RESUMO
PURPOSE: In this systematic review and individual patient data (IPD) meta-analysis, we analysed the diagnostic performance of [18F]FDG PET/CT in detecting primary tumours in patients with CUP and evaluated whether the location of the predominant metastatic site influences the diagnostic performance. METHODS: A systematic literature search from January 2005 to February 2024 was performed to identify articles describing the diagnostic performance of [18F]FDG PET/CT for primary tumour detection in CUP. Individual patient data retrieved from original articles or obtained from corresponding authors were grouped by the predominant metastatic site. The diagnostic performance of [18F]FDG PET/CT in detecting the underlying primary tumour was compared between predominant metastatic sites. RESULTS: A total of 1865 patients from 32 studies were included. The largest subgroup included patients with predominant bone metastases (n = 622), followed by liver (n = 369), lymph node (n = 358), brain (n = 316), peritoneal (n = 70), lung (n = 67), and soft tissue (n = 23) metastases, leaving a small group of other/undefined metastases (n = 40). [18F]FDG PET/CT resulted in pooled detection rates to identify the primary tumour of 0.74 (for patients with predominant brain metastases), 0.54 (liver-predominant), 0.49 (bone-predominant), 0.46 (lung-predominant), 0.38 (peritoneal-predominant), 0.37 (lymph node-predominant), and 0.35 (soft-tissue-predominant). CONCLUSION: This individual patient data meta-analysis suggests that the ability of [18F]FDG PET/CT to identify the primary tumour in CUP depends on the distribution of metastatic sites. This finding emphasises the need for more tailored diagnostic approaches in different patient populations. In addition, alternative diagnostic tools, such as new PET tracers or whole-body (PET/)MRI, should be investigated.
RESUMO
Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose-escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose-levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/mL d1/d22. After two cycles, patients continued olaparib 300 mg BID as monotherapy. Primary objective was to assess the maximum tolerable dose (MTD). Twenty-four patients with a confirmed diagnosis of advanced cancer were included. Most common adverse events were nausea (46%), fatigue (33%) and platelet count decrease (33%). Dose-level 3 (olaparib 75 mg BID and carboplatin AUC 4 mg*min/mL; n = 6) was defined as MTD. Fourteen out of 24 patients (56%) had a partial response as best response (RECIST 1.1). Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with olaparib tablet AUC0-12 of 16.3 µg/mL*h at MTD. Polymers of ADP-ribose levels in peripheral blood mononuclear cells were reduced by 98.7% ± 0.14% at Day 8 compared to Day 1 for dose-level 3. Olaparib tablets 75 mg BID and carboplatin AUC 4 mg*min/mL for two cycles preceding olaparib monotherapy 300 mg is a feasible and tolerable treatment schedule for patients with advanced cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cápsulas , Carboplatina/efeitos adversos , Esquema de Medicação , Sinergismo Farmacológico , Estudos de Viabilidade , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Comprimidos , Resultado do TratamentoRESUMO
LESSONS LEARNED: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined. BACKGROUND: Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase-AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors. METHODS: Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy. RESULTS: Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response. CONCLUSION: Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Colorretais , Neoplasias Pulmonares , Neoplasias Pancreáticas , Afatinib/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic-pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Variação Genética/genética , Farmacogenética , Adulto , Algoritmos , Antineoplásicos Fitogênicos/administração & dosagem , Disponibilidade Biológica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/administração & dosagem , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Ritonavir/administração & dosagemRESUMO
BACKGROUND: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER). METHODS: In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336). RESULTS: Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC. CONCLUSIONS: Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Difenilamina/análogos & derivados , Receptores ErbB/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinazolinonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Difenilamina/administração & dosagem , Difenilamina/efeitos adversos , Difenilamina/farmacocinética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinéticaRESUMO
Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicities (DLTs) were recorded. The aim of current analysis was to develop a pharmacokinetic (PK)-toxicodynamic (TOX) model to quantify the relationship between docetaxel plasma exposure and DLTs. Methods A total of 85 patients was included in the current analysis, 18 patients showed a DLT in the four-week observation period. A PK-TOX model was developed and simulations based on the PK-TOX model were performed. Results The final PK-TOX model was characterized by an effect compartment representing the toxic effect of docetaxel, which was linked to the probability of developing a DLT. Simulations of once-weekly, once-daily 60 mg and once-weekly, twice-daily 30 mg followed by 20 mg of oral docetaxel suggested that 14% and 34% of patients, respectively, would have a probability >25% to develop a DLT in a four-week period. Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens.
