Population Pharmacokinetics of SCT510 (a Bevacizumab Biosimilar) and Avastin® in Healthy Subjects and Patients with Non-squamous Non-small Cell Lung Cancer.

CMAB008 is a monoclonal antibody developed as a biosimilar to infliximab (Remicade®, Janssen). The pharmacokinetic characteristics of CMAB008 and Remicade® in healthy subjects and patients with moderately to severely active rheumatoid arthritis (RA) were investigated using a population modeling approach, and the pharmacokinetic similarity of CMAB008 to Remicade® was assessed. The population pharmacokinetic model was developed on the basis of intensive pharmacokinetic data from a phase1 study in healthy male subjects and combined intensive and sparse pharmacokinetic data from a phase3 study in patients with RA. A two-compartment model with first-order elimination adequately described CMAB008 and Remicade® concentration data in healthy subjects and patients with RA. The analysis of covariates identified anti-drug antibody (ADA), neutralizing antibody (NAB), real-time body weight (BWT), and real-time albumin (ALB) as significant covariates on clearance, and BWT was also a significant covariate for the central volume of distribution. The treatment type (CMAB008 versus Remicade®) and the study population (healthy subjects versus patients with RA) were not identified as significant covariates on the pharmacokinetics of infliximab, demonstrating pharmacokinetic similarity between CMAB008 and Remicade® in both study populations. The effect of BWT and ALB changes on exposures to infliximab was within the acceptable range, suggesting that the 3mg/kg regimen is appropriate in clinical practice for patients with RA and BTW and ALB distribution within the range evaluated in the current analysis. The pharmacokinetic characteristics were similar between CMAB008 and Remicade® in healthy subjects and patients with RA. CMAB008 can be considered bioequivalent to Remicade®. ClinicalTrials.gov identifiers NCT04779892, NCT03478111.

MYL-1402O is a bevacizumab (Avastin®) biosimilar. Pharmacokinetic and safety similarity of MYL-1402O and reference Avastin® authorized in the European Union (EU-Avastin®) and the US (US-Avastin®) was demonstrated in healthy subjects (phase I, NCT02469987). The key objectives of this study were to establish a population pharmacokinetic (PopPK) model on pooled data from the phase I and phase III clinical studies to assess pharmacokinetic linearity of MYL-1402O and Avastin® across dose ranges, to assess the pharmacokinetic similarity of MYL-1402O and Avastin® in patients with non-squamous non-small cell lung cancer (nsNSCLC), and to explore potential covariates to account for systematic sources of variability in bevacizumab exposure. Efficacy and safety of MYL-1402O compared with EU-Avastin® was investigated in a multicenter, double-blind, randomized, parallel-group study in patients with stage IV nsNSCLC (phase III, NCT04633564). PopPK models were developed using a nonlinear mixed effects approach (NONMEM® 7.3.0). The pharmacokinetics of Avastin® and MYL-1402O were adequately described with a two-compartment linear model. Fourteen covariates were found to be statistically significant predictors of bevacizumab pharmacokinectics. The impact of each covariate on area under the concentration-timecurve, half-life, andmaximum plasma concentration was modest, and ranges were similar between the treatment groups, MYL-1402O and EU-Avastin®, in patients with nsNSCLC. The pharmacokinectics of bevacizumab appeared to be linear. PopPK analysis revealed no significant differences between pharmacokinetics of MYL-1402O and Avastin® in patients with nsNSCLC. The developed PopPK model was considered robust, as it adequately described bevacizumab pharmacokinetics in healthy participants and nsNSCLC patients.

