Evaluation of the potential effect of dacomitinib, an EGFR tyrosine kinase inhibitor, on ECG parameters in patients with advanced non-small cell lung cancer.

Purpose The study evaluated the potential effect of dacomitinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, on the electrocardiogram (ECG) parameters in adult patients with advanced non-small cell lung cancer enrolled in a multicenter, open-label, phase 2 study. Methods Patients received dacomitinib for six doses of 45 mg every 12 h in a 7-day lead-in cycle (cycle 0), then 60 mg every 12 h for six doses in a 14-day cycle (cycle 1). Clock time-matched triplicate ECGs were performed at 0, 2, 4, 6, 8 and 10 h on day 1 (baseline) and day 4 of cycle 0, and prior to dose on days 1 and 4 of cycle 1. The QT interval was corrected for heart rate using Fridericia's correction (QTcF) and a study specific correction factor (QTcS). Results Thirty-two patients in the study comprised the QTc-evaluable population. Dacomitinib had no effect on the heart rate. The upper limits of the 95% confidence interval (CI) for the mean change from baseline in QTcF and QTcS were < 10 ms at all time points. A lack of relationship between plasma concentrations of dacomitinib or total active moiety on QTcF and QTcS was evidenced. All upper 90% CIs of the PR intervals were < 200 ms, although a small mean increase from baseline (2.7-6.6 ms) was observed. Conclusions There was a lack of a clinically relevant effect of dacomitinib on ECG parameters at dacomitinib concentrations comparable to those obtained at its highest therapeutic dosing regimen of 45 mg once daily. ClinicalTrials.gov identifier: NCT01858389.

Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma.

This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CLt) term and identified potential covariates that may be important predictors of variability in InO distribution and elimination. This analysis was conducted by pooling data from 2 studies of single-agent InO in patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL), 3 studies of single-agent InO, 5 studies of InO plus rituximab (R-InO), and 1 study of R-InO plus chemotherapy in patients with R/R B-cell non-Hodgkin lymphoma (NHL). Pharmacokinetic data included 8361 InO concentration-time observations that were modeled using nonlinear mixed-effects analysis. Covariate relations were identified using generalized additive modeling on base model parameters and then tested in a stepwise manner via covariate modeling. InO concentration was described with a 2-compartment model with linear and time-dependent clearance components. Based on the final model, baseline body surface area was a covariate of the linear and time-dependent clearance components and volume of distribution in the central compartment; baseline percentage of blasts in the peripheral blood was a covariate of the decay coefficient of the time-dependent clearance term (CLt); and concomitant rituximab treatment was a covariate of the linear clearance component (CL1). The magnitude of change of each pharmacokinetic parameter due to these covariates was not considered clinically relevant. Therefore, no dose adjustment of InO for the treatment of patients with R/R B-cell ALL or NHL is needed on the basis of selected covariates.

An Investigation in the Comparability of the Exposure and Recommended Dose of Selected Pfizer Drugs in East Asian Countries: Is Mutual Usage of Clinical Data Among East Asian Countries Feasible?

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.

Optimizing benefit/risk in oncology: Review of post-marketing dose optimization and reflections on the road ahead.

Oncology therapies shifted from chemotherapy to molecularly targeted agents and finally to the era of immune-oncology agents. In contrast to cytotoxic agents, molecularly targeted agents are more selective, exhibit a wider therapeutic window, and may maximally modulate tumor growth at doses lower than the maximum tolerated dose (MTD). However, first-in-patient oncology studies for molecularly targeted agents continued to evaluate escalating doses using limited number of patients per dose cohort assessing dose-limiting toxicities to identify the MTD which is commonly selected for further development adopting a 'more is better' approach that led to several post-marketing requirement (PMR) studies to evaluate alternative, typically lower, doses or dosing frequencies to optimize the benefit-risk profile. In this review, post-marketing dose optimization efforts were reviewed including those required by a regulatory pathway or voluntarily conducted by the sponsor to improve efficacy, safety, or method of administration. Lessons learned and future implications from this deep dive review are discussed considering the evolving regulatory landscape on dose optimization for oncology compounds.

