RESUMEN
As tumors are very heterogeneous, investigating the penetration and concentration of an anticancer drug in different histological regions of a tumor is key to evaluate the efficacy, to improve the pharmacokinetics/pharmacodynamics (PK/PD) relationship evaluation, and to confirm the adequacy of the dose regimen. Quantitative mass spectrometry imaging (QMSI) allows for the determination of the tissue distribution of drugs, metabolites, and biomarkers to support quick and precise evaluation of drug efficacy and safety in a single experiment. QMSI was applied in a preoperative window-of-opportunity (WoO) study of the inhibitor of apoptosis protein antagonist xevinapant (Debio 1143) in patients with resectable squamous cell carcinoma of the head and neck (SCCHN). Tumors were isolated, immediately snap-frozen, and sectioned, and then, the molecular distribution of the drug was generated by matrix-assisted laser desorption ionization (MALDI) imaging. Additionally, the different histological regions (tumor, epithelium, salivary glands, muscle, nerve, and blood vessels) were identified on stained sections adjacent to the ones used for QMSI, leading to a specific quantification integrating the biological characterization of the tumor heterogeneity. This innovative approach allowed one to highlight the high affinity of xevinapant for the tumor tissues.
Asunto(s)
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Proteínas Inhibidoras de la Apoptosis , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
BACKGROUND: Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. METHODS: This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18-75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0-3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1-14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting. FINDINGS: Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6-29·4) in the Debio 1143 group and 24·2 months (6·6-26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39-69) of 48 patients in the Debio 1143 group versus 16 (33%; 20-48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13-6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3-4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. INTERPRETATION: To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. FUNDING: Debiopharm.
Asunto(s)
Cisplatino/administración & dosificación , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Adulto JovenRESUMEN
Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.
Asunto(s)
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Cisplatino/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Leucocitos Mononucleares/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/inducido químicamente , Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF-κB signaling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre-operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day [D]1-15 +/- 2); Debio 1143 (200 mg/day D1-15 +/- 2) plus cisplatin (40 mg/m2 D 1 and 8); cisplatin alone (40 mg/m2 D 1 and 8; EudraCT: 2014-004655-31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary end point; effect of Debio 1143 on cellular IAP-1 (cIAP-1). Levels of cIAP-1/-2, X-linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs), including CD8+ T cells, programmed cell death protein 1 (PD-1), PD-ligand 1 (PD-L1), and gene expression were also analyzed. Twenty-three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n = 13), mean tumor concentrations of Debio 1143 were 18-fold (maximum 55.2-fold) greater than in plasma, exceeding the half-maximal inhibitory concentration for cIAPs and XIAP by 100 to 1000-fold, with significant engagement/degradation of cIAP-1 (p < 0.05). Overall, levels of CD8+ TILs, PD-1, and PD-L1 positive immune cells increased significantly (p < 0.05) following Debio 1143 treatment. Changes were observed in the expression of genes related to NF-κB signaling. Treatments were well-tolerated. Debio 1143 penetrated SCCHN tumors, engaged cIAP-1, and induced immune inflammatory changes in the tumor microenvironment. Based on the mode of action demonstrated here and in previous studies, these data support future combinations of Debio 1143 with immune-checkpoint agents.
Asunto(s)
Proteínas Inhibidoras de la Apoptosis/farmacología , Proteínas Inhibidoras de la Apoptosis/farmacocinética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Ensayos Clínicos como Asunto , Estudios de Cohortes , Humanos , Proteínas Inhibidoras de la Apoptosis/administración & dosificación , FarmacogenéticaRESUMEN
PURPOSE: Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported. PATIENTS AND METHODS: Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment. RESULTS: Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%. CONCLUSIONS: The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/métodos , Neoplasias de Cabeza y Cuello/terapia , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Adolescente , Adulto , Anciano , Azocinas/administración & dosificación , Compuestos de Bencidrilo/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Adulto JovenRESUMEN
PURPOSE: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert's syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients. EXPERIMENTAL DESIGN: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment. RESULTS: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert's syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity. CONCLUSIONS: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert's syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/toxicidad , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Glucuronosiltransferasa/genética , Polimorfismo Genético , Adulto , Anciano , Antineoplásicos Fitogénicos/toxicidad , Secuencia de Bases , Cartilla de ADN/química , Cartilla de ADN/genética , Femenino , Fluorouracilo/administración & dosificación , Vectores Genéticos , Genotipo , Heterocigoto , Homocigoto , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Metástasis de la Neoplasia , Reacción en Cadena de la Polimerasa , Riesgo , Análisis de Secuencia de ADNRESUMEN
