The Experts below are selected from a list of 111 Experts worldwide ranked by ideXlab platform

Iñaki F. Trocòniz - One of the best experts on this subject based on the ideXlab platform.

  • JPET #223776 1
    2016
    Co-Authors: Víctor Mangas-sanjuan, María J. Garrido, Núria Buil-bruna, Elena Soto, Iñaki F. Trocòniz
    Abstract:

    Semi-mechanistic cell cycle type based pharmacokinetic/pharmacodynamic model of chemotherapy-induced neutropenic effects of Diflomotecan under different dosing schedule

  • semimechanistic cell cycle type based pharmacokinetic pharmacodynamic model of chemotherapy induced neutropenic effects of Diflomotecan under different dosing schedules
    Journal of Pharmacology and Experimental Therapeutics, 2015
    Co-Authors: Victor Mangassanjuan, Elena Soto, María J. Garrido, Nuria Builbruna, Iñaki F. Trocòniz
    Abstract:

    The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug Diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of Diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.

  • Semimechanistic Cell-Cycle Type–Based Pharmacokinetic/Pharmacodynamic Model of Chemotherapy-Induced Neutropenic Effects of Diflomotecan under Different Dosing Schedules
    The Journal of pharmacology and experimental therapeutics, 2015
    Co-Authors: Víctor Mangas-sanjuan, María J. Garrido, Núria Buil-bruna, Elena Soto, Iñaki F. Trocòniz
    Abstract:

    The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug Diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of Diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.

  • Pharmacodynamic Model of Chemotherapy-Induced Neutropenic Effects of Diflomotecan under Different
    2014
    Co-Authors: Dosing Scheduless, María J. Garrido, Víctor Mangas-sanjuan, Núria Buil-bruna, Elena Soto, Iñaki F. Trocòniz
    Abstract:

    The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug Diflomotecan (9,10-difluoro-homocamptothecin) under dif-ferent dosing schedules to patients (n5 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to dru

  • Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies
    Investigational New Drugs, 2011
    Co-Authors: Elena Soto, Rosendo Obach, Josep M. Cendros, Iñaki F. Trocòniz, Ron J. Keizer, Alwin D. R. Huitema, Jos H. Beijnen, Jan H. M. Schellens, Jantien Wanders, Concepción Peraire
    Abstract:

    In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for Diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For Diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.

Rosendo Obach - One of the best experts on this subject based on the ideXlab platform.

  • Phase I Pharmacological and Bioavailability Study of Oral Diflomotecan (BN80915), a Novel E-Ring-modified Camptothecin Analogue in Adults with Solid Tumors
    2016
    Co-Authors: Hans Gelderblom, Jaap Verweij, Rosendo Obach, Ramon Salazar, George Pentheroudakis, Maja J. A. De Jonge, Martin Devlin, Christel Van Hooije, Francis Seguy, Paola Principe
    Abstract:

    Purpose: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stabil-ity in plasma compared with other topoisomerase I inhibi-tors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacolog-ical and clinical advantages. This Phase I study was per-formed to assess the feasibility of the administration of oral Diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. Experimental Design: An initial i.v. bolus was adminis-tered to assess the bioavailability of Diflomotecan. Fourteen days later, Diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone for

  • Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies
    Investigational New Drugs, 2011
    Co-Authors: Elena Soto, Rosendo Obach, Josep M. Cendros, Iñaki F. Trocòniz, Ron J. Keizer, Alwin D. R. Huitema, Jos H. Beijnen, Jan H. M. Schellens, Jantien Wanders, Concepción Peraire
    Abstract:

    In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for Diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For Diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.

  • A multicentre phase I and pharmacokinetic study of BN80915 (Diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours
    Annals of oncology : official journal of the European Society for Medical Oncology, 2007
    Co-Authors: L. Scott, Jaap Verweij, Rosendo Obach, Paola Principe, Otto Soepenberg, Maja J. A. De Jonge, A. S. Th. Planting, D. Mcgovern, Chris Twelves
    Abstract:

    textabstractBackground: BN80915 (Diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (d×5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity. Patients and methods: Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of Diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of Diflomotecan and its metabolite BN80942 were quantified. Results: Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m2/day. The 0.15-mg/m2dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m2/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation. Conclusions: The MTD and RD of Diflomotecan administered according to a d×5 repeated three weekly are 0.15 and 0.125 mg/m2/ day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan.

  • Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous Diflomotecan in patients with advanced malignant tumours
    Cancer Chemotherapy and Pharmacology, 2006
    Co-Authors: Iñaki F. Trocòniz, Paola Principe, Josep M. Cendros, María J. Garrido, Cristina Segura, Concepción Peraire, Rosendo Obach
    Abstract:

    Purpose : To determine the maximum tolerated dose (MTD) of intravenous (iv) Diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design : Twenty-four patients received a total of 75 cycles of iv Diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m^2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of Diflomotecan were measured after the first drug administration. Results : Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m^2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m^2 was considered the MTD and the dose of 4 mg/m^2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m^2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m^2 and one patient at each dose level of 2, 5, and 6 mg/m^2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of Diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment ( V _c) increased linearly with body surface area (BSA) as: V _c (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions : The MTD and RD after a 20-min iv infusion of Diflomotecan every 3 weeks are 4 and 5 mg/m^2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m^2 of Diflomotecan was 0.86 × 10^9 /L neutrophil cell counts and 11 days, respectively.

  • phase i dose finding study and a pharmacokinetic pharmacodynamic analysis of the neutropenic response of intravenous Diflomotecan in patients with advanced malignant tumours
    Cancer Chemotherapy and Pharmacology, 2006
    Co-Authors: Iñaki F. Trocòniz, Paola Principe, Josep M. Cendros, María J. Garrido, Cristina Segura, Concepción Peraire, Rosendo Obach
    Abstract:

    Purpose: To determine the maximum tolerated dose (MTD) of intravenous (iv) Diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design: Twenty-four patients received a total of 75 cycles of iv Diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of Diflomotecan were measured after the first drug administration. Results: Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m2 was considered the MTD and the dose of 4 mg/m2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m2 and one patient at each dose level of 2, 5, and 6 mg/m2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of Diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (Vc) increased linearly with body surface area (BSA) as: Vc (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions: The MTD and RD after a 20-min iv infusion of Diflomotecan every 3 weeks are 4 and 5 mg/m2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m2 of Diflomotecan was 0.86 × 109 /L neutrophil cell counts and 11 days, respectively.

María J. Garrido - One of the best experts on this subject based on the ideXlab platform.

  • JPET #223776 1
    2016
    Co-Authors: Víctor Mangas-sanjuan, María J. Garrido, Núria Buil-bruna, Elena Soto, Iñaki F. Trocòniz
    Abstract:

    Semi-mechanistic cell cycle type based pharmacokinetic/pharmacodynamic model of chemotherapy-induced neutropenic effects of Diflomotecan under different dosing schedule

  • semimechanistic cell cycle type based pharmacokinetic pharmacodynamic model of chemotherapy induced neutropenic effects of Diflomotecan under different dosing schedules
    Journal of Pharmacology and Experimental Therapeutics, 2015
    Co-Authors: Victor Mangassanjuan, Elena Soto, María J. Garrido, Nuria Builbruna, Iñaki F. Trocòniz
    Abstract:

    The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug Diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of Diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.

  • Semimechanistic Cell-Cycle Type–Based Pharmacokinetic/Pharmacodynamic Model of Chemotherapy-Induced Neutropenic Effects of Diflomotecan under Different Dosing Schedules
    The Journal of pharmacology and experimental therapeutics, 2015
    Co-Authors: Víctor Mangas-sanjuan, María J. Garrido, Núria Buil-bruna, Elena Soto, Iñaki F. Trocòniz
    Abstract:

    The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug Diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of Diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.

