Troconiz, I.F. (Iñaki F.)
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- Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors(Springer Science and Business Media LLC, 2019) Ciccolini, J. (Joseph); Coen-van-Hasselt, J.G. (J. G.); Centanni, M. (Maddalena); Troconiz, I.F. (Iñaki F.); Moes, D.J.A.R. (Dirk Jan A. R.)Immune checkpoint inhibitors (ICIs) have demonstrated signifcant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20–40% of patients will show long-lasting survival. Further clarifcation of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the signifcant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efcacy and safety, the pharmacodynamics (PD), of ICIs, including exposure–response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure–response analysis. Biomarkers to identify patients benefting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.
- A population pharmacodynamic model for lactate dehydrogenase and neuron specific enolase to predict tumor progression in small cell lung cancer patients(Springer Link, 2014) Martin-Algarra, S. (Salvador); Ribba, B. (B.); Troconiz, I.F. (Iñaki F.); Lopez-Picazo, J.M. (José M.); Buil-Bruña, N (Núria); Moreno-Jimenez, M. (Marta)The development of individualized therapies poses a major challenge in oncology. Significant hurdles to overcome include better disease monitoring and early prediction of clinical outcome. Current clinical practice consists of using Response Evaluation Criteria in Solid Tumors (RECIST) to categorize response to treatment. However, the utility of RECIST is restricted due to limitations on the frequency of measurement and its categorical rather than continuous nature. We propose a population modeling framework that relates circulating biomarkers in plasma, easily obtained from patients, to tumor progression levels assessed by imaging scans (i.e., RECIST categories). We successfully applied this framework to data regarding lactate dehydrogenase (LDH) and neuron specific enolase (NSE) concentrations in patients diagnosed with small cell lung cancer (SCLC). LDH and NSE have been proposed as independent prognostic factors for SCLC. However, their prognostic and predictive value has not been demonstrated in the context of standard clinical practice. Our model incorporates an underlying latent variable (“disease level”) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment; these assumptions are in agreement with the known physiology of SCLC and these biomarkers. Our model predictions of unobserved disease level are strongly correlated with disease progression measured by RECIST criteria. In conclusion, the proposed framework enables prediction of treatment outcome based on circulating biomarkers and therefore can be a powerful tool to help clinicians monitor disease in SCLC.
- Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies(Boston Springer US, 2011) Wanders, J. (Jantien); Peraire, C. (Concepción); Keizer, R. (Ron); Huitema, A.D.R (Aldwin D. R.); Karlsson, M.O. (Mats O.); Troconiz, I.F. (Iñaki F.); Soto, E. (Elena); Friberg, L. (Lena); Schellens, J.H.M (Jan H.M.); Beijnen, J.H. (Jos H.); Obach, R. (Rosendo); Cendros, J.M. (Josep Maria)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.
- Mechanistic characterization of oscillatory patterns in unperturbed tumor growth dynamics: The interplay between cancer cells and components of tumor microenvironment(PLOS, 2023) Mangas-Sanjuan, V. (Víctor); Parra-Guillen, Z.P. (Zinnia Patricia); Troconiz, I.F. (Iñaki F.); Sancho-Araiz, A. (Aymara); Ardanza-Trevijano, S. (Sergio); Bragard, J. (Jean)Mathematical modeling of unperturbed and perturbed tumor growth dynamics (TGD) in preclinical experiments provides an opportunity to establish translational frameworks. The most commonly used unperturbed tumor growth models (i.e. linear, exponential, Gompertz and Simeoni) describe a monotonic increase and although they capture the mean trend of the data reasonably well, systematic model misspecifications can be identified. This represents an opportunity to investigate possible underlying mechanisms controlling tumor growth dynamics through a mathematical framework. The overall goal of this work is to develop a data-driven semi-mechanistic model describing non-monotonic tumor growth in untreated mice. For this purpose, longitudinal tumor volume profiles from different tumor types and cell lines were pooled together and analyzed using the population approach. After characterizing the oscillatory patterns (oscillator half-periods between 8–11 days) and confirming that they were systematically observed across the different preclinical experiments available (p<10−9), a tumor growth model was built including the interplay between resources (i.e. oxygen or nutrients), angiogenesis and cancer cells. The new structure, in addition to improving the model diagnostic compared to the previously used tumor growth models (i.e. AIC reduction of 71.48 and absence of autocorrelation in the residuals (p>0.05)), allows the evaluation of the different oncologic treatments in a mechanistic way. Drug effects can potentially, be included in relevant processes taking place during tumor growth. In brief, the new model, in addition to describing non-monotonic tumor growth and the interaction between biological factors of the tumor microenvironment, can be used to explore different drug scenarios in monotherapy or combination during preclinical drug development.
