Model-informed drug development of envafolimab, a subcutaneously injectable PD-L1 antibody, in patients with advanced solid tumors.

BACKGROUND AND OBJECTIVES: Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. METHODS: In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. RESULTS: The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. CONCLUSIONS: No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

Exposure-Response Analyses of Olaparib in Real-Life Patients with Ovarian Cancer.

BACKGROUND: Olaparib is given in a fixed dose of twice-daily 300 mg in patients who are diagnosed with ovarian cancer, breast cancer, prostate cancer or pancreas cancer and has a high interpatient variability in pharmacokinetic exposure. The objective of this study was to investigate whether pharmacokinetic exposure of olaparib is related to efficacy and safety in a real-life patient' cohort. METHODS: A longitudinal observational study was conducted in patients who received olaparib for metastatic ovarian cancer of whom pharmacokinetic samples were collected. A Kaplan-Meier analyses was used to explore the relationship between olaparib exposure, measured as (calculated) minimum plasma concentrations (Cmin), and efficacy, Univariate and multivariate cox-regression analyses were performed. Also, the Cmin of patients who experienced toxicity was compared with patients who did not experience any toxicity. RESULTS: Thirty-five patients were included in the exposure-efficacy analyses, with a median olaparib Cmin of 1514 ng/mL. There was no statistical significant difference in PFS of patients below and above the median Cmin concentration of olaparib, with a hazard ratio of 1.06 (95% confidence interval: 0.46-2.45, p = 0.9)). For seven patients pharmacokinetic samples were available before toxicity occurred, these patients had a higher Cmin of olaparib in comparison with patients who had not experienced any toxicity (n = 33), but it was not statistically significant (p = 0.069). CONCLUSIONS: Our study shows that exposure of olaparib is not related to PFS. This suggests that the approved dose of olaparib yields sufficient target inhibition in the majority of patients.

Exposure-Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting.

BACKGROUND: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting. METHODS: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (Cmin,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship. RESULTS: A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 - 19.1) months and 9.3 (95% CI: 7.2 - 11.1) months for patients with Cmin,pred < 166 µg/L and Cmin,pred ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,pred < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 - 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 - 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). CONCLUSION: In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

Application of machine learning based methods in exposure-response analysis.

Robust estimation of exposure response analysis relies on correct specification of the model structure with traditional parametric approach. However, the assumptions of the handcrafted model may not always hold or verifiable. Here, we conducted a simulation study to assess the performance of machine learning-based techniques in exposure-response (E-R) analysis where data were generated by a complicated nonlinear system under one dose level. Two analysis options involving machine learning were evaluated. The first option was based on marginal structural model with inverse probability weighting, where machine learning (ML) was employed to improve the performance of propensity score estimation. The simulation results showed that propensity score predicted by ML was more robust than traditional multinomial logistic regression in terms of adjusting the confounding effects and unbiasedly estimating the E-R relationship. The second option estimated the E-R relationship by employing artificial neural network as a universal function approximator to the data generating mechanism, without the requirement of accurately hand-crafting the whole simulation system. The results demonstrated that the trained network was able to correctly predict the treatment effects across a certain range of adjacent dose levels. In contrast, traditional regression provided biased predictions, even when all confounders were included in the model. Our study demonstrated that ML may serve as a powerful tool for pharmacometrics analysis with its prediction flexibility in a nonlinear system and its capacity of approximating the ground truth.

Off-label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure-response analysis.

AIMS: Recently, letrozole has been used off-label to treat short pubertal boys. The experience on letrozole effectiveness and safety has been obtained primarily from Caucasian children. A simple extrapolation of the data to Chinese paediatric populations is questionable because of the substantial ethnic differences between the two populations. Therefore, the present study aimed to determine the effectiveness and safety of letrozole use in Chinese short pubertal boys as well as to establish an exposure-response relationship. METHODS: Forty-one Chinese boys were included in the study. Patients were given letrozole tablets (2.5 mg) once daily in combination with growth hormone, and follow-up visits were made after 1, 3, 6 and 12 months of treatment. Plasma samples were taken from clinical examinations and analysed using high performance liquid chromatography with fluorescence detection. RESULTS: After 1 year of treatment, 35 (88%) boys showed increased predicted adult heights. However, possible adverse drug reactions were seen in nine boys (22%). Predicted adult heights increased significantly from 168.4 ± 3.7 to 173.0 ± 4.2 cm, while oestrogen levels dropped from 33.2 ± 7.4 to 21.6 ± 7.3 pg/mL. Increments in predicted adult height were significantly correlated with trough letrozole concentrations (r = 0.39, P = .01). CONCLUSION: Letrozole treatment in Chinese pubertal populations should be further optimized, and more personalized therapies should be developed.

