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Blockade of CTLA‐4 by tremelimumab combined with anti‐PD‐L1 durvalumab and chemotherapy provided increased antitumor activity and long‐term survival benefits in first‐line metastatic non‐small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2‐compartment model with linear and time‐varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates. Improved progression‐free survival (PFS) and overall survival (OS) in the tremelimumab arm (in combination with durvalumab and chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum concentration at 5th dose (Cmin,dose5) and area under the curve at 5th dose (AUCdose5)). However, further case‐matching analyses yielded hazard ratios for the comparison of tremelimumab‐treated patients in the Cmin,dose5 quartile 1 (Q1) subgroup with matched chemotherapy‐treated patients of 1.04 (95% confidence interval (CI): 0.76–1.44) for OS and 0.99 (95% CI: 0.72–1.36) for PFS, suggesting that the observed apparent exposure–response relationship might be confounded. No relationship between tremelimumab exposure and safety (grade ≥3 treatment‐emergent adverse events [AEs], AEs of special interest, or discontinuation due to AEs) was identified. These results support the consistent benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in combination with durvalumab and chemotherapy in POSEIDON as first‐line therapy for mNSCLC. [ABSTRACT FROM AUTHOR]

A novel single‐dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit–risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure–response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter‐ and intra‐individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2‐compartment model with both linear and time‐dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression‐free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil‐to‐lymphocyte ratio (NLR) were associated with OS (P <.001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC. [ABSTRACT FROM AUTHOR]

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single‐dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long‐term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T‐cell count was included in the final model. With the full covariate model, the half‐maximal effective concentration (EC50) of tremelimumab was 6.10 μg/mL (standard error = 1.07 μg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 μg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti‐cytotoxic T‐lymphocyte‐associated antigen 4 (anti‐CTLA‐4) and anti‐programmed cell death ligand‐1 (anti‐PD‐L1) therapy primes an immune response that may then be sustained by anti‐PD‐L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti‐CTLA‐4 plus anti‐PD‐L1 combination strategies. [ABSTRACT FROM AUTHOR]

Monalizumab is a novel, first‐in‐class humanized immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets the inhibitory CD94/NKG2A receptors. The objectives of this analysis were to develop a population pharmacokinetic (PK) model of monalizumab, evaluate the impact of clinically relevant covariates on monalizumab PK, and provide dose justification for clinical trials. We developed a monalizumab population PK model to characterize the PK properties of monalizumab in patients with advanced solid tumors or head and neck squamous cell carcinoma. Data from clinical studies D419NC00001 (NCT02671435) and IPH2201‐203 (NCT02643550) were pooled for the analysis, resulting in a data set of 3066 PK samples derived from 507 subjects. The PK of monalizumab were reasonably described by a 2‐compartment model with first‐order elimination. Monalizumab generally exhibited linear PK over a dose range of 22.5‐750 mg or 10 mg/kg every 2 weeks. The estimate of clearance was ≈0.255 L/day, and apparent volume of distribution was 6.36 L for a typical individual, consistent with previous findings for endogenous immunoglobulin Gs and other therapeutic monoclonal antibodies. Baseline albumin and body weight were identified as significant covariates of clearance; body weight, sex, and smoking status had a significant impact on volume of distribution; and none of these covariates had impact on peripheral volume of distribution. Although these covariates were identified as statistically significant, they are considered to be not clinically meaningful, as changes in monalizumab exposure were <30%. Therefore, no dose adjustments of monalizumab based on patient or disease characteristics are recommended. [ABSTRACT FROM AUTHOR]

Aims: Tremelimumab, a cytotoxic T‐lymphocyte‐associated protein 4 human monoclonal antibody of the immunoglobulin G2 κ isotype, has been studied in oncology clinical trials as both monotherapy and in combination with durvalumab. This study characterized the pharmacokinetics of tremelimumab as monotherapy and in combination with durvalumab and evaluated the impact of patient covariates on pharmacokinetics. Methods: A pooled‐analysis population pharmacokinetics model was built using NONMEM methodology. Pharmacokinetic data from 5 studies spanning different tumour types and therapy regimens were pooled for model development (956 patients). A dataset pooled from 4 additional studies was used for external validation (554 patients). Demographic and relevant clinical covariates were explored during model development. Results: Tremelimumab exhibited linear pharmacokinetics, well described by a 2‐compartment model, with time‐varying clearance (0.276 L/day at baseline) associated primarily with therapy regimen and linked with changes in disease status. As monotherapy and combination therapy, tremelimumab clearance over 1 year increased by ~16% and decreased by ~17%, respectively. Pharmacokinetic behaviour was consistent across patient demographics and cancer subtypes. Patients with higher bodyweight and lower albumin levels at baseline had significantly higher clearance; however, no dosage adjustments are warranted. A flat dose (75 mg) was projected to provide comparable exposure to weight‐based dosing (1 mg/kg) in adults. Conclusion: Tremelimumab exhibited linear pharmacokinetics but consistently opposite trends of time‐varying clearance as monotherapy and in combination with durvalumab. Baseline bodyweight and albumin were significant covariates, but conversion from weight‐based dosing at 1 mg/kg to flat dosing at 75 mg had no clinically relevant impact. [ABSTRACT FROM AUTHOR]

In this study, we developed a method for coordinating and optimizing the train connection plans of different lines under the conditions of urban rail transit (URT) network operation. The method allows trains of different lines to form good connections at transfer stations, which can shorten the waiting time of passengers for transfers and reduce passenger retention. A mathematical model was developed to simulate the interaction between passengers and trains. Two optimization models were developed for the train connection plan of network transfer stations based on different optimization objectives during peak and off-peak hours. Subsequently, a corresponding solution method based on a genetic algorithm and simulation was designed. Finally, the Suzhou URT network was used as a case study, and the passenger flow of the transfer station was simulated and calculated using relevant automatic fare collection (AFC) data. The results indicated that the average waiting time and the number of passengers stranded were reduced using the proposed method. The calculation example demonstrated the effectiveness of the model and algorithm, which can guide the coordinated preparation of a network train connection plan. [ABSTRACT FROM AUTHOR]

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast‐changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology‐related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China‐specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology‐related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data. [ABSTRACT FROM AUTHOR]

The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti‐PD‐L1 antibody, and quantify the impact of baseline and time‐varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two‐compartment model with both linear and nonlinear clearances. Three candidate models were evaluated: a time‐invariant clearance (CL) model, an empirical time‐varying CL model, and a semimechanistic time‐varying CL model incorporating longitudinal covariates related to disease status (tumor shrinkage and albumin). The data supported a slight decrease in durvalumab clearance with time and suggested that it may be associated with a decrease in nonspecific protein catabolic rate among cancer patients who benefit from therapy. No covariates were clinically relevant, indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following weight‐based and flat‐dosing regimens. [ABSTRACT FROM AUTHOR]