PURPOSE: To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. METHODS: This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. RESULTS: Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. CONCLUSION: DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Azocinas/administración & dosificación , Azocinas/uso terapéutico , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Azocinas/efectos adversos , Azocinas/farmacocinética , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/farmacocinética , Quimiocina CCL2/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/sangre , Masculino , Dosis Máxima Tolerada , Neoplasias/etiología , Neoplasias/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Treatment of acute myeloid leukemia (AML) remains difficult owing to the development of treatment resistance, which might be overcome through antagonists of inhibitors of apoptosis proteins (IAPs). PATIENTS AND METHODS: The present multicenter, open-label, dose-escalation study aimed to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Debio1143 (formerly AT-406), a new IAP antagonist, when given along with a standard "7 plus 3 regimen" of daunorubicin and cytarabine to poor-risk patients with AML during the induction cycle. Consecutive patient cohorts received once-daily 100, 200, 300, or 400 mg of oral Debio1143 on treatment days 1 to 5. Blood samples were collected regularly until hematologic recovery or response was documented. Bone marrow samples were collected on days 0, 14, and 29 and PK and PD samples on days 1, 3, 5, 8, and 10 and 1, 2, and 8, respectively. RESULTS: Of the 29 enrolled patients, 23 completed the study. The most common adverse events of any grade deemed related to treatment were nausea (31% of patients), diarrhea (14%), and febrile neutropenia (14%). Exposure exceeded dose proportionality, without accumulation over 5 days. Inhibition of cellular IAP1 was detectable in the CD34/CD117(+) cells and blasts. A total of 11 patients (38%) achieved complete remission, most in the 100-mg dose cohort. Of these, 6 (56%) developed a relapse within the study period. The patients with a response more frequently showed plasma increases of tumor necrosis factor-α and interleukin-8 after the first dose of Debio1143. CONCLUSION: Debio1143 ≤ 400 mg/d showed good tolerability in combination with daunorubicin and cytarabine. Additional studies in subsets of patients with AML are warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azocinas/administración & dosificación , Compuestos de Bencidrilo/administración & dosificación , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Citarabina/administración & dosificación , Citocinas/sangre , Daunorrubicina/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Masculino , Persona de Mediana EdadRESUMEN
Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in phase 3 clinical development for epilepsy. A phase 1, single-center, randomized, double-blind, placebo-controlled, single (2.5-100 mg) and multiple (2.5-50 mg twice daily) rising oral dose study (N01209) was conducted to assess the adverse event profile and pharmacokinetics of brivaracetam in healthy Japanese men, and the influence of the cytochrome P450 (CYP) 2C19 genotype. Plasma and urine were collected serially for analysis of brivaracetam and its three main metabolites: acid, hydroxy and hydroxy acid. Overall, 79/80 randomized participants completed the study. Brivaracetam was generally well tolerated. After single- and multiple-dose administration, brivaracetam was rapidly absorbed, with dose-proportional pharmacokinetics over the dose ranges tested. Steady state was reached after 2 days of repeated dosing. Brivaracetam clearance (averaged across the five single dose levels) was reduced from 0.99 mL/min/kg in homozygous extensive metabolizers (EM; n = 10) to 0.81 mL/min/kg (-18%) in heterozygous EM (n = 17) and 0.70 mL/min/kg (-29%) in poor metabolizers (PM; n = 9). Exposure and urinary excretion of hydroxy metabolite were reduced 10-fold in PM participants, compared with EM participants. Results suggest that brivaracetam is hydroxylated by CYP2C19, but this pathway is minor compared with hydrolysis to the acid metabolite.
Asunto(s)
Citocromo P-450 CYP2C19/genética , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacocinética , Administración Oral , Adulto , Pueblo Asiatico/genética , Citocromo P-450 CYP2C19/metabolismo , Método Doble Ciego , Genotipo , Voluntarios Sanos , Humanos , Japón , Masculino , Pirrolidinonas/metabolismo , Adulto JovenRESUMEN
PURPOSE: To compare the relative bioavailability of levetiracetam extended-release tablets (XR) with immediate release tablets (IR) following single and multiple dosing; to assess the food effect and the dose-proportionality of XR from 1000 to 3000mg. METHODS: Two panels of 24 healthy subjects were enrolled. Study N01160 was a three-way crossover between IR fasted (single and repeated 500mg b.i.d.), XR fasted (single and repeated 1000mg o.d.) and XR with food (1000mg single dose). Study N01260 was a three-way crossover single dose-proportionality between XR 1000, 2000 and 3000mg. RESULTS: After single dose, levetiracetam XR and IR were bioequivalent with respect to AUC((0-t)), AUC(infinity) and C(max). The median t(max) was delayed from 0.9 to 4h. For the fed/fasted comparison, the confidence intervals around the C(max) and AUC ratios were within the 80-125% limits. At steady-state, the AUC(24h) were also bioequivalent. In the dose-proportionality trial, the AUC and C(max) increased linearly with the dose. Levetiracetam XR was well tolerated. CONCLUSIONS: Levetiracetam XR 1000mg o.d. is bioequivalent to levetiracetam IR 500mg b.i.d. There is no food effect, and the absorption of XR is dose-proportional from 1000 to 3000mg.
Asunto(s)
Anticonvulsivantes/farmacocinética , Piracetam/análogos & derivados , Comprimidos/farmacocinética , Adolescente , Adulto , Análisis de Varianza , Anticonvulsivantes/sangre , Área Bajo la Curva , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Tolerancia a Medicamentos , Electrocardiografía/métodos , Humanos , Levetiracetam , Persona de Mediana Edad , Piracetam/sangre , Piracetam/farmacocinética , Método Simple Ciego , Comprimidos/administración & dosificación , Equivalencia Terapéutica , Adulto JovenRESUMEN
Irinotecan (CPT-11) is a topoisomerase I inhibitor used in the treatment of metastatic colorectal cancer. Its conversion by carboxyl esterases is necessary to form the active metabolite SN-38. The aims of the study were to evaluate the linearity of CPT-11 pharmacokinetics and the influence of the schedule of administration of CPT-11 in mice, using a population pharmacokinetic approach with the NON-linear Mixed Effects Model (NONMEM) program. Mice were treated using two doses and two schedules of administration [10 mg/kg/day (dailyx5)x2 or 50 mg/kg/day on days 1 and 12]. Plasma concentrations of both CPT-11 and SN-38 were determined by HPLC. A pharmacokinetic model based on both immediate conversion of CPT-11 to SN-38 for a fraction of the administered dose and saturable process for the remaining fraction fitted the data well. Refinements of the model allowed us to evaluate both the impacts of the dose and the schedule of administration on the pharmacokinetic parameters. We conclude that the pharmacokinetics of CPT-11 is not linear in mice. Extrapolation of both pharmacokinetic and pharmacodynamic preclinical results to humans may be limited by species particularities for this drug.