Exposure-response analysis of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukaemia and comparison with standard of care chemotherapy.

AIMS: The relationship between blinatumomab exposure and efficacy endpoints (occurrence of complete remission [CR] and duration of overall survival [OS]) or adverse events (occurrence of cytokine release syndrome [CRS] and neurological events) were investigated in adult patients with relapsed/refractory acute lymphoblastic leukaemia (r/r ALL) receiving blinatumomab or standard of care (SOC) chemotherapy to evaluate appropriateness of the blinatumomab dosing regimen. METHODS: Exposure, efficacy and safety data from adult patients (n = 646) with r/r ALL receiving stepwise (9 then 28 µg/day, 4-week cycle) continuous intravenous infusion (n = 537) of blinatumomab or SOC (n = 109) chemotherapy were pooled from phase 2 and 3 studies. The occurrence of CR, neurological and CRS events, and duration of OS were analysed using Cox proportional hazards models or logistic regression, as appropriate. Confounding factors were tested multivariately as needed. RESULTS: Blinatumomab steady-state concentration following 28 µg/day dosing was associated with the probability of achieving CR (odds ratio and 95% confidence interval: 1.073 [1.033-1.114]), and a longer duration of OS compared to SOC (hazard ratio and 95% confidence interval: 0.954 [0.936-0.973], P < .05) in multivariate analyses. The exposure-safety analyses indicated that blinatumomab steady-state concentration following the 9 or 28 µg/day dose was not associated with increased probability of CRS or neurological events, after accounting for blinatumomab treatment effect (P > .05). CONCLUSIONS: Blinatumomab step-dosing regimen of 9/28 µg/day provided treatment benefit in achieving CR and increasing the duration of OS over SOC and was appropriate in management of CRS and neurological events in patients with r/r ALL.

Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist.

OBJECTIVE: The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study. METHODS: The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure-response (ER) analysis. Results from the two studies were compared. RESULTS: In both studies, moxifloxacin effect established assay sensitivity. IUT analysis revealed comparable pitolisant-induced maximum mean (90 % confidence interval (CI)) placebo-corrected increase from baseline (ΔΔQTcF) in both the studies, being 13.3 (8.1; 18.5) ms at 200-mg and 9.9 (4.7; 15.1) ms at 240-mg doses in SAD study and 5.27 (2.35; 8.20) ms at 120-mg dose in TQT study. ER analysis revealed that ER slopes in SAD and TQT studies were comparable and significantly positive (0.031 vs 0.027 ms/ng/mL, respectively). At geometric mean concentrations, bootstrap predicted ΔΔQTcF (90 % CI) were 9.23 (4.68; 14.4) ms at 279 ng/mL (240-mg dose) in the SAD study and 4.97 (3.42; 8.19) ms at 156 ng/mL (120-mg dose) in the TQT study. CONCLUSION: Pitolisant lacked an effect of regulatory concern on QTc interval in both the studies, however analysed, suggesting that the results from the SAD study could have mitigated the need for a TQT study. Our findings add to the growing evidence that intensive ECG monitoring in early phase clinical studies can replace a TQT study.

Occupational exposure to silica dust and risk of lung cancer: an updated meta-analysis of epidemiological studies.