PurposeThe objectives of this analysis were to characterize the population pharmacokinetics (PK) of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin®) sourced from the European Union (bevacizumab-EU) in patients with advanced non-squamous non-small cell lung cancer (NSCLC), and to quantify the difference in PK parameters between the two drug products via covariate analysis.MethodsPooled PF-06439535 and bevacizumab-EU serum concentration data from a comparative clinical efficacy and safety study (NCT02364999) in patients with NSCLC (N = 719) were analyzed using a non-linear mixed-effects modeling approach. Patients received PF-06439535 plus chemotherapy or bevacizumab-EU plus chemotherapy every 21 days for 4–6 cycles, followed by monotherapy with PF-06439535 or bevacizumab-EU. PF-06439535 or bevacizumab-EU was administered intravenously at a dose of 15 mg/kg. Effects of patient and disease covariates, as well as the drug product (PF-06439535 versus bevacizumab-EU), on PK were investigated.ResultsOverall, 8632 serum bevacizumab concentrations from 351 patients in the PF-06439535 group and 354 patients in the bevacizumab-EU group were included in the analysis. A two-compartment model adequately described the combined data. Clearance (CL) and central volume of distribution (V1) estimates were 0.0113 L/h and 2.99 L for a typical 71-kg female patient with NSCLC administered bevacizumab-EU. CL and V1 increased with body weight and were higher in males than females even after accounting for differences in body weight. The 95% confidence intervals for the effect of drug product on CL and V1 encompassed unity.ConclusionsThe population PK of PF-06439535 and bevacizumab-EU were well characterized by a two-compartment model. Covariate analysis did not reveal any appreciable differences between PK parameters for PF-06439535 and bevacizumab-EU in patients with NSCLC.Clinical trial registrationClinicalTrials.gov, NCT02364999.

e21087 Background: MYL-1402O (MYL) is a proposed biosimilar to bevacizumab reference product. A multicenter, double blind randomized, phase 3 study compared the efficacy, safety, PK, and immunogenicity of MYL and Avastin in patients with Stage IV metastatic nsNSCLC. Patients received either MYL or reference product, in combination with carboplatin-paclitaxel up to 18 weeks (6 cycles) followed by monotherapy for up to an additional 24 weeks (8 cycles). The objective was to develop a Pop PK model based on data from a phase 3 study pooled with a single dose healthy volunteer phase 1 study data; to assess PK linearity across the dose levels of 1 mg/kg to 15 mg/kg in 2 clinical studies; to assess the PK similarity of MYL and reference product in patients with nsNSCLC; and to explore potential covariates to account for variability in Pop PK model parameters. Methods: A Pop PK model was developed based on preliminary analyses of MYL phase 1 data and published population analyses of reference product using a 2-compartment linear model (Han K et al., 2016). Individual empiric Bayesian parameter estimates of nsNSCLC patients were used to predict PK measures reflecting exposure to drug and were compared qualitatively between treatments. Results: The data subset used for model development consisted of 8724 records from 771 subjects. Population PK analyses indicated no differences between PK profiles of patients in the MYL and reference product arms. Importantly, treatment was not a significant covariate of clearance ( P = 0.453) or volume of the central compartment ( P = 0.161) using the likelihood ratio χ2 test. Model-based steady state exposure measures, predicted based on the final model for all patients, were also similar between treatment arms (Table). Conclusions: The model supported linear PK at clinical doses in patients with nsNSCLC; there were no clinically relevant/significant differences between the PK of MYL and reference product; and the findings were consistent with the PK study in normal, healthy volunteers. Bayesian Parameter Clinical trial information: 2015-005141-32. [Table: see text]

Aims: This study aimed to develop a population pharmacokinetic (PopPK) model of ilaprazole in healthy subjects and patients with duodenal ulcer in Chinese and investigate the effect of potential covariates on pharmacokinetic (PK) parameters. Methods: Pharmacokinetic data from 4 phase I clinical trials and 1 phase IIa clinical trial of ilaprazole were included in PopPK analysis. Phoenix NLME 8.3 was used to establish a PopPK model and quantify the effects of covariate, such as demographic data, biochemical indicators and disease state on the PK parameters of ilaprazole. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and visual predictive check. Results: A two-compartment model with first-order elimination successfully described the pharmacokinetic properties of ilaprazole. In the final PopPK model, body weight and sex were identified as statistically significant covariates for volume of peripheral compartment (Vp) and clearance of central compartment (CL), respectively, and disease status was also screened as a significant covariate affecting both CL and Vp. The validation results demonstrated the good predictability of the model, which was accurate and reliable. Conclusion: This is the first population pharmacokinetics study of ilaprazole in the Chinese, and the PopPK model developed in this study is expected to be helpful in providing relevant PK parameters and covariates information for further studies of ilaprazole.

