Clinical Trial Simulations for Dosage Optimization of Docetaxel in Patients with Liver Dysfunction, Based on a Log-binominal Regression for Febrile Neutropenia

Abstract

This study was aimed to perform clinical trial simulations to evaluate the dose reduction strategy of docetaxel for Japanese patients with liver dysfunction, which we previously proposed. For this purpose, a log-binominal regression (LBR) was performed for febrile neutropenia (FN) induced by docetaxel in these patients. A LBR analysis was conducted using clinical data from cancer patients treated with docetaxel and incorporated in the subsequent trial simulation. Virtual patients with liver dysfunction were randomly assigned to receive the Japanese standard dose (60 mg/m 2 ) or reduced dose (40 or 50 mg/m 2 ) of docetaxel. The primary endpoint was overall survival of the reduced dose to the standard dose. The secondary endpoint was the number of patients who experienced FN in response to the two treatment regimens. From the LBR analysis, the performance status and the area under the plasma concentration-time curve (AUC) were selected as covariates associated signiˆcantly ( p＜0.05) with FN occurrence. From the results of the present trial simulation, the median proportion of patients who experienced FN was decreased by about 20％ in the reduced dose arm. Non-inferiority criteria, the reduced dose group to the standard dose group were met in 85.5％ of the simulated clinical trials with a decrease in the FN frequency. In conclusion, clinical trial simulation models for the e‹ca-cy (survival) and toxicity (FN) wasˆrst performed in Japanese patients, and the feasibility of docetaxel therapy for liver-dysfunction patients under the dose reduction strategy was supported.

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability

“…It has been reported that an average of 37% of obese patients undergoing bariatric surgery have NASH, which is higher than the rate observed in the general US adult population (Lazo and Clark, 2008). For both morphine and docetaxel, hepatic dysfunction is well documented to alter PK and requires dose-adjustment to avoid the occurrence of ADRs, potentially due to alteration in hepatic metabolism and transporter function (Bruno et al, 2001; Eckmann et al, 2014; Hasselström et al, 1990; Linares et al, 2009; Ozawa et al, 2008, 2009; Yoon et al, 2012). For docetaxel, several studies have attempted to assess whether doses should be adjusted based on various measures of obesity and body surface area (Griggs et al, 2012; Rudek et al, 2004; Sparreboom et al, 2007).…”

Pharmacokinetics, Food Effect, Ketoconazole Interaction, and Safety of JTK‐853, a Novel Nonnucleoside HCV Polymerase Inhibitor, After Ascending Single and Multiple Doses in Healthy Subjects

“…22,23 In the current assessment, the structural PK model parameters and associated variability estimates were used to simulate plasma concentration vs time profiles in 1000 hypothetical subjects at each of the following doses: 800 mg BID, 1200 mg BID, 1600 mg BID, and 1200 mg 3 times daily (TID). The estimated mean parameters and variability estimates from the modeled data were used in Trial Simulator (version 2.2; Certara, Princeton, New Jersey) for dose selection and justification in a (separate) 3-day PoC study in HCV patients.…”

“…The Trial Simulator uses Monte Carlo simulations based on a stochastic drug model to test various assumptions and scenarios. 22,23 In the current assessment, the structural PK model parameters and associated variability estimates were used to simulate plasma concentration vs time profiles in 1000 hypothetical subjects at each of the following doses: 800 mg BID, 1200 mg BID, 1600 mg BID, and 1200 mg 3 times daily (TID). At each dose level, the distribution of individual trough JTK-853 concentrations (ie, at 24, 48, and 72 hours) were categorized based on EC 90 multiples (<1, ࣙ1, 1 to <2, 2 to <3, and ࣙ3), and the percentage of subjects in each category was computed.…”

Receiver Operating Characteristic Analysis and Clinical Trial Simulation to Inform Dose Titration Decisions

“…Selecting an optimal dosing regimen for new molecular entities is pivotal in the demonstration of positive benefit‐to‐risk balance, and, in turn, to drug approval. For drugs having a wide therapeutic margin, a single available dose (flat dosing) may be safe and effective even without regard to dose adjustments in special populations despite pharmacokinetic (PK) variability resulting from intrinsic and extrinsic factors . However, for drugs with narrow therapeutic indices, flat dosing generally does not provide the optimal benefit‐to‐risk ratio across subjects in the target population.…”

“…For drugs having a wide therapeutic margin, a single available dose (flat dosing) may be safe and effective even without regard to dose adjustments in special populations despite pharmacokinetic (PK) variability resulting from intrinsic and extrinsic factors. [1][2][3][4] However, for drugs with narrow therapeutic indices, flat dosing generally does not provide the optimal benefit-to-risk ratio across subjects in the target population. In such cases, dose titration algorithms may be needed to achieve a desirable benefit-to-risk balance.…”