BACKGROUND: Crystalline silica is considered as one of the most common and serious occupational hazards to workers' health. Although its association with lung cancer has been studied for many decades, the conclusion remains somewhat controversial. Our objectives are to review and summarize the epidemiological evidence on the relationship between occupational silica exposure and risk of lung cancer and to provide an update on this major occupational health concern. METHODS: Eligible studies up to 29 April 2016 were identified. Pooled effect estimates were calculated according to the reported outcome and the study design. Cohort, case control and proportional mortality studies were examined separately. Studies reporting results according to silicotic status were grouped together and analyzed. Due to the significant amount of heterogeneity expected, random effects models were implemented. Subgroup and meta-regression analyses (both univariate and multivariate) were performed in an attempt to explain heterogeneity. Studies which had adequate exposure characterization were selected to find out whether there was an exposure-response relationship between silica and lung cancer. RESULTS: The risk of lung cancer was found to be elevated in both silicotics and non-silicotics. The pooled standardized mortality ratio (SMR) was 2.32 with a 95 % confidence interval (95 % CI) of 1.91-2.81 and 1.78 (95 % CI 1.07-2.96) respectively. The pooled standardized incidence ratio (SIR) was 2.49 (95 % CI 1.87-3.33) and 1.18 (95 % CI 0.86-1.62) respectively. Subgroup analysis showed that workers in the mining industry had the highest risk of lung cancer with a pooled SMR of 1.48 (95 % CI 1.18-1.86) and the weakest association was seen in potteries with a pooled SMR of 1.14 (95 % CI 1.05-1.23). A positive exposure-response relation was found between cumulative silica exposure and risk of lung cancer. CONCLUSION: The results of our meta-analysis supported the carcinogenic role of silica on the lungs, which was more pronounced at higher levels of exposure, in the presence of silicosis and in the mining industry. Further research is needed to evaluate whether non-silicotics are truly at risk, whether a predisposing factor would explain this potential risk, and to determine the mechanism of carcinogenicity of silica in humans.

Establishing assay sensitivity in QT studies: experience with the use of moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a thorough QT study.

OBJECTIVE: To compare the effect of moxifloxacin as a positive control in a single ascending dose (SAD) study with that in a thorough QT (TQT) study. METHODS: Moxifloxacin was used as a positive control in a SAD study and a TQT study during the evaluation of the QT liability of a new drug. The SAD study had enrolled 24 males and the TQT study 25 males. Both studies intensively monitored electrocardiograms (ECGs) and pharmacokinetic sampling. Effect of moxifloxacin on QTc interval was analysed in each study by intersection union test (IUT) and by exposure-response (ER) analysis and the results compared. Cost-effectiveness of this approach was computed. RESULTS: Analysis by IUT revealed that the maximum mean (90 % confidence interval (CI)) placebo-corrected change from baseline (ΔΔQTcF) in the SAD study and the TQT study were remarkably similar (10.7 (6.5; 14.9) ms vs. 9.09 (6.20; 11.98) ms, respectively). In both studies, assay sensitivity was established by the 90 % lower bound exceeding 5 ms. ER analysis revealed the slopes in both studies to be significantly different from zero and comparable. Bootstrap-predicted effects of moxifloxacin at geometric mean concentrations of ~3000 ng/mL were 8.19 (90 % CI 5.86; 10.7) ms in the SAD study and 7.33 (90 % CI 5.69; 9.70) ms in the TQT study. CONCLUSION: Moxifloxacin can be integrated effectively in a SAD study to establish assay sensitivity, and a TQT study may be replaced by a SAD study which has the required assay sensitivity. Further experience is warranted to verify this conclusion.

Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

Objective: To assess the pharmacokinetics and pharmacodynamics of the long-acting terminal complement 5 (C5) inhibitor ravulizumab in adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the phase 3, open-label CHAMPION-NMOSD trial (NCT04201262). Methods: Patients aged 18 years or older received a weight-based intravenous loading dose of ravulizumab (2,400-3,000 mg) on day 1, followed by weight-based maintenance doses (3,000-3,600 mg) on day 15 and once every 8 weeks thereafter. Pharmacokinetic assessments were maximum observed concentration (Cmax, assessed at the end of the infusion) and concentration at the end of the dosing interval (Ctrough, assessed before dosing) for ravulizumab. Pharmacodynamic assessment was time-matched observed free C5 concentration in serum up to 50 weeks. Results: The pharmacokinetic/pharmacodynamic analysis included 58 patients treated with ravulizumab. Serum ravulizumab concentrations at or above the therapeutic threshold (175 µg/mL) were achieved in all patients after administration of the first dose and maintained for 50 weeks. At week 50, the mean (standard deviation) Cmax (n = 51) and Ctrough (n = 52) were 1,887.6 (411.38) and 764.4 (217.68) µg/mL, respectively. Immediate and complete terminal complement inhibition (free C5 serum concentrations < 0.5 µg/mL) was achieved by the end of the first ravulizumab infusion and sustained throughout the treatment period. No treatment-emergent antibodies to ravulizumab were observed. No impact on ravulizumab pharmacokinetics was seen for age, sex, race, hematocrit, hemoglobin, markers of renal and liver impairment, or medications commonly used by patients with NMOSD. Body weight and BMI were significant covariates of ravulizumab pharmacokinetics. Conclusions: Serum ravulizumab concentrations were maintained above the therapeutic threshold in all patients through 50 weeks of treatment. Ravulizumab achieved immediate and complete terminal complement inhibition that was sustained throughout the treatment period in adults with AQP4+ NMOSD.