BackgroundPembrolizumab combined with chemotherapy is now first-line standard of care in advanced non-small cell lung cancer. This real-life study aimed to assess efficacy and safety of carboplatin-pemetrexed plus pembrolizumab in advanced non-squamous non-small cell lung cancer.MethodsCAP29 is a retrospective, observational, multicenter real-life study conducted in 6 French centers. We evaluated efficacy of first-line setting chemotherapy plus pembrolizumab (November 2019 to September 2020) in advanced (stage III-IV) non-squamous non-small cell lung cancer patients without targetable alterations. Primary endpoint was progression-free survival. Secondary endpoints were overall survival, objective response rate and safety.ResultsWith a median follow-up of 4.5 months (0 to 22 months), a total of 121 patients were included. Baseline characteristics were: median age of 59.8 years with 7.4% ≥75 years, 58.7% of males, 91.8% PS 0-1, 87.6% of stage IV with ≥3 metastatic sites in 62% of cases. Patients had brain and liver metastases in 24% and 15.7% of cases, respectively. PD-L1 was <1% (44.6%), 1–49% (28.1%) and ≥50% (21.5%). Median progression-free survival and overall survival achieved 9 and 20.6 months, respectively. Objective response rate was 63.7% with 7 prolonged complete responses. Survival benefit seemed to be correlated with PD-L1 expression. Brain and liver metastases were not statistically associated with decreased overall survival. Most common adverse events were asthenia (76%), anemia (61.2%), nausea (53.7%), decreased appetite (37.2%) and liver cytolysis (34.7%). Renal and hepatic disorders were the main causes of pemetrexed discontinuation. Grade 3–4 adverse events concerned 17.5% of patients. Two treatment-related deaths were reported.ConclusionsFirst-line pembrolizumab plus chemotherapy confirmed real-life efficacy for patients with advanced non-squamous non-small cell lung cancer. With median progression-free survival and overall survival of 9.0 and 20.6 months, respectively and no new safety signal, our real-life data are very close to results provided by clinical trials, confirming the benefit and the manageable toxicity profile of this combination.

To explore the therapeutic effects of pembrolizumab combined with paclitaxel and cisplatin chemotherapy on advanced non-squamous non-small cell lung cancer and its influencing factors is the main objective. A total of 87 patients with advanced non-squamous non-small cell lung cancer treated in our hospital from October 2016 to May 2018 were enrolled and allocated into control group and observation group according to their disease conditions and willingness. Paclitaxel and cisplatin chemotherapy regimen was employed for control group, based on which pembrolizumab was used for observation group. Cellular immunity indices, cytokine indices, short-term efficacy, adverse reactions, and long-term prognosis were compared, and the factors affecting short-term efficacy and long-term prognosis were analyzed. After treatment, observation group exhibited increased cluster of differentiation 3+ T lymphocytes, cluster of differentiation 4+ T lymphocytes, and cluster of differentiation 4+/cluster of differentiation 8+ ratio and decreased cluster of differentiation 8+ T lymphocytes compared with control group (p<0.05). After treatment, the levels of interleukin-6 and tumor necrosis factor-alpha in observation group were lower than those in control group (p<0.05). The short-term efficacy and long-term prognosis in observation group were better than those in control group (p<0.05), but statistically no significant difference in the incidence rate of adverse reactions was found between the two groups (p>0.05). Decreased cluster of differentiation 4+/cluster of differentiation 8+ ratio increased tumor necrosis factor-alpha level and chemotherapy were risk factors for the poor short-term efficacy and long-term prognosis in patients with advanced non-squamous nonsmall cell lung cancer (p<0.05), and clinical stage IV was a risk factor for the unfavorable long-term prognosis as well (p<0.05). Pembrolizumab combined with paclitaxel and cisplatin chemotherapy regimen can relieve the cellular immune suppression and alleviate inflammatory responses to improve the shortterm efficacy and long-term prognosis, without raising the incidence rate of severe adverse reactions in the treatment of advanced non-squamous non-small cell lung cancer