Tumor growth inhibition modeling to support the starting dose for dacomitinib.

Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor for first-line treatment of patients with metastatic non-small cell lung cancer and EGFR-activating mutations. A high rate of dose reductions in the pivotal trial led to an observed inverse exposure-response (ER) relationship with the primary end points. Three ER models were developed to determine if the starting dose from the pivotal trial, 45 mg once daily (q.d.) dose, is appropriate: a longitudinal logistic regression model for adverse event-related dose changes, a Claret tumor growth inhibition (TGI) model, and a Cox model for progression-free survival (PFS) based on the TGI model predictions. This analysis included 266 patients taking dacomitinib with a starting dose of 45 mg (N = 250) or 30 mg (N = 16) q.d. The ER relationships with the time-varying exposure metrics, most recent maximum plasma concentration (Cmax ) and average concentration (Cavg ) from the first dose, were established for the dose reduction and TGI models, respectively. The TGI model characterized the tumor inhibition over time with constant growth rate (kL  = 0.0012 years-1 ) and highly variable kill rate (kD  = 1.002 years-1 /[µg/L]θcavg , coefficient of variation [CV] = 89%) and drug resistance (λ = 14.47 years-1 , CV = 96%) leading to prolonged tumor shrinkage. The ER relationship was characterized using an exposure parameter with a power parameterization (θcavg = 0.454, p < 0.0001). The Cox model found that baseline tumor size (p = 0.0166) and week 8 tumor shrinkage rate (p = 0.0726) were the best predictors of PFS. Simulations of dose reductions and drug interruptions on tumor shrinkage over time showed greater and more prolonged tumor shrinkage with a starting dose of 45 mg q.d.

Analysis of US Food and Drug Administration Oncology Approvals on the Characterization of Hepatic Impairment Effect and Dosing Recommendations.

Patients with cancer and advanced hepatic impairment (HI) (i.e., moderate and severe impairment) are often excluded from first-in-patient, phase II, and phase III studies. Thus, dose recommendations for this subgroup of patients are often derived using a combination of dedicated phase I studies conducted in participants without cancer and a population pharmacokinetic (PK) modeling approach. A standardized risk-based approach to guide the evaluation of HI in patients with cancer is needed. In this review, we evaluated available oncology drug approvals by the US Food and Drug Administration (FDA) from 1999 to 2019, identified strategies utilized by sponsors to characterize the effect of HI on the PK of oncology drugs, and assessed regulatory expectations for each strategy. Finally, we constructed a decision tree that complements current FDA guidance to enable efficient evaluation of the effect of HI on PK and provide guidance for dose recommendations.

Discordance Between Child-Pugh and National Cancer Institute Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for Oncology Compounds.

Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA-approved oncology compounds. Discordance between Child-Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child-Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child-Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child-Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child-Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child-Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions bears consideration. When Child-Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted. Prescribers should attempt to use the same classification system in the product label for dosing decisions.

Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials.

Although without clear scientific rationale, body size-based dosing is often used for administering monoclonal antibodies (mAbs). This simulation study compared the performance of body size-based and fixed dosing in reducing pharmacokinetic (PK) and/or pharmacodynamic (PD) variability in adults for 12 mAbs with published population PK and/or PD models. At the population level, 95th percentile intervals of concentration-time profiles, distribution, and variability of exposure for 1000 subjects after both dosing approaches were examined. At the individual level, the difference between the exposures of patients with extreme body sizes from the typical exposure following both approaches was compared. The results show that the 2 dosing approaches perform similarly across the mAbs investigated with fixed dosing being better for some mAbs and body size-based dosing being better for the others. Based on this finding, we recommend using fixed dosing in first-in-human (FIH) adult studies because it offers other advantages. When sufficient data become available, a full assessment of body size effect on PK/PD should be conducted to determine the optimal dosing approach for phase 3 trials. Other factors that may affect the selection of dosing approach were also discussed. Dosing approach for mAbs in the pediatric population is out of the scope of this study.