Population pharmacokinetic/pharmacodynamic modeling of H018, a selective JAK1 inhibitor, in healthy Chinese volunteers.

H018 is an orally administered, selective, small-molecule inhibitor of Janus kinase 1 (JAK1) made for the treatment of rheumatoid arthritis. A population pharmacokinetic/pharmacodynamic analysis was conducted to characterize the pharmacokinetic and pharmacodynamic profile of H018 and its active metabolite using data from 48 healthy Chinese volunteers who received a single dose of 10-160 mg of H018 in a phase I clinical study. A two-compartment model with delayed absorption and linear elimination adequately described the pharmacokinetic data of H018. The apparent clearance of H018 was estimated to be 39.0 L/h, and triglyceride was identified as a covariate on it. Pharmacokinetic data of the active metabolite could be well described by a two-compartment model with linear elimination. The exposure-effect relationships in terms of pSTAT1 inhibition were well described by a direct response model, with exposure captured by an active moiety that consisted of H018 and its metabolite, weighted by the ratio of in vitro JAK1 inhibitory activity (1.13). The estimated EC50 value for the active moiety is 601 nM. In the simulation using the final model, the inhibitory effect appeared to have reached a plateau in the high-dose groups, with max inhibition rates of 81.42 %, 88.42 %, and 91.89 % for 80, 120, and 160 mg dose groups, respectively. Taken together, this study will provide an instructive reference of dose selection for subsequent clinical trials.

Exposure-response analysis and risk assessment for lung cancer in relationship to silica exposure: a 44-year cohort study of 34,018 workers.

Crystalline silica has been classified as a human carcinogen by the International Agency for Research on Cancer (Lyon, France); however, few previous studies have provided quantitative data on silica exposure, silicosis, and/or smoking. We investigated a cohort in China (in 1960-2003) of 34,018 workers without exposure to carcinogenic confounders. Cumulative silica exposure was estimated by linking a job-exposure matrix to work history. Cox proportional hazards model was used to conduct exposure-response analysis and risk assessment. During a mean 34.5-year follow-up, 546 lung cancer deaths were identified. Categorical analyses by quartiles of cumulative silica exposure (using a 25-year lag) yielded hazard ratios of 1.26, 1.54, 1.68, and 1.70, respectively, compared with the unexposed group. Monotonic exposure-response trends were observed among nonsilicotics (P for trend < 0.001). Analyses using splines showed similar trends. The joint effect of silica and smoking was more than additive and close to multiplicative. For workers exposed from ages 20 to 65 years at 0.1 mg/m(3) of silica exposure, the estimated excess lifetime risk (through age 75 years) was 0.51%. These findings confirm silica as a human carcinogen and suggest that current exposure limits in many countries might be insufficient to protect workers from lung cancer. They also indicate that smoking cessation could help reduce lung cancer risk for silica-exposed individuals.

Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma.

PURPOSE: In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, this exposure-response analysis characterized the relationship of cabozantinib exposure with clinical endpoints. METHODS: Dose modification was allowed with cabozantinib (holds and reductions) to manage adverse events (AEs). The population pharmacokinetics analysis was updated and used to generate individual predicted cabozantinib exposure measures. Kaplan-Meier plots and time-to-event Cox proportional hazard (CPH) exposure-response models characterized the relationship of cabozantinib exposure with PFS, dose modifications, and selected AEs. RESULTS: Kaplan-Meier plots showed no clear difference in PFS across cabozantinib exposure quartiles. Cabozantinib exposure did not significantly affect the hazard of PFS in the CPH base model nor in the final model. In contrast, baseline albumin and nivolumab clearance had a significant effect on PFS. There was no significant relationship between cabozantinib clearance and risk of dose modification, but a significant relationship was identified between cabozantinib exposure and Grade ≥ 1 palmar-plantar-erythrodysesthesia and Grade ≥ 3 diarrhea in the exposure-response analysis. CONCLUSION: To optimize individual cabozantinib exposure, these data support the dose modification strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when combined with nivolumab.

Use of patient-reported outcomes (PRO) data to complement exposure-response analysis in early clinical cancer drug development.