  • Pharmacodynamic Model of Chemotherapy-Induced Neutropenic Effects of Diflomotecan under Different
    2014
    Co-Authors: Dosing Scheduless, María J. Garrido, Víctor Mangas-sanjuan, Núria Buil-bruna, Elena Soto, Iñaki F. Trocòniz
    Abstract:

    The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug Diflomotecan (9,10-difluoro-homocamptothecin) under dif-ferent dosing schedules to patients (n5 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to dru

  • Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous Diflomotecan in patients with advanced malignant tumours
    Cancer Chemotherapy and Pharmacology, 2006
    Co-Authors: Iñaki F. Trocòniz, Paola Principe, Josep M. Cendros, María J. Garrido, Cristina Segura, Concepción Peraire, Rosendo Obach
    Abstract:

    Purpose : To determine the maximum tolerated dose (MTD) of intravenous (iv) Diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design : Twenty-four patients received a total of 75 cycles of iv Diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m^2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of Diflomotecan were measured after the first drug administration. Results : Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m^2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m^2 was considered the MTD and the dose of 4 mg/m^2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m^2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m^2 and one patient at each dose level of 2, 5, and 6 mg/m^2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of Diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment ( V _c) increased linearly with body surface area (BSA) as: V _c (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions : The MTD and RD after a 20-min iv infusion of Diflomotecan every 3 weeks are 4 and 5 mg/m^2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m^2 of Diflomotecan was 0.86 × 10^9 /L neutrophil cell counts and 11 days, respectively.

Josep M. Cendros - One of the best experts on this subject based on the ideXlab platform.

  • Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies
    Investigational New Drugs, 2011
    Co-Authors: Elena Soto, Rosendo Obach, Josep M. Cendros, Iñaki F. Trocòniz, Ron J. Keizer, Alwin D. R. Huitema, Jos H. Beijnen, Jan H. M. Schellens, Jantien Wanders, Concepción Peraire
    Abstract:

    In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for Diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For Diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.

  • A multi-centre dose-escalation and pharmacokinetic study of Diflomotecan in patients with advanced malignancy
    Cancer Chemotherapy and Pharmacology, 2009
    Co-Authors: Janet S. Graham, Stephen Falk, Leslie M. Samuel, Josep M. Cendros, T. R. Jeffry Evans
    Abstract:

    Purpose Diflomotecan, a homocamptothecin, targets DNA topoisomerase I. Previous clinical trials have demonstrated a variable degree of dose limiting toxicity. The purpose of this study was to further evaluate the safety and pharmacokinetic profile of a range of Diflomotecan doses administered intravenously. Methods Patients with advanced solid malignant tumours, refractory to standard therapies, with adequate haematologic, renal and hepatic function, received Diflomotecan administered as a 20 min intravenous infusion every 21 days. Cohorts of six patients were recruited sequentially to one of three fixed starting dose groups—2, 4, or 7 mg, with drug administered by fixed-dose rather than dosing by body surface area. Pharmacokinetic analyses were performed on serial blood samples taken over the first 24 h after Diflomotecan administration (cycles 1 and 2). Cytochrome P450 3A4 (CYP3A4) activity was determined by an erythromycin breath test (EBT) prior to Diflomotecan administration in cycles 1 and 2. Results Thirteen patients, were treated with a starting dose of either 2 mg ( n  = 8) or 4 mg ( n  = 5) of Diflomotecan. Dose limiting toxicities (DLTs) were observed in 1 patient in the 2 mg starting dose level (grade 4 neutropenia which lasted for 8 days), and in 2 of 5 patients enrolled at the 4 mg starting dose level (grade 4 neutropenia for 11 days; grade 4 neutropenia leading to withdrawal from the study), and no further dose escalation was performed. Pharmacokinetic analyses revealed a less than dose-proportional increase in Diflomotecan and for the two metabolites BN80942 and P-20, with a magnitude of P-20 exposure similar to the parent drug. There was a high inter-patient variability in Diflomotecan exposure similar to that observed with other camptothecin derivatives. One minor response was observed in a patient with oesophageal cancer. Conclusions Diflomotecan administered as a 20-min intravenous infusion 3-weekly is characterised by a variable pharmacokinetic profile. Alternative oral dosing schedules of Diflomotecan have been shown to display a more predictable PK/PD and safety profile and should be selected for further evaluation in Phase II clinical trials.

