kg/m2) but otherwise healthy male and female subjects were enrolled in a single-center, randomized, double-blind, placebo-controlled, parallel-group study. Participants were hospitalized during days 1-3 and 33-42 of treatment and were treated as outpatients for the remaining days. RESULTS: Treatment with orlistat for 6 weeks resulted in significantly greater increases in fecal weight, total fecal fat, and fecal free fatty acids than placebo. Total fecal bile acid amounts decreased slightly with orlistat, and increased significantly with placebo treatment (P < .05 between-group difference). Orlistat did not alter colonic cell proliferation as assessed by the 3 proliferative indices (5-bromo-2-deoxyuridine, whole crypt mitotic count, and proliferating cell nuclear antigen). CONCLUSIONS: Biochemical changes in fecal composition related to the pharmacodynamic mode of action of orlistat are not accompanied by altered colonic cell proliferation, a putative biomarker of colon cancer risk.
Assuntos
Fármacos Antiobesidade/farmacologia , Ácidos e Sais Biliares/metabolismo , Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Fezes/química , Lactonas/farmacologia , Obesidade/tratamento farmacológico , Adulto , Idoso , Fármacos Antiobesidade/uso terapêutico , Biópsia , Bromodesoxiuridina/metabolismo , Proliferação de Células , Colo/metabolismo , Colo/patologia , Dieta com Restrição de Gorduras , Método Duplo-Cego , Feminino , Humanos , Lactonas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Obesidade/metabolismo , Orlistate , Antígeno Nuclear de Célula em Proliferação/metabolismoRESUMO
BACKGROUND & AIMS: Many patients with chronic hepatitis C virus (HCV) have persistently normal serum alanine transaminase (ALT) levels. We compared characteristics of chronic hepatitis C patients with patients with normal and elevated ALT levels using data from 3 randomized phase III trials of peginterferon alfa-2a (40 kDa). METHODS: The characteristics of 480 patients with normal ALT values (on >or=3 occasions without any increases in ALT level over a 6- to 18-month period) and 1993 patients with elevated ALT levels were compared. Sixty-eight of the 480 patients with normal ALT levels were randomized to no treatment and monitored for 72 weeks. RESULTS: More patients with normal ALT levels than patients with elevated ALT levels were women (59% vs 32%; P<.01). The serum HCV RNA titer was significantly lower in patients with normal ALT levels (P<.01 vs in patients with elevated ALT levels). Patients with normal ALT levels had significantly lower inflammation and fibrosis scores on liver biopsy examination than patients with elevated ALT levels, but almost two-thirds had portal fibrosis and 10% had bridging fibrosis. No correlation between baseline ALT activity, HCV RNA level, and liver histology was observed in patients with normal ALT levels. During the 72-week follow-up period, ALT activity elevated above the upper limit of normal in 53% of the untreated patients with normal levels of ALT. None became HCV RNA undetectable. CONCLUSIONS: Chronic hepatitis C patients with normal ALT levels should be evaluated in a similar manner as patients with elevated ALT levels because they are at risk for developing significant liver disease. The decision to treat with peginterferon alfa and ribavirin should be based on multiple factors, rather than on ALT levels alone.
Assuntos
Alanina Transaminase/sangue , Hepacivirus/isolamento & purificação , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Adulto , Alanina Transaminase/metabolismo , Antivirais/uso terapêutico , Estudos de Casos e Controles , Ensaios Clínicos Fase III como Assunto , DNA Viral/análise , Progressão da Doença , Feminino , Seguimentos , Hepatite C Crônica/tratamento farmacológico , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Valores de Referência , Índice de Gravidade de DoençaRESUMO
BACKGROUND/AIMS: In chronic hepatitis C, disease progression and clinical manifestations are heterogenous. To clarify the role and interactions of viral and host factors in inducing liver cell injury, we examined the associations of several virological and metabolic variables with serum alanine aminotransferase levels. METHODS: Patients with chronic hepatitis C enrolled in three phase III clinical trials of peginterferon alfa-2a (40KD) plus ribavirin (two studies analysing 'elevated' and one persistently 'normal' alanine aminotransferase) were included. RESULTS: Multivariate analyses of 2,881 patients before treatment and of 1,403 patients with a sustained virological response indicated that gender, viral factors (genotype, HCV RNA titer) and indicators of metabolic syndrome (body mass index, blood pressure, blood glucose, cholesterol and triglyceride concentration) were associated with alanine aminotransferase levels. In addition, hepatitis C virus infection influenced serum lipids concentration according to a genotype-specific effect. CONCLUSIONS: Heterogeneity in alanine aminotransferase levels in patients with chronic hepatitis C partially depends on the degree of derangement of fat and carbohydrate metabolism. As this is the result of an interaction of chronic hepatitis C infection with the patient's individual characteristics, treatment decisions should not be based on alanine aminotransferase level alone but rather on global evaluation of the patient.