Assuntos
Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Docetaxel , Modelos Biológicos , Ritonavir , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Simulação por Computador , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Docetaxel/farmacocinética , Docetaxel/toxicidade , Humanos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Ritonavir/toxicidadeRESUMO
Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1-2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/efeitos adversos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Paclitaxel/efeitos adversos , Ftalazinas/efeitos adversos , Ftalazinas/sangue , Ftalazinas/farmacocinética , Piperazinas/efeitos adversos , Piperazinas/sangue , Piperazinas/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
Background In the first part of this extensive phase I study (NCT00516724), continuous olaparib twice daily (bid) with carboplatin and/or paclitaxel resulted in myelosuppression and dose modifications. Here, we report the safety, tolerability, and efficacy of intermittent olaparib dosing combined with carboplatin and paclitaxel. Methods Patients with advanced solid tumors (part D) and enriched for ovarian and breast cancer (part E) received olaparib (capsule and tablet formulations) using intermittent schedules (2 to 10 days of a 21-day cycle) combined with carboplatin/paclitaxel. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs), and physical examinations. Pharmacokinetic assessments of olaparib capsule and tablet combined with carboplatin/paclitaxel were performed. Tumor responses (RECIST) were assessed every 2 cycles. Results In total, 132 heavily pre-treated patients were included. One DLT of grade 3 elevated alanine aminotransferase lasting for 8 days was reported (olaparib tablet 100 mg bid days 3-12, carboplatin area under the curve 4 and paclitaxel 175 mg/m2). The most common hematological AEs were neutropenia (47%) and thrombocytopenia (39%), which frequently led to dose modifications. Non-hematological AEs were predominantly grade 1-2, including alopecia (89%) and fatigue (84%). Overall objective response rate was 46%. Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1-5).
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adulto , Idoso , Alopecia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cápsulas , Carboplatina/efeitos adversos , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Ftalazinas/efeitos adversos , Ftalazinas/sangue , Ftalazinas/farmacocinética , Piperazinas/efeitos adversos , Piperazinas/sangue , Piperazinas/farmacocinética , Comprimidos , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). METHODS: Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. RESULTS: A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. CONCLUSION: The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1-14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Capecitabina/administração & dosagem , Capecitabina/farmacologia , Cronofarmacoterapia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Capecitabina/efeitos adversos , Capecitabina/sangue , Ritmo Circadiano , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Fluoruracila/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Timidilato Sintase/metabolismo , Uridina Trifosfato/análogos & derivados , Uridina Trifosfato/sangueRESUMO
Mitochondria play a crucial role in pathways of stress conditions. They can be transported from one cell to another, bringing their features to the cell where they are transported. It has been shown in cancer cells overexpressing multidrug resistance (MDR) that mitochondria express proteins involved in drug resistance such as P-glycoprotein (P-gp), breast cancer resistant protein and multiple resistance protein-1. The MDR phenotype is associated with the constitutive expression of COX-2 and iNOS, whereas celecoxib, a specific inhibitor of COX-2 activity, reverses drug resistance of MDR cells by releasing cytochrome