BACKGROUND: This proof-of-concept retrospective case study investigated whether patient-reported outcomes (PRO) instruments, designed to capture symptomatic adverse event data, could identity a known exposure-response (ER) relationship for safety characterized in an original FDA analysis of an approved anti-cancer agent. PRO instruments have been designed to uniquely quantify the tolerability aspects of exposure-associated symptomatic adverse events. We explored whether standard ER analyses of clinician-reported safety data for symptomatic adverse events could be complemented by ER analysis using PRO data that capture and quantify the tolerability aspects of these same symptomatic adverse events. METHODS: Exposure-associated adverse event data for diarrhea were analyzed in parallel in 120 patients enrolled in a clinical trial using physician reported Common Terminology Criteria for Adverse Events (CTCAE) and patient-reported symptomatic adverse event data captured by the National Cancer Institute's (NCI) PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument. Comparative ER analyses of diarrhea were conducted using the same dataset. Results from the CTCAE and PRO-CTCAE ER analyses were assessed for consistency with the ER relationship for diarrhea established in the original NDA using a 750-patient dataset. The analysis was limited to the 120-patient subset with parallel CTCAE and PRO-CTCAE assessments. RESULTS: Within the same 120-patient dataset, ER analysis using dense, longitudinal PRO-CTCAE-derived data was sensitive to identify the known ER relationship for diarrhea, whereas the standard CTCAE based ER analysis was not. CONCLUSIONS: ER analysis using PRO assessed symptomatic adverse event data may be a sensitive tool to complement traditional ER analysis. Improved identification of relationships for safety, by including quantification of the tolerability aspect of symptomatic adverse events using PRO instruments, may be useful to improve the sensitivity of exposure response analysis to support early clinical trial dosage optimization strategies, where decision making occurs within limited small patient datasets.

Exposure-response analysis using time-to-event data for bevacizumab biosimilar SB8 and the reference bevacizumab.

Purpose: This analysis aimed to characterize the exposure-response relationship of bevacizumab in non-small-cell lung cancer (NSCLC) and evaluate the efficacy of SB8, a bevacizumab biosimilar, and Avastin®, the reference bevacizumab sourced from the European Union (EU), based on the exposure reported in a comparative phase III efficacy and safety study (EudraCT, 2015-004026-34; NCT02754882). Materials and methods: The overall survival (OS) and progression-free survival (PFS) data from 224 patients with steady-state trough concentrations (Css,trough) were analyzed. A parametric time-to-event (TTE) model was developed using NONMEM®, and the effects of treatments (SB8 and bevacizumab-EU) and patient demographic and clinical covariates on OS and PFS were evaluated. Simulations of median OS and PFS by bevacizumab Css,trough were conducted, and concentrations required to achieve 50% and 90% of the maximum median TTE were computed. Results: A log-logistics model with Css,trough best described the OS and PFS data. Treatment was not a predictor of the hazard for OS or PFS. Simulations revealed steep exposure-response curves with a phase of rapid rise before saturating to a plateau. The median Css,trough values of SB8 and bevacizumab-EU reported from the clinical study were on the plateaus of the exposure-response curves. The concentrations required to achieve 50% and 90% of the maximum effect were 82.4 and 92.2 µg/mL, respectively, for OS and 79.7 and 89.1 µg/mL, respectively, for PFS. Conclusion: Simulations based on the constructed TTE models for OS and PFS have well described the exposure-response relationship of bevacizumab in advanced NSCLC. The analysis demonstrated comparable efficacy between SB8 and bevacizumab-EU in terms of OS and PFS based on their exposure levels.

The Relationship Between Efficacy and Safety of Osimertinib Blood Concentration in Patients With EGFR Mutation-positive Lung Cancer: A Prospective Observational Study.