  • A multi-centre dose-escalation and pharmacokinetic study of Diflomotecan in patients with advanced malignancy.
    Cancer chemotherapy and pharmacology, 2008
    Co-Authors: Janet Graham, Stephen Falk, Josep M. Cendros, Leslie Samuel, T. R. Jeffry Evans
    Abstract:

    Purpose Diflomotecan, a homocamptothecin, targets DNA topoisomerase I. Previous clinical trials have demonstrated a variable degree of dose limiting toxicity. The purpose of this study was to further evaluate the safety and pharmacokinetic profile of a range of Diflomotecan doses administered intravenously.

  • Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous Diflomotecan in patients with advanced malignant tumours
    Cancer Chemotherapy and Pharmacology, 2006
    Co-Authors: Iñaki F. Trocòniz, Paola Principe, Josep M. Cendros, María J. Garrido, Cristina Segura, Concepción Peraire, Rosendo Obach
    Abstract:

    Purpose : To determine the maximum tolerated dose (MTD) of intravenous (iv) Diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design : Twenty-four patients received a total of 75 cycles of iv Diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m^2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of Diflomotecan were measured after the first drug administration. Results : Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m^2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m^2 was considered the MTD and the dose of 4 mg/m^2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m^2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m^2 and one patient at each dose level of 2, 5, and 6 mg/m^2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of Diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment ( V _c) increased linearly with body surface area (BSA) as: V _c (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions : The MTD and RD after a 20-min iv infusion of Diflomotecan every 3 weeks are 4 and 5 mg/m^2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m^2 of Diflomotecan was 0.86 × 10^9 /L neutrophil cell counts and 11 days, respectively.

  • phase i dose finding study and a pharmacokinetic pharmacodynamic analysis of the neutropenic response of intravenous Diflomotecan in patients with advanced malignant tumours
    Cancer Chemotherapy and Pharmacology, 2006
    Co-Authors: Iñaki F. Trocòniz, Paola Principe, Josep M. Cendros, María J. Garrido, Cristina Segura, Concepción Peraire, Rosendo Obach
    Abstract:

    Purpose: To determine the maximum tolerated dose (MTD) of intravenous (iv) Diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design: Twenty-four patients received a total of 75 cycles of iv Diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of Diflomotecan were measured after the first drug administration. Results: Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m2 was considered the MTD and the dose of 4 mg/m2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m2 and one patient at each dose level of 2, 5, and 6 mg/m2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of Diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (Vc) increased linearly with body surface area (BSA) as: Vc (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions: The MTD and RD after a 20-min iv infusion of Diflomotecan every 3 weeks are 4 and 5 mg/m2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m2 of Diflomotecan was 0.86 × 109 /L neutrophil cell counts and 11 days, respectively.

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  • Phase I Pharmacological and Bioavailability Study of Oral Diflomotecan (BN80915), a Novel E-Ring-modified Camptothecin Analogue in Adults with Solid Tumors
    2016
    Co-Authors: Hans Gelderblom, Jaap Verweij, Rosendo Obach, Ramon Salazar, George Pentheroudakis, Maja J. A. De Jonge, Martin Devlin, Christel Van Hooije, Francis Seguy, Paola Principe
    Abstract:

    Purpose: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stabil-ity in plasma compared with other topoisomerase I inhibi-tors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacolog-ical and clinical advantages. This Phase I study was per-formed to assess the feasibility of the administration of oral Diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. Experimental Design: An initial i.v. bolus was adminis-tered to assess the bioavailability of Diflomotecan. Fourteen days later, Diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone for

  • A multicentre phase I and pharmacokinetic study of BN80915 (Diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours
    Annals of oncology : official journal of the European Society for Medical Oncology, 2007
    Co-Authors: L. Scott, Jaap Verweij, Rosendo Obach, Paola Principe, Otto Soepenberg, Maja J. A. De Jonge, A. S. Th. Planting, D. Mcgovern, Chris Twelves
    Abstract:

    textabstractBackground: BN80915 (Diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (d×5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity. Patients and methods: Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of Diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of Diflomotecan and its metabolite BN80942 were quantified. Results: Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m2/day. The 0.15-mg/m2dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m2/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation. Conclusions: The MTD and RD of Diflomotecan administered according to a d×5 repeated three weekly are 0.15 and 0.125 mg/m2/ day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan.

  • Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous Diflomotecan in patients with advanced malignant tumours
    Cancer Chemotherapy and Pharmacology, 2006
    Co-Authors: Iñaki F. Trocòniz, Paola Principe, Josep M. Cendros, María J. Garrido, Cristina Segura, Concepción Peraire, Rosendo Obach
    Abstract:

    Purpose : To determine the maximum tolerated dose (MTD) of intravenous (iv) Diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design : Twenty-four patients received a total of 75 cycles of iv Diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m^2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of Diflomotecan were measured after the first drug administration. Results : Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m^2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m^2 was considered the MTD and the dose of 4 mg/m^2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m^2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m^2 and one patient at each dose level of 2, 5, and 6 mg/m^2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of Diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment ( V _c) increased linearly with body surface area (BSA) as: V _c (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions : The MTD and RD after a 20-min iv infusion of Diflomotecan every 3 weeks are 4 and 5 mg/m^2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m^2 of Diflomotecan was 0.86 × 10^9 /L neutrophil cell counts and 11 days, respectively.

  • phase i dose finding study and a pharmacokinetic pharmacodynamic analysis of the neutropenic response of intravenous Diflomotecan in patients with advanced malignant tumours
    Cancer Chemotherapy and Pharmacology, 2006
    Co-Authors: Iñaki F. Trocòniz, Paola Principe, Josep M. Cendros, María J. Garrido, Cristina Segura, Concepción Peraire, Rosendo Obach
    Abstract:

    Purpose: To determine the maximum tolerated dose (MTD) of intravenous (iv) Diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design: Twenty-four patients received a total of 75 cycles of iv Diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of Diflomotecan were measured after the first drug administration. Results: Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m2 was considered the MTD and the dose of 4 mg/m2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m2 and one patient at each dose level of 2, 5, and 6 mg/m2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of Diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (Vc) increased linearly with body surface area (BSA) as: Vc (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions: The MTD and RD after a 20-min iv infusion of Diflomotecan every 3 weeks are 4 and 5 mg/m2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m2 of Diflomotecan was 0.86 × 109 /L neutrophil cell counts and 11 days, respectively.

  • Oral absorption of Diflomotecan, a new E-ring modified camptothecin analogue, administered as soft-gel capsule
    Journal of Clinical Oncology, 2004
    Co-Authors: Thierry Lesimple, Paola Principe, J. Egreteau, P. Fumoleau, Mario Campone, Alain Lortholary, Patrick Soulié, C. Peraire, B. Le Mosquet, C. Granger
    Abstract:

    2045 Background: The E-ring modified camptothecin analogue Diflomotecan (BN80915, Ipsen Group) is a new topoisomerase I inhibitor. Its clinical development includes five phase I studies using the iv and oral routes of administration. The trial reported here is in progress to explore the safety, PK and PK/PD haematotoxicity correlation of Diflomotecan delivered as a soft-gel capsule, daily for 5 days, every 3 weeks. Methods: To assess the absolute bioavailability, patients received an iv administration at the same daily dose 2 weeks prior the soft-gel capsules. To date, five daily dose levels have been explored (0.15, 0.20, 0.25, 0.30 and 0.35 mg) and 17 patients have been treated with Diflomotecan. Results: Three patients have been included at each dose level, except at the RD (0.30 mg), the cohort being extended to six patients. The MTD has been reached at 0.35 mg since 2 out of 3 patients experienced DLTs (neutropenia G4 > 7 days and neutropenia-induced cycle delay). Mean exposure at 0.35 mg was 10.1±4....