c from mitochondria. It is possible that COX-2 and iNOS are also expressed in mitochondria of cancer cells overexpressing the MDR phenotype. This study involved experiments using the human HCC PLC/PRF/5 cell line with and without MDR phenotype and melanoma A375 cells that do not express the MDR1 phenotype but they do iNOS. Western blot analysis, confocal immunofluorescence and immune electron microscopy showed that iNOS is localized in mitochondria of MDR1-positive cells, whereas COX-2 is not. Low and moderate concentrations of celecoxib modulate the expression of iNOS and P-gp in mitochondria of MDR cancer cells independently from inhibition of COX-2 activity. However, A375 cells that express iNOS also in mitochondria, were not MDR1 positive. In conclusion, iNOS can be localized in mitochondria of HCC cells overexpressing MDR1 phenotype, however this phenomenon appears independent from the MDR1 phenotype occurrence. The presence of iNOS in mitochondria of human HCC cells phenotype probably concurs to a more aggressive behaviour of cancer cells.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Celecoxib/farmacologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Microscopia Confocal , Microscopia Imunoeletrônica , Mitocôndrias/genética , Óxido Nítrico Sintase Tipo II/genéticaRESUMO
BACKGROUND: Olaparib (AZD2281), a PARP-1/2 inhibitor, has been extensively investigated in clinical trials. However, limited clinical data are available about its long-term safety and anti-tumour activity. METHODS: Patients had first participated in a phase I study of olaparib combined with carboplatin and/or paclitaxel. They continued with olaparib monotherapy in their best interest if they failed to tolerate the combination due to the treatment-related adverse events (TRAEs). Safety data were collected by physical examination and regular laboratory evaluations. Disease evaluations were performed by CT scan. RESULTS: At data cutoff, 21 patients were included; 10 with breast, 9 with ovarian and 2 with fallopian tube cancer of whom 16 patients had a BRCA mutation (13 BRCA1; 3 BRCA2). TRAEs were mostly haematological and most prominent shortly after switching from combination to monotherapy, probably due to carry-over effects of chemotherapy. Over time, both severity and frequency of TRAEs decreased. Responses to olaparib were durable with a median treatment duration of 52 (range 7-183) weeks. In total, nine (43%) patients were still on study at data cutoff. CONCLUSION: Continued long-term daily olaparib was found to be safe and tolerable. Encouragingly, patients who showed a favourable response on earlier combination therapy maintained this response on olaparib monotherapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carboplatina/administração & dosagem , Progressão da Doença , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Terapia de Salvação , Falha de TratamentoRESUMO
BMS-275,183 is a novel oral C-4 methyl carbonate analogue of paclitaxel. Recently, a drug-drug interaction between BMS-275,183 and benzimidazole proton pump inhibitors (PPIs) was suggested in clinical trials resulting in elevated drug exposure and toxicity. We explored whether the interaction takes place at the level of P-glycoprotein (Pgp, MDR1, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and MRP2 (ABCC2) using in vitro and in vivo models. In vitro cell survival, drug accumulation, efflux and transport studies with BMS-275,183 were performed employing MDCKII (wild-type, MDR1, BCRP, MRP2) and LLCPK (wild-type and MDR1) cells. In vivo the pharmacokinetics and tissue distribution of BMS-275,183 after p.o. and i.v. administration were explored in Mdr1a/1b(-/-) and wild-type mice, in presence or absence of the PPI pantoprazole. Results In vitro, BMS-275,183 was found to be a good substrate for MDR1, a moderate substrate for MRP2 and not a substrate for BCRP. In vivo, oral bioavailability, plasma AUC0-6h and brain concentrations