Eduardo Asín-Prieto

Lurbinectedin is an oncogenic transcription inhibitor indicated for the treatment of small cell lung cancer (SCLC), which has also shown activity against other malignancies. In this work, two independent cohorts of 180 (discovery cohort) and 719 (validation cohort) cancer patients receiving lurbinectedin in Phases I, II, or III clinical trials were enrolled. Using a population pharmacokinetic (popPK) model of the discovery cohort, patients with extremely high (n = 10, cohort 1) and low (n = 10, cohort 2) etaCL values (i.e., a variable used as a surrogate of unexplained CL interindividual variability) were identified. They were sequenced for 42 candidate genes involved in lurbinectedin pharmacokinetics. A total of 34 variants located in 20 genes were significantly associated with lurbinectedin etaCL; the best nine hits (located in CYP3A5, CYP3A4, ABCB1, ARNT, NR5A2, NR1H4, and FOXA3) were subsequently genotyped in the validation cohort. A strong additive association between CYP3A4 and CYP3A5 genotypes (informed as a CYP3A activity score [AS] variable) and lurbinectedin clearance (CL) and exposure was confirmed, for example, patients with an AS of 3, 2, or 1 showed a 2.3‐, 1.6‐, and 1.5‐fold higher total lurbinectedin CL compared to those with an AS of 0 and 2.3‐, 1.8‐, and 1.6‐fold higher unbound lurbinectedin CL. In conclusion, preemptive CYP3A genotyping may offer a valuable approach for personalizing treatment with lurbinectedin in cancer patients.

Background/Objectives: Pathophysiological variability in patients with cancer is associated with differences in responses to pharmacotherapy. In this work, we aimed to describe the demographic characteristics and hematological, biochemical, and coagulation variables in a large oncology cohort and to develop, optimize, and provide open access to modeling equations for the estimation of variables potentially relevant in pharmacokinetic modeling. Methods: Using data from 1793 patients with cancer, divided into training (n = 1259) and validation (n = 534) datasets, a modeling network was developed and used to simulate virtual oncology populations. All analyses were conducted in RStudio 4.3.2 Build 494. Results: The simulation network based on sex, age, biogeographic origin/ethnicity, and tumor type (fixed or primary factors) was successfully validated, able to predict age, height, weight, alpha-1-acid glycoprotein, albumin, hemoglobin, C-reactive protein and lactate dehydrogenase serum levels, platelet–lymphocyte and neutrophil–lymphocyte ratios, and hematocrit. This network was then successfully extrapolated to simulate the laboratory variables of eight oncology populations (n = 1200); only East Asians, Sub-Saharan Africans, Europeans, only males, females, patients with an ECOG performance status equal to 2, and only patients with pancreas cancer or ovarian cancer. Conclusions: this network constitutes a valuable tool to predict relevant characteristics/variables of patients with cancer, which may be useful in the evaluation and prediction of pharmacokinetics in virtual oncology populations, as well as for model-based optimization of oncology treatments.

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

Crohn9s 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 aiming to find new therapeutic strategies. Currently, systems pharmacology (SP) modelling has been gaining importance as it integrates the available knowledge of the system into a single computational model. In this work, the following workflow for robust application of SP modelling was followed: (i) scope definition, (ii) species selection and circulating plasma levels based on a search in the literature, (iii) representation of model topology and parametrization of the interactions, after literature data extraction and curation, and the implementation of ordinary differential equations in SimBiology® (MATLAB®vR2018b) and (iv) model curation and evaluation by visual comparison of simulated interleukins (ILs) concentrations with the reported levels in plasma, and sensitivity analysis performed to confirm model robustness and identify the most influential parameters. Finally, (v) exposure to two dose levels of recombinant human IL10 was evaluated by simulation and comparison with reported clinical study results. In summary, we present a QSP model for the main ILs involved in CD developed using a standardized methodology and supported by a comprehensive repository summarizing the most relevant literature in the field. However, it has to be taken into account that external validation is still pending as available clinical data was primarily used for model training. SIGNIFICANCE STATEMENT Crohn9s Disease (CD) is a complex heterogeneous inflammatory bowel disorder. Systems pharmacology (SP) modelling offers a great opportunity for integration of the available knowledge on the disease using a computational framework. As a result of this work, a comprehensive repository along with a QSP model for the main ILs involved in CD is provided. This model is useful for the in silico evaluation of biomarkers and potential therapeutic targets and can be adapted to address research gaps regarding CD.

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC₂₄/MIC > 80 and 100% T_>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

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.

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 comparing bolus-continuous infusion with bolus-dosed cefuroxime prophylaxis in colorectal surgery. This is a pilot randomised controlled trial in which participants received cefuroxime bolus-infusion (intervention arm) targeting free serum cefuroxime concentrations of 64 mg/L, or 1.5 g cefuroxime as a bolus dose four-hourly (standard arm). Patients in both arms received metronidazole (500 mg intravenously). Eligible participants were adults undergoing colorectal surgery expected to last for over 2 h. Results were analysed on an intention-to-treat basis. The study was successfully piloted, with 46% (90/196) of eligible patients recruited and 89% (80/90) of participants completing all components of the protocol. A trialled bolus-continuous dosing regimen was successful in maintaining free serum cefuroxime concentrations of 64 mg/L. No serious adverse reactions were identified. Rates of SSIs (superficial and deep SSIs) were lower in the intervention arm than the standard treatment arm (24% (10/42) vs. 30% (13/43)), as were infection within 30 days of operation (41% (17/43) vs 51% (22/43)) and urinary tract infections (2% (1/42) vs. 9% (4/43)). These infection rates can be used to power future clinical trials. This study demonstrates the feasibility of cefuroxime bolus-continuous infusion of antibiotic prophylaxis trials, and provides safety data for infusions targeting free serum cefuroxime concentrations of 64 mg/L. Trial registration: NCT02445859 .