Iñaki F Trocóniz

Iñaki F Trocóniz
Universidad de Navarra | UNAV · Pharmacometrics & Systems Pharmacology

Professor

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254
Publications
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Publications

Publications (254)
Article
Full-text available
Background IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem a...
Article
Full-text available
There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets a...
Article
Objectives Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic (PK) model for piperacillin to evaluate the efficacy of standard dosing in childre...
Article
Full-text available
Background and purpose: Acute intermittent porphyria (AIP) is a rare disease caused by a genetic mutation that impairs the hepatic activity of the porphobilinogen-deaminase (PBGD) enzyme. We aimed to develop a mechanistic model for the enzymatic restoration effects of a novel therapy based on the administration of different formulations of recombi...
Article
Full-text available
PurposeBoth inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of cr...
Article
Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9...
Poster
Full-text available
Introduction: The application of population pharmacokinetics (PopPK) modelling to data from bioequivalence studies can provide valuable insight on the pharmacokinetics (PK) and identify covariates that might explain the variability in exposure of drugs, as population used on these trials usually includes healthy subjects that are highly standardize...
Article
Full-text available
Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80-90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infe...
Article
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V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated in vitro and in vivo data from six d...
Article
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Immuno-oncology (IO) focuses on the ability of the immune system to detect and eliminate cancer cells. Since the approval of the first immune checkpoint inhibitor, immunotherapies have become a major player in oncology treatment and, in 2021, represented the highest number of approved drugs in the field. In spite of this, there is still a fraction...
Article
Aims: The aims of this work were to build a semi-mechanistic tumor growth inhibition (TGI) model for metastatic colorectal cancer (mCRC) patients receiving either cetuximab+chemotherapy or chemotherapy alone and to identify early predictors of overall survival (OS). Methods: A total of 1716 patients from four mCRC clinical studies were included...
Article
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Background The immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (α-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox...
Article
Full-text available
Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possibl...
Article
Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell p...
Article
Full-text available
Background: Ceftolozane-tazobactam is a new antibiotic against multidrug-resistant pathogens such as Pseudomonas aeruginosas. Ceftolozane-tazobactam dosage is still uncertain in children, especially in those with renal impairment or undergoing continuous renal replacement therapy (CRRT). Methods: Evaluation of different ceftolozane-tazobactam dosin...
Preprint
Full-text available
Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possibl...
Article
The model-informed drug discovery and development paradigm is now well established among the pharmaceutical industry and regulatory agencies. This success has been mainly due to the ability of pharmacometrics to bring together different modeling strategies, such as population pharmacokinetics/pharmacodynamics (PK/PD) and systems biology/pharmacolog...
Article
Full-text available
This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naïve and schizophrenic (SCZ-like) rats and developed a semi-mechanistic model to describe changes in both compartments following administration of drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/mL) presented 166 {plus minus} 39 nm, low polyd...
Article
Identification of optimal schedules for combination drug administration relies on accurately estimating the correct pharmacokinetics, pharmacodynamics, and drug interaction effects. Misspecification of pharmacokinetics can lead to wrongly predicted timing or order of treatments, leading to schedules recommended on the basis of incorrect assumptions...
Article
Full-text available
Advanced melanoma remains a disease with poor prognosis. Several serologic markers have been investigated to help monitoring and prognostication, but to date only lactate dehydrogenase (LDH) has been validated as a standard prognostic factor biomarker for this disease by the American Joint Committee on Cancer. In this work, we built a semi-mechanis...
Article
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Total tumor size (TS) metrics used in TS models in oncology do not consider tumor heterogeneity, which could help to better predict drug efficacy. We analyzed individual target lesions (iTLs) of patients with metastatic colorectal carcinoma (mCRC) to determine differences in TS dynamics by using the ClassIfication Clustering of Individual Lesions (...
Article
Background and purpose: Acute intermittent porphyria (AIP) results from haploinsufficiency of the porphobilinogen deaminase (PBGD) gene encoding the third enzyme in the heme biosynthesis pathway. As liver is the main organ of pathology for AIP, emerging therapies that restore enzyme hepatic levels are appealing. The objective of this work was to d...
