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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.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m 2 , 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m 2 , 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m 2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for C max , area under the curve (AUC) 2.4-fold for AUC 0-t and 2.7-fold for AUC 0-∞ . Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

This open-label, two-way, crossover, phase Ib drug-drug interaction study investigated whether the pharmacokinetics (PKs) and safety profile of lurbinectedin (LRB) are affected by co-administration of a moderate CYP3A4 inducer (bosentan, BOS) in adult patients with advanced solid tumors. Eleven patients were randomly assigned to Sequence 1 (LRB + BOS in Cycle 1 [C1] and LRB alone in Cycle 2 [C2]) or Sequence 2 (LRB alone in C1 and LRB + BOS in C2), and finally, eight patients (four per sequence) were considered evaluable for PK assessment. LRB (3.2 mg/m 2 , 1 h [h], intravenous) was administered alone or combined with multiple BOS administration (125 mg/12 h oral; 5.5 days). Co-administration with BOS decreased the systemic total exposure (area under the curve, AUC) of LRB by 21% for AUC 0-t and 20% for AUC 0-∞ and increased clearance by 25%. Co-administration with BOS did not significantly modify the unbound plasma LRB PK parameters. BOS increased the conversion of LRB to its metabolite M1, with no changes on its metabolite M4. The LRB safety profile was consistent with the toxicities previously described for this drug. No differences in terms of toxicity were found between LRB with and without BOS. In summary, the magnitude of the observed changes precludes a clinically relevant effect of BOS co-administration on LRB exposure and its safety profile.

Introduction: Lurbinectedin is a selective inhibitor of oncogenic transcription U.S. Food and Drug Administration (FDA)-approved for patients with relapsed small cell lung cancer (SCLC) as monotherapy at 3.2 mg/m 2 every 3 weeks (q3wk). ATLANTIS was a phase 3 study in SCLC with lurbinectedin 2.0 mg/m 2 plus doxorubicin 40 mg/m 2 q3wk vs physician's choice, with overall survival (OS) as the primary endpoint and objective response rate (ORR) as the secondary endpoint. This work aimed to dissect the contribution of lurbinectedin and doxorubicin to antitumor effects in SCLC, and to predict the efficacy of single-agent lurbinectedin at 3.2 mg/m 2 in ATLANTIS to allow for a head-to-head comparison with the control arm., Methods: The dataset included exposure and efficacy data from 387 patients with relapsed SCLC (ATLANTIS, n=288; study B-005, n=99). Patients in the ATLANTIS control arm (n=289) were used for comparison. Unbound plasma lurbinectedin area under the concentration-time curve (AUC u ) and total plasma doxorubicin area under the concentration-time curve (AUC DOX ) were used as exposure metrics. Univariate and multivariate analyses were conducted to determine the best predictors and predictive model for OS and ORR. OS baseline hazard was best described by a log-logistic distribution, with chemotherapy-free interval (CTFI), lactate dehydrogenase, albumin, brain metastases, neutrophils/lymphocytes ratio, AUC u , and the interaction between AUC u and AUC DOX as predictors. Effect of AUC u on ORR best fitted to a sigmoid-maximal response ( E max ) logistic model, where E max was dependent on CTFI., Results: Head-to-head comparisons with predicted 3.2 mg/m 2 lurbinectedin resulted in a positive outcome in ATLANTIS, with hazard ratio (95% prediction intervals [95% PI]) for OS of 0.54 (0.41, 0.72), and odds ratio (95% PI) for ORR of 0.35 (0.25, 0.5)., Conclusion: These results support the superiority of lurbinectedin monotherapy for relapsed SCLC over other approved therapies., Competing Interests: Authors SF, LP-R, EA-P, AZ, and RL were employed by the company PharmaMar S.A., (Copyright © 2023 Fudio, Pérez-Ramos, Asín-Prieto, Zeaiter and Lubomirov.)

During the last decade, the treatment for many cancer indications has evolved due to intensive clinical research into anti-tumor agents' combination. In most instances, new combination treatments consist of an add-on to the standard of care (SOC), which then demonstrate a substantial gain in efficacy and no detrimental effect in tolerability. In the era of targeted therapies, for which maximum tolerated dose (MTD)-based dosing strategies are no longer applicable, early stage studies exploring new combinations are often conducted in the population of interest, expediting the collection of preliminary safety data, to be promptly expanded to collect preliminary efficacy data. Nevertheless, rule-based dose-finding studies are still a prevailing approach for early stage cancer, especially for chemotherapy (CT)-containing combinations. Pharmacokinetic (PK) assessments play a key role throughout the clinical development of drug combinations, informing potential PK interactions. But most importantly, they allow the development of innovative exposure-response (E-R) models aimed at exploring the contribution of each agent to the overall effect of the combination therapy. This review identifies 81 new drug combinations approved by the United States Food and Drug Administration (FDA) for hemato-oncology during the 2011-2021 period and summarizes the main design features of clinical trials and the role of PK assessments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)