- Disentangling anti-tumor response of immunotherapy combinations: a physiologically based framework for V937 oncolytic virus and Pembrolizumab(Wiley, 2024) Parra-Guillen, Z.P. (Zinnia Patricia); Troconiz, I.F. (Iñaki F.); Sancho-Araiz, A. (Aymara); Freshwater, T. (Tomoko)Immuno-oncology (IO) is a growing strategy in cancer treatment. Oncolytic viruses (OVs) can selectively infect cancer cells and lead to direct and/or immune-dependent tumor lysis. This approach represents an opportunity to potentiate the efficacy of immune checkpoint inhibitors (ICI), such as pembrolizumab. Currently, there is a lack of comprehensive quantitative models for the aforementioned scenarios. In this work, we developed a mechanistic framework describing viral kinetics, viral dynamics, and tumor response after intratumoral (i.t.) or intravenous (i.v.) administration of V937 alone or in combination with pembrolizumab. The model accounts for tumor shrinkage, in both injected and non-injected lesions, induced by: viral-infected tumor cell death and activated CD8 cells. OV-infected tumor cells enhanced the expansion of CD8 cells, whereas pembrolizumab inhibits their exhaustion by competing with PD-L1 in their binding to PD-1. Circulating viral levels and treatment effects on tumor volume were adequately characterized in all the different scenarios. This mechanistic-based model has been developed by combining top-down and bottom-up approaches and provides individual estimates of viral and ICI responses. The robustness of the model is reflected by the description of the tumor size time profiles in a variety of clinical scenarios. Additionally, this platform allows us to investigate not only the contribution of processes related to the viral kinetics and dynamics on tumor response, but also the influence of its interaction with an ICI. Additionally, the model can be used to explore different scenarios aiming to optimize treatment combinations and support clinical development.
- Prognostic value of serum paraprotein response kinetics in patients with newly diagnosed multiple myeloma(2022) Blanchard, M.J. (María Jesús); González, M.E. (María Esther); Cedena, M.T. (María Teresa); Casado, L.F. (Luis Felipe); Krsnik, I. (Isabel); Ríos, R. (Rafael) de los; Gironella, M. (Mercedes); Bladé, J. (Joan); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Troconiz, I.F. (Iñaki F.); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Lopez-Anglada, L. (Lucia); Arguiñano, J.M. (José María); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Rodriguez-Otero, P. (Paula); Paiva, B. (Bruno); Jarque, I. (Isidro); Oriol, A. (Albert); Marti, J.M. (J.M.); Sureda-Balari, A. M. (Anna Maria); González-Rodriguez, A.P. (Ana Pilar); Bargay, J. (Joan); Gonzalez-Montes, Y. (Yolanda); Jiménez-Ubieto, A. (Ana); San-Miguel, J.F. (Jesús F.); Tamariz-Amador, L.E. (Luis Esteban); Cabañas, V. (Valentín)Introduction Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a “resistance” parameter that reflects the stagnation in the response after an initial descent. Results Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P = .02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P = .02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P < .002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies.
- Application of different methods to formulate PEG-liposomes of oxaliplatin: Evaluation in vitro and in vivo(Elsevier, 2012) Tros-de-Ilarduya, C. (Conchita); Troconiz, I.F. (Iñaki F.); Zalba, S. (Sara); Navarro-Blasco, I. (Iñigo); Garrido, M.J. (María Jesús)In this work the film method (FM), reverse-phase evaporation (REV) and the heating method (HM) were applied to prepare PEG-coated liposomes of oxaliplatin with natural neutral and cationic lipids, respectively. The formulations developed with the three methods, showed similar physicochemical characteristics, except in the loading of oxaliplatin, which was statistically lower (P<0.05) using the HM. The incorporation of a semi-synthetic lipid in the formulation developed by FM, provided liposomes with a particle size of 115 nm associated to the lowest polydispersity index and the highest drug loading, 35%, compared to the other two lipids, suggesting an increase of the membrane stability. That stability was also evaluated according to the presence of cholesterol, the impact of the temperature, and the application of different cryoprotectans during the lyophilization. The results indicated long-term stability of the developed formulation, because after its intravenous in-vivo administration to HT-29 tumor bearing mice was able to induce an inhibition of tumor growth statistically higher (P < 0.05) than the inhibition caused by the free drug. In conclusion, the FM was the simplest method in comparison with REV and HM to develop in vivo stable and efficient PEG-coated liposomes of oxaliplatin with a loading higher than those reported for REV.