were significantly 1.5-, 4-, and 2-fold increased, respectively, in Mdr1a/1b(-/-) compared with wild-type mice (p < 0.001). However, oral co-administration of pantoprazole (40 mg/kg) did not alter the pharmacokinetics of BMS-275,183 in wild-type mice. Conclusions BMS-275,183 is efficiently transported by Pgp and to a lesser extent by MRP2 in vitro. Genetic deletion of Pgp significantly altered the pharmacokinetics and brain distribution of p.o. and i.v. administered BMS-275,183 in Mdr1a/1b-/- compared to wild-type mice. Oral co-administration of BMS-275,183 with pantoprazole did not affect the pharmacokinetics of BMS-275,183 in wild-type mice, suggesting no interaction with PPI at the dose employed.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacologia , Encéfalo/metabolismo , Hidrocarbonetos Aromáticos com Pontes/sangue , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dibenzocicloeptenos/farmacologia , Cães , Interações Medicamentosas , Feminino , Humanos , Rim/metabolismo , Pulmão/metabolismo , Camundongos Knockout , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Miocárdio/metabolismo , Proteínas de Neoplasias/genética , Paclitaxel/farmacologia , Pantoprazol , Quinolinas/farmacologia , Baço/metabolismo , Suínos , Distribuição TecidualRESUMO
We explored whether barasertib (AZD1152), a selective Aurora B kinase inhibitor, is a substrate for P-glycoprotein (Pgp, MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in vitro. Cell survival, drug transport, and competition experiments with barasertib pro-drug and the more active form of the drug (barasertib-hQPA) were performed using MDCKII (wild type, MDR1, BCRP, and MRP2) and LLCPK (wild type and MDR1) cells and monolayers, and Sf9-BCRP membrane vesicles. Moreover we tested whether P-gp and BCRP affect the oral pharmacokinetics, tissue distribution, and myelotoxicity of barasertib in vivo using Bcrp1(-/-)/Mdr1a/1b (-/-) (triple knockout) and wild type mice. In cell survival experiments expression of BCRP and MDR1 resulted in significant resistance to barasertib. In transwell experiments, barasertib-hQPA was transported by BCRP and MDR1 efficiently. In Sf9-BCRP membrane vesicles, both barasertib and barasertib-hQPA significantly inhibited the BCRP-mediated transport of methotrexate. In contrast, no active transport of barasertib by MRP2 was observed, and overexpression of MRP2 did not affect cytotoxicity of barasertib. In vivo, systemic exposure as well as bioavailability, brain penetration, kidney and liver distribution and myelotoxicity of barasertib-hQPA were statistically significantly increased in Bcrp1(-/-)/Mdr1a/1b(-/-) compared with wild type mice (p<0.001). Barasertib is transported efficiently by P-gp and BCRP/Bcrp1 in vitro. In vivo, genetic deletion of P-gp and BCRP in mice significantly affected pharmacokinetics, tissue distribution and myelotoxicity of barasertib-hQPA. Possible clinical consequences for the observed affinity of barasertib for P-gp and BCRP need to be explored.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Organofosfatos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Aurora Quinase B/antagonistas & inibidores , Disponibilidade Biológica , Cães , Hemoglobinas , Humanos , Rim/metabolismo , Contagem de Leucócitos , Fígado/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Proteína 2 Associada à Farmacorresistência Múltipla , Contagem de Plaquetas , Distribuição TecidualRESUMO
AIM: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours. METHODS: An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m(-2) eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and C(max) for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m(-2) eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed. RESULTS: Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and C(max) = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%). CONCLUSIONS: These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.
