Population Pharmacokinetic Modeling and Exposure-Efficacy and Body Weight-Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.

Clinical dose rationale of tislelizumab in patients with solid or hematological advanced tumors.

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune-mediated AEs, and infusion-related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure-response (E-R) analyses by logistic regression using data from study BGB-A317-001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018-2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E-R relationship. Overall, the totality of data, including efficacy, safety, and E-R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.

Model-based population pharmacokinetic analysis of tislelizumab in patients with advanced tumors.

Tislelizumab, a humanized immunoglobulin G4 monoclonal antibody, is a programmed cell death protein 1 (PD-1) inhibitor designed to minimize Fc gamma receptor binding on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The pharmacokinetic (PK) profile of tislelizumab was analyzed with population PK modeling using 14,473 observed serum concentration data points from 2596 cancer patients who received intravenous (i.v.) tislelizumab at 0.5-10 mg/kg every 2 weeks or every 3 weeks (q3w), or a 200 mg i.v. flat dose q3w in 12 clinical studies. Tislelizumab exhibited linear PK across the dose range tested. Baseline body weight, albumin, tumor size, tumor type, and presence of antidrug antibodies were identified as significant covariates on central clearance, whereas baseline body weight, sex, and age significantly affected central volume of distribution. Sensitivity analysis showed that these covariates did not have clinically relevant effects on tislelizumab PK. Other covariates evaluated, including race (Asian vs. White), lactate dehydrogenase, estimated glomerular filtration rate, renal function categories, hepatic function measures and categories, Eastern Cooperative Oncology Group performance status, therapy (monotherapy vs. combination therapy), and line of therapy did not show a statistically significant impact on tislelizumab PK. These results support the use of tislelizumab 200 mg i.v. q3w without dose adjustment in a variety of patient subpopulations.

Covariate effects and population pharmacokinetic analysis of the anti-FGFR2b antibody bemarituzumab in patients from phase 1 to phase 2 trials.

PURPOSE: A population pharmacokinetic (PK) analysis of the anti-fibroblast growth factor receptor 2b antibody, bemarituzumab, was performed to evaluate the impact of covariates on the PK and assess whether dose adjustment is necessary for a future phase 3 trial. METHODS: Serum concentration data were obtained from three clinical trials, with 1552 bemarituzumab serum samples from 173 patients, and were analyzed using nonlinear mixed-effects modeling. RESULTS: A two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment best described the bemarituzumab serum concentration data. The final model estimated a typical linear clearance (CL) of 0.311 L/day, volume of distribution in the central compartment (Vc) of 3.58 L, distribution clearance (Q) of 0.952 L/day, volume of distribution in the peripheral compartment (Vp) of 2.71 L, maximum drug elimination by nonlinear clearance (Vmax) of 2.80 µg/day, and Michaelis-Menten constant (Km) of 4.45 µg/mL. Baseline body weight, baseline albumin, gender, and chemotherapy were identified as statistically significant covariates on the PK of bemarituzumab. Given the low interindividual variability of bemarituzumab key PK parameters (CL and Vc) and the small or modest effect of all statistically significant covariates on bemarituzumab exposure at steady-state, no covariate is expected to have clinically meaningful effects on bemarituzumab exposure. CONCLUSION: No covariate had a clinically meaningful impact on bemarituzumab exposure. These results indicate that dose adjustment of bemarituzumab is not necessary, based on the aforementioned covariates, for a future phase 3 trial in gastric and gastroesophageal junction adenocarcinoma population with FGFR2b overexpression in combination with mFOLFOX6.

Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma.

This report summarizes a totality-of-evidence approach supporting recommendation of a 320-mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

Comprehensive PBPK model to predict drug interaction potential of Zanubrutinib as a victim or perpetrator.

A physiologically based pharmacokinetic (PBPK) model was developed to evaluate and predict (1) the effect of concomitant cytochrome P450 3A (CYP3A) inhibitors or inducers on the exposures of zanubrutinib, (2) the effect of zanubrutinib on the exposures of CYP3A4, CYP2C8, and CYP2B6 substrates, and (3) the impact of gastric pH changes on the pharmacokinetics of zanubrutinib. The model was developed based on physicochemical and in vitro parameters, as well as clinical data, including pharmacokinetic data in patients with B-cell malignancies and in healthy volunteers from two clinical drug-drug interaction (DDI) studies of zanubrutinib as a victim of CYP modulators (itraconazole, rifampicin) or a perpetrator (midazolam). This PBPK model was successfully validated to describe the observed plasma concentrations and clinical DDIs of zanubrutinib. Model predictions were generally within 1.5-fold of the observed clinical data. The PBPK model was used to predict untested clinical scenarios; these simulations indicated that strong, moderate, and mild CYP3A inhibitors may increase zanubrutinib exposures by approximately four-fold, two- to three-fold, and <1.5-fold, respectively. Strong and moderate CYP3A inducers may decrease zanubrutinib exposures by two- to three-fold or greater. The PBPK simulations showed that clinically relevant concentrations of zanubrutinib, as a DDI perpetrator, would have no or limited impact on the enzyme activity of CYP2B6 and CYP2C8. Simulations indicated that zanubrutinib exposures are not impacted by acid-reducing agents. Development of a PBPK model for zanubrutinib as a DDI victim and perpetrator in parallel can increase confidence in PBPK models supporting zanubrutinib label dose recommendations.

Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B-Cell Malignancies.