Objective: To evaluate the pharmacokinetic (PK) parameters of ripretinib and its active metabolite in Chinese patients with gastrointestinal stromal tumor (GIST), and to examine potential ethnic differences in drug exposure between Chinese and the global patient populations using both population and non-compartmental PK methods. Methods: An ongoing clinical phase 2 bridging study in China had enrolled 29 advanced GIST patients who underwent intensive or sparse PK sampling at a ripretinib dose of 150 mg QD. The plasma samples were collected and then analyzed with LC-MS/MS to quantitatively determine the concentration of ripretinib and its active metabolite. Non-compartmental analysis (NCA) was performed using Phoenix WinNonlin® software and population PK analysis was conducted with nonlinear mixed-effect modeling (NONMEM) and R software. In total, there were 15 Chinese GIST patients included in the NCA analysis and 379 patients (350 from global studies and 29 from China bridging study) were involved in the population PK analysis. Evaluation of potential exposure differences between the Chinese population and the global population were based on steady state NCA data and population PK modeling results. Results: Based on the NCA results, the PK exposure of ripretinib and its active metabolite in the Chinese population were similar to that in the global population: 1) The steady state AUC of parent drug (geometric mean of AUC0-12 was 7280 hr*ng/mL, CV 53.8%) in Chinese patients showed differences of 28.2% compared with the global population. 2) The steady state AUC of active metabolite (geometric mean of AUC0-12 was 8490 hr*ng/mL, CV 80.7%) in Chinese patients showed differences of 19.1% compared with the global population. 3) For Cmax of parent drug in Chinese patients, the multiple dosing (geometric mean of Cmax was 787 ng/mL, CV 50.2%) showed differences of 3.4% compared with the global population. 4) For Cmax of active metabolite in Chinese patients, the multiple dosing (geometric mean of Cmax was 860 ng/mL, CV 72.2%) showed differences of 7.0% compared with the global population. In addition, the population PK results showed no ethnical effect on steady-state exposure of parent and its active metabolite between Asians and non-Asians (p &amp;gt; 0.05) and between Chinese and non-Chinese patients (p &amp;gt; 0.05). Conclusion: Based on population PK modeling data and the NCA results of ripretinib and its active metabolite, no significant PK differences were observed between the Chinese patient population and the global patient population. Citation Format: Jian Li, Jun Zhang, Xingye Wu, Chao Wu, Juan Dong, Liang Huang, Lin Shen. Population and non-compartmental pharmacokinetic analysis of ripretinib and its active metabolite in Chinese patients with gastrointestinal stromal tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB126.

2012 American College of Clinical Pharmacology Annual Meeting September 23^rd–25^th San Diego, California

Tapentadol is a new, centrally active analgesic agent with two modes of action--mu opioid receptor agonism and norepinephrine reuptake inhibition--and the immediate-release (IR) formulation is approved in the US for the relief of moderate to severe acute pain. The aims of this analysis were to develop a population pharmacokinetic model to facilitate the understanding of the pharmacokinetics of tapentadol IR in healthy subjects and patients following single and multiple dosing, and to identify covariates that might explain variability in exposure following oral administration. The analysis included pooled data from 11,385 serum pharmacokinetic samples from 1827 healthy subjects and patients with moderate to severe pain. Population pharmacokinetic modelling was conducted using nonlinear mixed-effects modelling (NONMEM) software to estimate population pharmacokinetic parameters and the influence of the subjects' demographic characteristics, clinical laboratory chemistry values and disease status on these parameters. Simulations were performed to assess the clinical relevance of the covariate effects on tapentadol exposure. A two-compartment model with zero-order release followed by first-order absorption and first-order elimination best described the pharmacokinetics of tapentadol IR following oral administration. The interindividual variability (coefficient of variation) in apparent oral clearance (CL/F) and the apparent central volume of distribution after oral administration were 30% and 29%, respectively. An additive error model was used to describe the residual variability in the log-transformed data, and the standard deviation values were 0.308 and 0.314 for intensively and sparsely sampled data, respectively. Covariate analysis showed that sex, age, bodyweight, race, body fat, hepatic function (using total bilirubin and total protein as surrogate markers), health status and creatinine clearance were statistically significant factors influencing the pharmacokinetics of tapentadol. Total bilirubin was a particularly important factor that influenced CL/F, which decreased by more than 60% in subjects with total bilirubin greater than 50 micromol/L. The population pharmacokinetic model for tapentadol IR identified the relationship between pharmacokinetic parameters and a wide range of covariates. The simulations of tapentadol exposure with identified, statistically significant covariates demonstrated that only hepatic function (as characterized by total bilirubin and total protein) may be considered a clinically relevant factor that warrants dose adjustment. None of the other covariates are of clinical relevance, nor do they necessitate dose adjustment.

Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration. A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models. The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649(*)(age/86)((-3.3856)), Ka=0.6750 h(-1), V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks. A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients.

First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: A randomised, phase 3 trial

An Enterohepatic Recirculation Population Pharmacokinetic and MIC-1 Pharmacokinetic-Pharmacodynamic Model for the MDM2 Inhibitor Navtemadlin (KRT-232) in Healthy Subjects

ABSTRACTPegbing (peginterferon alpha‐2b) is a polyethylene glycol‐modified interferon α‐2b injection that has demonstrated favorable efficacy and safety profiles in the treatment of chronic hepatitis B (CHB). This study aimed to develop a population pharmacokinetic (PopPK) model of Pegbing in both healthy subjects and CHB patients and to investigate the influence of covariates on its pharmacokinetic behavior. Pharmacokinetic data were obtained from a Phase I trial in healthy volunteers and a Phase II trial in CHB patients. A one‐compartment model with a target‐mediated drug disposition (TMDD) component incorporating IFN receptor downregulation was established to describe the pooled data from 28 healthy subjects and 39 CHB patients. Physiologically reasonable parameters were estimated, providing a good description and prediction of the model. Furthermore, the final PopPK model was externally validated using an independent dataset of 115 CHB patients. In the covariate analysis, health status (healthy v.s. CHB) was a significant covariate, affecting the Pegbing absorption rate, creatinine clearance was associated with clearance, and body weight affected the volume of distribution. Compared with healthy subjects, CHB patients exhibited a consistent area under the curve (AUC) but a higher Cmax. A PopPK model of Pegbing in both healthy volunteers and CHB patients was successfully established. Based on the model simulation, covariate‐based dose adjustment is unnecessary for CHB patients with normal renal function.

Ranjith K.The objective of this study was to compare the efficacy, safety, pharmacokinetics, and immunogenicity of a proposed bevacizumab biosimilar (DRL_BZ) with the innovator Avastin (reference medicinal product [RMP]) in patients with nonresectable metastatic colorectal cancer (mCRC) over a period of 9 months and advanced nonsquamous non-small cell lung cancer (NSCLC) over 6 months. The study was planned as a randomized, double-blind trial. In part A, a total of 117 mCRC patients were intended to receive 5 mg/kg of bevacizumab every 2 weeks along with mFOLFOX6 chemotherapy for a maximum of 18 cycles. In part B, 60 NSCLC patients were to receive 15 mg/kg of bevacizumab every 3 weeks along with pemetrexed and carboplatin for the initial four cycles, followed by pemetrexed for another four cycles. The primary endpoint was the progression-free survival rate at 6 months (PFS6) in both subparts. The anticipated sample size was 106 evaluable mCRC patients to achieve 85% statistical power for concluding noninferiority with a margin of half the difference (18.8%) between DRL_BZ and Avastin, along with a pilot study involving 60 evaluable NSCLC patients. Safety comparison included assessing adverse events (AEs), infusion reactions, and lab abnormalities. Immunogenicity comparison involved the incidence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs). Pharmacokinetic comparison was planned after the first and fourth dosing cycles of treatment in 24 NSCLC patients. The PFS6 for mCRC patients treated with DRL_BZ and RMP was 57.8% and 50% respectively, with a difference in efficacy of 7.8 (-8.7, 23.7). The PFS9 was 31.1% and 22.9%, with a difference of 8.2% (-6.9%, 22.9%). The objective response rate (ORR) for DRL_BZ and RMP was 28.8% and 22.4%, while the disease control rate (DCR) was 44.2% and 37.9% respectively. For NSCLC patients, the PFS6 was 44% and 45%, showing a difference of -1.0 (-4.2, 22.1). The ORR was 41.4% and 48.1%, and the DCR was 62.1% and 63%. The frequency, type, and severity of AEs were similar in both indications. Blood levels during the first and fourth dosing cycles exhibited comparable values. All NSCLC patients tested negative for ADA, while no mCRC patients on DRL_BZ tested positive for ADA. Low incidences of ADA (8%) and NAbs (4.0%) were reported in patients on RMP. Overall, the efficacy, safety, immunogenicity, and pharmacokinetic parameters of DRL_BZ and RMP were found to be comparable. Clinical Trial Registration For BZ-01-002: CTRI/2016/01/006481.