Predicting Overall Survival and Progression-Free Survival Using Tumor Dynamics in Advanced Breast Cancer Patients.

Prediction of survival endpoints, e.g., overall survival (OS) and progression-free survival (PFS), based on early observations, i.e., tumor size, may facilitate early decision making in oncology drug development. In this paper, using data from six randomized trials for first- or second-line advanced breast cancer (ABC) treatments with various mechanisms of action, tumor size change from baseline at different observation time points was evaluated as a predictor for survival endpoints using different modeling approaches. The aim is to establish a predictive model where tumor size change from baseline can be used as a treatment independent predictive marker for PFS and OS in first- and second-line ABC. The results showed that tumor size change at single time point (TSP) or up to certain time points as a time-varying covariate (TSTVC) were significant predictors for OS and PFS in the survival models along with other covariates identified for each line of treatment. TSP and TSTVC models performed similarly for first-line treatments; TSTVC performed significantly better for second-line treatments. Eight weeks was selected as the recommended early evaluation time of tumor size change to predict OS and PFS in both first- and second-line treatment, while better prediction can be achieved for first-line OS by using 16 weeks tumor size change. The result of this study is treatment independent and can be used to predict the outcome of the clinical trials using early readout of tumor size change for the classes of drugs that have been evaluated in this study.

Clinical Implications of the Pharmacokinetics of Crizotinib in Populations of Patients with Non-Small Cell Lung Cancer.

PURPOSE: We assessed the effect of baseline patient demographic and disease characteristics on the crizotinib pharmacokinetic parameters oral clearance (CL/F), volume of distribution (V2/F), and area under the curve at steady state (AUCss) following multiple crizotinib 250-mg twice-daily dosing in patients with ALK-positive cancer. EXPERIMENTAL DESIGN: A pharmacokinetic model was fit to data from 1,214 patients. We identified statistically significant covariates (P ≤ 0.001) by evaluating their effects on CL/F and V2/F and estimated their magnitudes. RESULTS: Age, Eastern Cooperative Oncology Group performance status, aspartate aminotransferase (AST) levels, albumin levels, and smoking status had no effect on CL/F or V2/F. Statistically significant covariates were Asian race and female sex for CL/F and V2/F and body weight, creatinine clearance (CLcr), and total bilirubin for CL/F only. The model predicted that CL/F would be 9% lower or higher in a 40-kg or a 100-kg patient, respectively; 16% lower in patients with CLcr 30 mL/minute; 23% lower in Asians; and 11% lower in females than the reference patient (65-kg non-Asian male; baseline CLcr, 91.6 mL/minute; total bilirubin, 0.41 mg/dL). The effect of total bilirubin on CL/F was small. V2/F was 23% lower in Asians than non-Asians and females than males. Effects of all significant covariates on AUCss were not predicted to be clinically relevant. CONCLUSIONS: Crizotinib at a 250-mg twice-daily starting dose appears to be appropriate for all patients irrespective of age, sex, race, body weight, mild or moderate renal impairment, or hepatic function (in the range evaluated: bilirubin ≤ 2.1 mg/dL or AST ≤124 U/L). Clin Cancer Res; 22(23); 5722-8. ©2016 AACR.

Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma.