Zanubrutinib is a potent, second-generation Bruton's tyrosine kinase inhibitor that is currently being investigated in patients with B-cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B-cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed-effects modeling. Zanubrutinib PKs were adequately described by a two-compartment model with sequential zero-order then first-order absorption, and first-order elimination. A time-dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B-cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft-Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid-reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.

Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial.

PURPOSE: To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab. METHODS: Nonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target Ctrough in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma. RESULTS: Bemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab Ctrough of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial. CONCLUSION: A projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.

Effects of radiation dose levels and spectral iterative reconstruction levels on the accuracy of iodine quantification and virtual monochromatic CT numbers in dual-layer spectral detector CT: an iodine phantom study.

BACKGROUND: The purpose of this study is to investigate the accuracy of iodine quantification and virtual monochromatic CT numbers obtained with the dual-layer spectral CT (DLCT) using a phantom at different radiation dose levels and spectral iterative reconstruction (IR) levels. METHODS: An abdomen phantom with seven iodine inserts (2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0 mg/mL) was imaged using a DLCT scanner. Five repeated scans were performed at computed tomography dose index volume (CTDIvol) levels of 5, 10, 15, 20, 25 mGy at tube voltages of 120 and 140 kVp, respectively. Spectral-based images were reconstructed using four spectral IR levels (spectral level of 0, 2, 4, 6). Iodine density images and virtual monochromatic images (VMI) at energy levels of 50, 70 and 120 keV were created. The absolute percentage bias (APB) of the measured iodine concentration and the true iodine concentration, and the measured VMI CT numbers and the theoretical VMI CT numbers were compared to determine the difference of radiation dose levels and different spectral IR levels. RESULTS: At CTDIvol levels of 25, 20, 15, 10 mGy, radiation dose levels had no effect on the accuracy of iodine quantitation; at CTDIvol level of 5 mGy, the accuracy of iodine quantification was the poorest, with the mean APBiodine of 4.33% (P<0.05). There was no significant difference in the accuracy of iodine quantitation between 120 and 140 kVp (P=0.648). At energy levels of 50, 70 and 120 keV, there was no significant difference in the accuracy of the VMI CT numbers among the CTDIvol levels of 25, 20 and 15 mGy. However, the accuracy of VMI CT numbers was significantly degraded at the CTDIvol levels of 10 and 5 mGy (P<0.05). At energy level of 50 keV, the accuracy of VMI CT numbers was not affected by tube voltages (kVps) used (P=0.125). At the energy levels of 70 and 120 keV, 140 kVp produced a smaller bias than 120 kVp, with the mean APBHU at 120 and 140 kVp being of 3.62% vs. 2.99% for 70 keV (P<0.01), and 11.65% vs. 9.28% for 120 keV (P<0.01), respectively. Spectral IR levels did not affect the accuracy of iodine quantification and VMI CT numbers (P=0.998, P=0.963). CONCLUSIONS: The accuracy of iodine quantification and VMI CT numbers was only affected by very low radiation dose levels. At the clinically applied radiation dose levels of >10 mGy, the accuracy of both iodine quantification and VMI CT numbers is relatively stable and high.

Correction to: Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC).

The online version of the original article can be.

Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC).

PURPOSE: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC). METHODS: Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined. RESULTS: T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V c) of 4.48 L, distribution clearance (Q) of 0.62 L/day, volume of distribution in the peripheral compartment (V p) of 1.49 L, nonlinear CL of 2.06 L/day, and KM of 1.63 µg/mL. Parameter uncertainty was low to moderate for fixed effects, except KM (estimated with poor precision). Patients with high body weight and low baseline trastuzumab concentrations had significantly faster linear CL; those with higher body weight had significantly larger V c. CONCLUSIONS: In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.

Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.

PURPOSE: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities. METHODS: Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy. RESULTS: NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population. CONCLUSIONS: These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.

Population pharmacokinetic modeling of idelalisib, a novel PI3Kδ inhibitor, in healthy subjects and patients with hematologic malignancies.

PURPOSE: Idelalisib is a potent PI3Kδ inhibitor that was recently approved for treating hematologic malignancies. The objective of this analysis was to develop a population pharmacokinetic model for idelalisib and its inactive metabolite GS-563117 and to evaluate the impact of covariates on idelalisib/GS-563117 PK. METHODS: Data from 10 phase I or II studies in healthy volunteers or patients with hematologic malignancies (n = 736) were analyzed using NONMEM. Stepwise forward addition followed by backward elimination was implemented in the covariate (age, gender, race, body weight, baseline CLcr, AST, ALT, disease status, and type of cancer) model building process. Various model assessment methods were used to evaluate the models. RESULTS: Idelalisib plasma PK was best described by a two-compartment model with first-order absorption, first-order elimination from the central compartment, and a lag time. A nonlinear relationship between dose and relative bioavailability was included in the final model. Two statistically significant covariates were identified and incorporated into the final model: health status (healthy vs. patient) on CL/F and Q/F and body weight on CL/F. Despite being a statistically significant covariate, the effect of body weight on idelalisib exposures was weak, as evidenced by minor changes of steady-state exposure (C trough: 16%; AUC and C max: 10%) for a patient with extreme body weight (5th and 95th percentile) relative to the typical patient, and not considered to be clinically relevant. CONCLUSIONS: PopPK models were developed to adequately describe the plasma concentrations of idelalisib and GS-563117. There were no covariate that had a clinically meaningful impact on idelalisib or GS-563117 exposure.

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates.

PURPOSE: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates. METHODS: Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used. RESULTS: A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V c) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure. CONCLUSIONS: T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.