- A pharmacokinetic-pharmacodynamic assessment of oral antibiotics for pyelonephritis(Springer Science and Business Media LLC, 2019) Cattral, J.W.S. (J. W. S.); Troconiz, I.F. (Iñaki F.); Asin, E. (E.); Freeman, J. (J.); Kirby, A. (A.)Antibiotic resistance to oral antibiotics recommended for pyelonephritis is increasing. The objective was to determine if there is a pharmacological basis to consider alternative treatments/novel dosing regimens for the oral treatment of pyelonephritis. A systematic review identified pharmacokinetic models of suitable quality for a selection of antibiotics with activity against Escherichia coli. MIC data was obtained for a population of E. coli isolates derived from patients with pyelonephritis. Pharmacokinetic/pharmacodynamic (PK/PD) simulations determined probability of target attainment (PTA) and cumulative fraction response (CFR) values for sub-populations of the E. coli population at varying doses. There are limited high-quality models available for the agents investigated. Pharmacokinetic models of sufficient quality for simulation were identified for amoxicillin, amoxicillin-clavulanic acid, cephalexin, ciprofloxacin, and fosfomycin trometamol. These antibiotics were predicted to have PTAs ≥ 0.85 at or below standard doses for the tested E. coli population including cephalexin 1500 mg 8 hourly for 22% of the population (MIC ≤ 4 mg/L) and ciprofloxacin 100 mg 12 hourly for 71% of the population (MIC ≤ 0.06 mg/L). For EUCAST-susceptible E. coli isolates, doses achieving CFRs ≥ 0.9 included amoxicillin 2500 mg 8 hourly, cephalexin 4000 mg 6 hourly, ciprofloxacin 200 mg 12 hourly, and 3000 mg of fosfomycin 24 hourly. Limitations in the PK data support carrying out additional PK studies in populations of interest. Oral antibiotics including amoxicillin, amoxicillin-clavulanic acid, and cephalexin have potential to be effective for a proportion of patients with pyelonephritis. Ciprofloxacin may be effective at lower doses than currently prescribed.
- Population Pharmacokinetics of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy(Adis Press, 2008) Maynar, J. (Javier); Bueno, L. (Lorea); Pedraz, J.L. (José Luis); Rodriguez-Gascón, A. (Alicia); Solinis, M.A. (María Ángeles); Troconiz, I.F. (Iñaki F.); Sanchez-Izquierdo, J.A. (José Ángel); Isla, A. (Arantxazu)BACKGROUND AND OBJECTIVE: Meropenem is a carbapenem antibacterial frequently prescribed for the treatment of severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT. PATIENTS AND METHODS: A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CL(CR)), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied. RESULTS: The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CL(CR) was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CL(CR) on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 x CL(CR) for septic patients and CL = 6.63 + 0.72 x CL(CR) for polytraumatized patients). The volume of distribution of the central compartment (V(1)) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V(1) were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of > or =4 mg/L are isolated. Infections caused by pathogens with an MIC of > or =8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary. CONCLUSION: A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CL(CR) and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT.
- Modelling the Anti-Migraine Effects of BIBN 4096 BS(Adis Press, 2006) Troconiz, I.F. (Iñaki F.); Schaefer, H. (Hans); Tillmann, C. (Christiane); Roth, W. (Willy); Wolters, J.M. (Jan Markus)Migraine attacks are associated with release of the calcitonin gene-related peptide (CGRP) from trigeminal nerves. BIBN 4096 BS is the first CGRP receptor antagonist tested in humans showing response rates similar to those reported for triptans, together with very good safety and tolerability profiles. The objective of the current study is to develop a population pharmacokinetic/pharmacodynamic model resembling the mechanism of action of BIBN 4096 BS, and to extract by model-based simulations dosage formulations and pharmacodynamic properties that can assist in the development of CGRP receptor antagonists. METHODS: 126 patients with an acute moderate to severe migraine attack lasting not more than 6 hours were enrolled in this phase IIa study. BIBN 4096 BS was given as a single intravenous 10-minute infusion at different dose levels ranging from 0.25 to 10 mg. Severity of headache was measured up to 24 hours. Patients who did not show pain relief by 2 hours were allowed to take rescue medication. Severity of headache and time to rescue medication measurements were fitted simultaneously using logistic regression and time-to-event analysis with nonlinear mixed-effect modelling software NONMEM version V. RESULTS: Severity of headache and time to rescue medication were described as a function of the fraction of the CGRP receptors blocked by BIBN 4096 BS, and controlled by the second- and first-order rate constants representing the onset (k(on)) and offset (k(off)) of the anti-migraine effects. The model predicted a slow rate of offset of the anti-migraine effect (half-life of k(off) = 21 hours). The model developed described the data well and was validated properly. DISCUSSION: A semi-mechanistic population pharmacokinetic/pharmacodynamic model has been developed for the anti-migraine effects of BIBN 4096 BS, characterised by the severity of headache and time to rescue medication. Simulations exploring the effect of the rate of absorption, bioavailability after an extravascular administration and the rate of activation/inactivation of the anti-migraine effect were performed. The rate of absorption seems to play a minor role; however, at least bioavailability fractions of 0.2-0.3 should be obtained. With regard to the kinetics of the anti-migraine effect, and to achieve a response rate of 60% at 2 hours, values of k(on) should be > 0.081 mL/ng/h. At later times after administration higher values of k(off) are associated with faster offset of the response. The simulations showed that molecules with high k(on) and low k(off) values are the most promising.