Assuntos
Antimitóticos/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Furanos/farmacocinética , Cetonas/farmacocinética , Neoplasias/metabolismo , Rifampina/administração & dosagem , Administração Oral , Adulto , Idoso , Antimitóticos/administração & dosagem , Área Sob a Curva , Povo Asiático , Interações Medicamentosas , Feminino , Furanos/administração & dosagem , Humanos , Cetonas/administração & dosagem , Masculino , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Pessoa de Meia-Idade , População BrancaRESUMO
AIMS: The herbal medicine Echinacea purpurea (E. purpurea) has been shown to induce cytochrome P450 3A4 (CYP3A4) both in vitro and in humans. This study explored whether E. purpurea affects the pharmacokinetics of the CYP3A4 substrate docetaxel in cancer patients. METHODS: Ten evaluable cancer patients received docetaxel (135 mg, 60 min IV infusion) before intake of a commercially available E. purpurea extract (20 oral drops three times daily) and 3 weeks later after a 14 day supplementation period with E. purpurea. In both cycles, pharmacokinetic parameters of docetaxel were determined. RESULTS: Before and after supplementation with E. purpurea, the mean area under the plasma concentration-time curve of docetaxel was 3278 ± 1086 and 3480 ± 1285 ng ml(-1) h, respectively. This result was statistically not significant. Nonsignificant alterations were also observed for the elimination half-life (from 30.8 ± 19.7 to 25.6 ± 5.9 h, P = 0.56) and maximum plasma concentration of docetaxel (from 2224 ± 609 to 2097 ± 925 ng ml(-1) , P = 0.30). CONCLUSIONS: The multiple treatment of E. purpurea did not significantly alter the pharmacokinetics of docetaxel in this study. The applied E. purpurea product at the recommended dose may be combined safely with docetaxel in cancer patients.
Assuntos
Antineoplásicos/farmacocinética , Citocromo P-450 CYP3A/biossíntese , Echinacea/química , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Taxoides/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Docetaxel , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Indução Enzimática , Feminino , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/enzimologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Taxoides/efeitos adversos , Taxoides/sangue , Taxoides/uso terapêuticoRESUMO
INTRODUCTION: Docetaxel is widely used as intravenous (IV) chemotherapy. Oral docetaxel is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir to increase oral bioavailability. This research explores the relationship between the pharmacokinetics (PK) and toxicity of this novel oral chemotherapy. METHODS: The patients in two phase I trials were treated with different oral docetaxel formulations in combination with ritonavir in different dose levels, ranging from 20 to 80 mg docetaxel with 100 to 200 mg ritonavir a day. The patients were categorized based on the absence or occurrence of severe treatment-related toxicity (grade ≥3 or any grade leading to treatment alterations). The docetaxel area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) were associated with toxicity. RESULTS: Thirty-four out of 138 patients experienced severe toxicity, most frequently observed as mucositis, fatigue, diarrhea, nausea and vomiting. The severe toxicity group had a significantly higher docetaxel AUC (2231 ± 1405 vs 1011 ± 830 ng/mL*h, p<0.0001) and Cmax (218 ± 178 vs 119 ± 77 ng/mL, p<0.0001) as compared to the patients without severe toxicity. When extrapolated from IV PK data, the patients without severe toxicity had a similar cumulative docetaxel AUC as with standard 3-weekly IV docetaxel, while the Cmax was up to 10-fold lower with oral docetaxel and ritonavir. CONCLUSION: Severe toxicity was observed in 25% of the patients treated with oral docetaxel and ritonavir. This toxicity seems related to the PK, as the docetaxel AUC0-inf and Cmax were up to twofold higher in the severe toxicity group as compared to the non-severe toxicity group. Future randomized trials will provide a further evaluation of the toxicity and efficacy of the new weekly oral docetaxel and ritonavir regimen in comparison to standard IV docetaxel.
RESUMO
INTRODUCTION: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. OBJECTIVES: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. METHODS: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration-time curve (AUC)0-48, AUC0-inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93-1.33), 1.19 (90% CI 1.00-1.41) and 1.07 (90% CI 0.81-1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69-0.90), whereas the AUC0-48 and AUC0-inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. CONCLUSIONS: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS. GOV IDENTIFIER: NCT03147378, date of registration: May 10 2017.