Article
Aim: Busulfan and treosulfan are cytotoxic agents used in the conditioning regime prior to paediatric hematopoietic stem cell transplantation (HSCT). These agents cause suppression of myeloid cells leaving patients severely immunocompromised in the early post-HSCT period. The main objectives were: (i) to establish a mechanistic PKPD model for the...
Article
Full-text available
The aim of this work is to build a mechanistic multi‐scale pharmacokinetic model for the anticancer drug gemcitabine (dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumour tissue in dependence of physiological and genetic patient characteristics, and, more in general, to explore the capabilities and limitations of...
Article
Crohn's Disease (CD) is a complex inflammatory bowel disease whose pathogenesis appears to involve several immunological defects causing functional impairment of the gut. Its complexity and the reported loss of effectiveness over time of standard of care together with the increase in its worldwide incidence require the application of techniques aim...
Article
Full-text available
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 ant...
Article
In the oncology field, understanding the relationship between the dose administered and the exerted effect is particularly important because of the narrow therapeutic index associated with anti-cancer drugs and the high interpatient variability. Therefore, in this review, we provide a critical perspective of the different methods of characterising...
Article
Over the past decade, the insulin‐like growth factor (IGF)‐signalling pathway has gained substantial interest as potential therapeutic target in oncology. Xentuzumab, a humanised IgG1 monoclonal antibody, binds to IGF‐I and IGF‐II thereby inhibiting the downstream signalling essential for survival and tumour growth. This pathway is further regulate...
Article
The liver is a well-known immunotolerogenic environment, which provides the adequate setting for liver infectious pathogens persistence such as the hepatitis B virus (HBV). Consequently, HBV infection can derive in the development of chronic disease in a proportion of the patients. If this situation persists in time, chronic hepatitis B (CHB) would...
Article
Full-text available
Background Perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacok...
Data
Study’s underlying anonymized data set. (XLSX)
Article
Immunoliposomes (ILs), obtained with monoclonal antibodies (mAbs) decorating the liposome surface, are used for cancer treatment. These mAbs provide the recognition of molecules upregulated in cancer cells, like Programmed Death-Ligand 1 (PD-L1), an immune-checkpoint involved in tumor resistance, forming a complex that blocks this molecule and ther...
Article
Aims: Immunotherapy is a rising alternative to traditional treatment in breast cancer (BC) patients in order to transform cold into hot immune enriched tumours and improve responses and outcome. A computational modelling approach was applied to quantify modulation effects of immunotherapy and chemotherapy response on tumour shrinkage and progressio...
Article
The aim of this evaluation was to predict tumour response to gemcitabine in patients with advanced pancreas or ovarian cancer using pre-clinical data obtained from xenograft tumour-bearing mice. The approach consisted of building a translational model combining pre-clinical pharmacokinetic–pharmacodynamic (PKPD) models and parameters, with dosing p...
Article
Full-text available
Immune checkpoint inhibitors (ICIs) have demonstrated significant 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 clarification of factors related to treatment response can support improvements in clinical outcome and guide...
Article
Full-text available
Standard bolus-dosed antibiotic prophylaxis may not inhibit growth of antibiotic resistant colonic bacteria, a cause of SSIs after colorectal surgery. An alternative strategy is continuous administration of antibiotic throughout surgery, maintaining concentrations of antibiotics that inhibit growth of resistant bacteria. This study is a pilot compa...
Article
Full-text available
This report provides a brief description of the 2018 RedIF Congress that took place in Guadalajara (Mexico), on November 7‐9. The meeting aimed to foster modeling & simulation approaches for drug development, regulatory sciences and clinical application in Latin America. Organizations that cosponsored the meeting were: University of Guadalajara, In...
Article
Full-text available
Objectives: To evaluate the relationship between pharmacokinetic descriptors of dexmedetomidine (predicted area under the curve during the procedure, predicted plasma level at the end of the procedure, and duration of procedure) and sedation depth (proportion of time with bispectral index < 85 during the procedure) with recovery time after ambulat...
Article
Introduction: Acute intermittent porphyria (AIP) is characterized by hepatic over-production of the heme precursors when aminolevulinic acid (ALA)-synthase 1 is induced by endogenous or environmental factors. The aim of this study was to develop a semi-mechanistic computational model to characterize urine accumulation of heme precursors during acu...