Tremelimumab, a fully human monoclonal antibody specific for human cytotoxic T-lymphocyte-associated antigen 4, has been studied in clinical trials. We have reported the results of population pharmacokinetics for tremelimumab in 654 metastatic melanoma patients. Population estimates (inter-individual variability [IIV]) for pharmacokinetic parameters in a final model were clearance (CL), 0.26 L/day (31.8%) and central volume of distribution, 3.97 L (20.4%). CL was faster in males, patients with higher values of creatinine clearance and endogenous immunoglobulin, and patients with relatively poor baseline prognostic factors. No dose adjustment was needed based on the magnitude of the change of CL (<30%). The association of CL and overall survival (OS) was investigated. In a Phase 3 trial evaluating tremelimumab as first-line-treatment, median OS for the 147 patients in the fast-CL group (≥ median CL value) was 9.6 months versus 15.8 months for the 146 patients in the slow-CL group (

Fixed dosing versus body size-based dosing of therapeutic peptides and proteins in adults.

Therapeutic biologics are often administered based on body size. A previous study has found that fixed dosing performs similarly to body size-based dosing in reducing intersubject variability in drug exposure across the mAbs studied. This study extended this evaluation to other therapeutic proteins and peptides. Eighteen therapeutic proteins and peptides with published population pharmacokinetic (PK) and/or pharmacodynamic (PD) models were selected for dosing approach evaluation. The relationships between body size and drug exposure (and PD end point when available) were evaluated, and simulation studies were conducted to compare the performance of the 2 dosing approaches. The results showed that fixed dosing performed better for 12 of 18 selected biologics in terms of reducing intersubject variability in exposure at both population and individual levels, whereas body size-based dosing performed better for the other 6 molecules. This result is consistent with the findings for mAbs. Therefore, fixed dosing is recommended for first-in-human studies of proteins and peptides along with mAbs. The final dosing approach for phase 3 studies should be determined based on a full assessment of body size effect on PK/PD when data are available and the therapeutic window of the drug.

The effect of mild and moderate hepatic impairment on the pharmacokinetics of valdecoxib, a selective COX-2 inhibitor.

PURPOSE: This study evaluated the effects of varying degrees of hepatic impairment on the pharmacokinetics and safety of valdecoxib following single and multiple dosing. METHODS: This was an open-label, randomised, parallel group study in 12 subjects with mild hepatic impairment (Child-Pugh Class A) and in 13 with moderate hepatic impairment (Child-Pugh Class B) matched for age, weight, sex, and smoking status; there were two control groups of 12 healthy volunteers, one for each study group. All subjects received a single dose of valdecoxib 20 mg on day 1 and valdecoxib 20 mg twice daily on days 4-7, followed by a single morning dose on day 8. Plasma concentrations of free (unbound) and total valdecoxib and its active hydroxylated metabolite (SC-66905) were measured following single and multiple dosing (day 1 and day 8). Additionally, all subjects received a single intravenous dose of lidocaine 60 mg during the pretreatment period to determine plasma concentrations of monoethylglycinexylidide (MEGX) as a marker of hepatic CYP3A4 activity. RESULTS: The mean apparent oral clearance of free valdecoxib in plasma at steady state decreased by 22-25% in those with mild to moderate impairment (corresponding to a 28-33% increase in the AUC of free valdecoxib and a 19-23% decrease in the AUC of total SC-66905). The mean free fraction of valdecoxib in plasma increased by 9-38%, resulting in a mean decrease in apparent oral clearance of total valdecoxib in plasma of 0-15% (corresponding to a 0-17% increase in the AUC of total valdecoxib). Individual AUCs for free valdecoxib and total SC-66905 did not correlate well with AUCs for MEGX, indicating that decreases in intrinsic clearance of valdecoxib in those with hepatic impairment could not solely be explained by decreased CYP3A4 expression in hepatic impairment. CONCLUSIONS: In our small study sample, mild and moderate hepatic impairment appeared to have only a modest effect on valdecoxib and SC-66905 pharmacokinetics. The adjustment of valdecoxib dose or dosing regimen does not appear mandatory in subjects with mild or moderate hepatic impairment, although caution is necessary during treatment of these patients with valdecoxib.