BACKGROUND/AIM: Osimertinib blood levels and their impact on treatment continuation in patients with EGFR mutation-positive lung cancer is not known. This study investigated the drug blood levels and risk factors affecting treatment continuation. PATIENTS AND METHODS: Fifty-six patients with recurrent and inoperable epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who received Osimertinib (80 mg once daily, daily dose) between October 1, 2016, and August 31, 2021, were included. Patients were classified into two groups using a cutoff blood level of 155 ng/ml. The primary endpoint was the relationship between Osimertinib exposure and efficacy, and secondary endpoints were the relationship between Osimertinib exposure and side effects, and the effect of covariates on efficacy and blood levels. RESULTS: The median progression-free survival (PFS) for evaluable patients in the steady-state trough concentration (Cmin ss) ≥155 ng/ml and Cmin ss <155 ng/ml groups was 18.7 months and 31.2 months. Serum albumin (Alb) levels were 3.73±0.40 g/dl and 3.93±0.28 g/dl (p=0.030), respectively, and in multivariate analysis, Alb <3.7 g/dl was associated with a hazard ratio of 5.304 (95%CI=1.431-19.66; p=0.013), indicating that Alb <3.7 g/dl significantly shortened PFS. CONCLUSION: Free blood concentration of Osimertinib may have been increased by a combination of factors, including decreased hepatic metabolic function and decreased albumin production caused by systemic inflammation in patients with cancer. However, there was no effect of Osimertinib Cmin ss on PFS.

Optimization of the dosage regimen of zoledronic acid with a kinetic-pharmacodynamic model and exposure-response analysis.

Purpose: In order to support the dose optimization of zoledronic acid, the kinetic-pharmacodynamic model and exposure-response analysis were used to describe the changes in bone mineral density in different doses of zoledronic acid and establish the relationship between dose and acute phase reaction. Methods: Data were extracted from literature in accessible public databases. The kinetic-pharmacodynamic model was developed based on the above data using the NONMEM package to estimate parameters describing the relationship between the dose of zoledronic acid and bone mineral density. Exposure-response analysis was developed to establish the relationship between dose and acute phase reaction. Model evaluation was performed using goodness-of-fit, coefficient of variation (CV%). And sensitivity analyses were performed to assess the necessity of related parameters. Then the established model was used to simulate the changes of bone mineral density under different administration regimens, and the literature data was verified. Results: The kinetic-pharmacodynamic model successfully described zoledronic acid dose and change of bone mineral density in osteoporosis patients, with coefficient of variation of most less than 71.5%. The exposure-response analysis showed the incidence of acute phase reaction is dose-dependent. The bone mineral density was simulated based on the developed kinetic-pharmacodynamic model. And the simulated change of bone mineral density and the incidence of acute phase reaction could be helpful to propose a dosage regimen. Conclusion: Overall, the kinetic-pharmacodynamic model described changes of bone mineral density in different doses of zoledronic acid in vivo. And, the model and the exposure-response analysis also showed to provide the assessment of dose-response relationship for zoledronic acid.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

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.

Model-Informed Dose Justifications of Posaconazole in Japanese Patients for Prophylaxis and Treatment Against Fungal Infection.

Posaconazole is a globally approved broad-spectrum triazole antifungal compound. In Japanese patients, posaconazole has identical dosing regimens as those approved globally for both tablet and intravenous formulations. This article aims to describe a model-informed approach for dose justification of posaconazole in the Japanese population as either high-risk patients with fungal infections (prophylaxis patients) or patients with fungal infections (treatment patients). A simultaneous population pharmacokinetic (PK) model for tablet and intravenous formulation was developed on the basis of a data set including Japanese data from healthy participants and treatment patients. The PK profiles and exposure distributions in Japanese patients were predicted and compared against foreign patients, that is, patients outside of Japan. Relationships between the post hoc posaconazole exposures and frequently observed clinical adverse events were evaluated. Although clinical trials for Japanese prophylaxis patients were not conducted, PK profiles in Japanese prophylaxis patients were predicted using the population PK model and demographic covariate information obtained from the published literature. Based upon the globally approved dosing regimen, posaconazole exposure distribution was predicted to be the highest in Japanese treatment patients, and generally similar between Japanese and foreign prophylaxis patients. Exposures in Japanese patients exceeded the efficacy target level (500 ng/mL). Safety profiles in Japanese treatment patients with the highest exposures were clinically acceptable without specific concerns to Japanese patients and appeared to have no relationship with posaconazole exposures. From PK, safety, and efficacy perspectives, the use of the same dosing regimen as in foreign patients was justified in Japanese prophylaxis and treatment patients.

Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients.

PURPOSE: To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. PATIENTS AND METHODS: EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. RESULTS: Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h (AUC0-24) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683-63,257 ng·h/mL) and 2338 ng·h/mL (581-5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound AUC0-24 on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state (Ctrough,ss) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound Ctrough,ss on day 7-15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). CONCLUSION: The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. CLINICAL TRIALS REGISTRATION NUMBER: UMIN000012862.