Article
Cytogenetic analysis is still an important and mandatory component of Acute Myeloid Leukemia (AML) diagnosis and prognosis. Pretreatment cytogenetic and molecular genetic findings are one of the major independent prognostic markers in AML, and they determine chemotherapy response and outcome. However, cytogenetic does not provide alternative treatm...
Article
Full-text available
Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3 + 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug...
Article
In a recent multicenter population pharmacokinetic study of ciprofloxacin administered to children suffering from complicated urinary tract infection (cUTI), the apparent volume of distribution (V) and total plasma clearance (CL) were decreased by 83.6% and 41.5% respectively, compared to healthy children. To understand these differences, a physiol...
Article
Background and Objectives Lurbinectedin is an inhibitor of RNA polymerase II currently under clinical development for intravenous administration as a single agent and in combination with other anti-tumor agents for the treatment of several tumor types. The objective of this work was to develop a population-pharmacokinetic model in this patient sett...
Article
Marketed formulations of erythropoietin (EPO) ior®EPOCIM, MIRCERA® and two newly developed pegylated-EPO analogues (PEG-EPO 32 and 40 kDa) formulations were intravenously administered to New Zealand rabbits. A semi-mechanistic Pharmacokinetic/Pharmacodynamic (PK/PD) model describing in a simultaneous and integrated form the time course of reticuloc...
Article
Full-text available
Xenograft mice are largely used to evaluate the efficacy of oncological drugs during preclinical phases of drug discovery and development. Mathematical models provide a useful tool to quantitatively characterise tumour growth dynamics and also optimise upcoming experiments. To the best of our knowledge, this is the first report where unperturbed gr...
Article
Full-text available
Author summary Mathematical models of the disease processes are widely used in computational biology to quantitatively describe the time course of disease progression and are often linked to pharmacokinetic–pharmacodynamic models in order to evaluate the effect of drug treatment on disease. Once the models are built from observed information and/or...
Data
Mathematics behind optimal control methods. Summary of the mathematics involving necessary and sufficient conditions for optimality in dynamic systems. (PDF)
Data
Original pharmacokinetic model of triptorelin. Original pharmacokinetic model of triptorelin from [3]. Dinf is the duration of the zero-order absorption process; KA1 and KA2 are the first order rate constants of the first and second depot compartments respectively; F1, F2 and Finf represent the fraction of the drug associated with the first and sec...
Data
APMonitor MATLAB code and datasets. APMonitor Optimization Suite code for MATLAB and datasets to reproduce the results of this work. (RAR)
Article
Pharmacokinetic modeling is widely used to support decision making in translational medicine and patient care, traditionally using circulating drug exposure. The development of mechanistic computational models that integrate drug concentrations at the site of action making use of existing knowledge opens a new paradigm in optimal dosing.
Article
Full-text available
Motivation The literature on complex diseases is abundant but not always quantitative. This is particularly so for Inflammatory Bowel Disease (IBD), where many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. We propose the elaborati...
Data
IBD Network Repository. Table of nodes and interactions supported by references. (PDF)
Data
Supporting_Information_Methods. Document with detailed description of the methodology. (DOCX)
Data
IBD_validation. Table of alterations in patients of IBD network nodes supported by references. (PDF)
Data
IBD.txt. Text document with the Boolean functions written in SPIDDOR nomenclature for iBD simulation. (TXT)
Data
User_Guide_SPIDDOR_IBD.html. Html tutorial about how to reproduce the results from the present manuscript with the SPIDDOR package. (HTML)
Article
A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the...
Data
Supplementary Table S1 Examples of diseases that have clinical analogs in dogs. References can be accessed online using the text hyperlink.
Article
The aim of this evaluation was to characterize the impact of the tumour size (TS) effects driven by the anticancer drug gemcitabine on overall survival (OS) in patients with advanced pancreatic cancer by building and validating a predictive semi-mechanistic joint TS-OS model. TS and OS data were obtained from one phase II and one phase III study wh...
Article
Full-text available
Objective: To describe quantitatively the variability associated to the pharmacokinetic (PK) processes of clarithromycin (CLA) in Mexican hospitalized patients with respiratory infection and to determine whether the 6-beta-hydroxycortisol(6p-OHC)/cortisol ratio, among other factors would partially explain such variability. Materials and Methods: Fi...