Assuntos
Antineoplásicos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Docetaxel/farmacocinética , Neoplasias/tratamento farmacológico , Ritonavir/farmacocinética , Administração Oral , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Área Sob a Curva , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Diarreia/induzido quimicamente , Dieta Hiperlipídica , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Docetaxel/sangue , Combinação de Medicamentos , Jejum , Fadiga/induzido quimicamente , Feminino , Interações Alimento-Droga , Humanos , Hipopotassemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/sangue , Comprimidos , Equivalência TerapêuticaRESUMO
Capecitabine is an oral pro-drug of 5-fluorouracil. Patients with solid tumours who are treated with capecitabine may develop hand-and-foot syndrome (HFS) as side effect. This might be a result of accumulation of intracellular metabolites. We characterised the pharmacokinetics (PK) of 5-fluorouridine 5'-triphosphate (FUTP) in peripheral blood mononuclear cells (PBMCs) and assessed the relationship between exposure to capecitabine or its metabolites and the development of HFS. Plasma and intracellular capecitabine PK data and ordered categorical HFS data was available. A previously developed model describing the PK of capecitabine and metabolites was extended to describe the intracellular FUTP concentrations. Subsequently, a continuous-time Markov model was developed to describe the development of HFS during treatment with capecitabine. The influences of capecitabine and metabolite concentrations on the development of HFS were evaluated. The PK of intracellular FUTP was described by an one-compartment model with first-order elimination (ke,FUTP was 0.028 h-1 (95% confidence interval 0.022-0.039)) where the FUTP influx rate was proportional to the 5-FU plasma concentrations. The predicted individual intracellular FUTP concentration was identified as a significant predictor for the development and severity of HFS. Simulations demonstrated a clear exposure-response relationship. The intracellular FUTP concentrations were successfully described and a significant relationship between these intracellular concentrations and the development and severity of HFS was identified. This model can be used to simulate future dosing regimens and thereby optimise treatment with capecitabine.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Síndrome Mão-Pé/etiologia , Modelos Biológicos , Uridina Trifosfato/análogos & derivados , Administração Oral , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Variação Biológica da População , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Simulação por Computador , Conjuntos de Dados como Assunto , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Síndrome Mão-Pé/sangue , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Cadeias de Markov , Neoplasias/tratamento farmacológico , Cultura Primária de Células , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Uridina Trifosfato/farmacocinéticaRESUMO
ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low-dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open-label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice-daily 30-mg paclitaxel combined with twice-daily 100-mg ritonavir (MP5/r 30-30/100-100) in 9 dose levels. Dose-limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20-20/100-100, the maximum paclitaxel plasma concentration and area under the concentration-time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng ⢠h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20-20/100-100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Ritonavir/administração & dosagemRESUMO
OBJECTIVES: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL).DESIGN Randomized controlled trial.SETTING Tertiary cancer hospital.PATIENTS Adults to be treated with high-dose cisplatin (≥ 75âmg/m2).INTERVENTION Selected by randomization, 0.1âM STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 hours before cisplatin administration. After amendment, the placebo ear was left untreated. MAIN OUTCOME MEASURE: Primary outcome was safety and feasibility. Secondary outcomes included pharmacokinetic analysis of systemic cisplatin and preliminary activity of STS. Clinically relevant CIHL was defined as a ≥ 10âdB threshold shift at pure-tone average 8-10-12.5âkHz (PTA8-12.5). Response to STS was defined as a threshold shift at PTA8-12.5 in the STS-treated ear of ≥ 10âdB smaller than the untreated ear. RESULTS: Twelve patients were treated. Average CIHL at PTA8-12.5 was 12.7âdB in untreated ears and 8.8âdB SPL in STS-treated ears (pâ=â0.403). Four patients did not develop CIHL. Four out of eight patients with CIHL responded to STS: CIHL at PTA8-12.5 in STS-treated ears was 18.4âdB less compared to untreated ears (pâ=â0.068). Grade 1 adverse events were reported. Pharmacokinetic results were available for 11 patients. CONCLUSION: Transtympanic application of STS was safe and feasible. Based on our pharmacokinetic analysis, we postulate that transtympanic STS does not interfere with the systemically available cisplatin. Our results provide a preliminary proof of concept for transtympanic application of STS in preventing CIHL and warrants further evaluation on a larger scale.