Dose Finding of Lenvatinib in Subjects With Advanced Hepatocellular Carcinoma Based on Population Pharmacokinetic and Exposure-Response Analyses

Abstract

Hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer occurrences worldwide. Lenvatinib, a multikinase inhibitor, was approved in radioiodine‐refractory differentiated thyroid cancer. In this phase 2 study (study 202), we aimed to identify the lenvatinib optimal dose for subjects with advanced HCC Child‐Pugh class A. Pooled data from phase 1 studies in healthy adults and in subjects with mixed tumor types, and from study 202 in subjects with HCC, were analyzed using a population pharmacokinetic approach. The relationship between treatment‐emergent adverse events leading to withdrawal or dose reduction during cycle 1 and lenvatinib exposure was explored by logistic regression analysis. A receiver operating characteristics analysis was used to investigate the best cutoff values of lenvatinib exposure and body weight to identify a high‐risk group for early dose modification. The final pharmacokinetic model included body‐weight effects on apparent clearance and volume. The relationship between the lenvatinib area under the plasma concentration–time curve (AUC) at steady state and body weight demonstrated an increase in AUC as body weight decreased in subjects with HCC. An exposure–response relationship was observed, with higher lenvatinib AUC and lower body weight resulting in earlier drug withdrawal or dose reduction. The best cutoff values for body weight and lenvatinib AUC were 57.8 kg and 2430 ng·h/mL, respectively, to predict the group at high risk for early drug withdrawal or dose reduction. We therefore recommend 12‐mg and 8‐mg starting doses for subjects ≥60 kg and <60 kg, respectively, in subjects with HCC Child‐Pugh class A.

Lenvatinib in Advanced Hepatocellular Carcinoma

“…AUC, area under plasma concentration-time curve at steady state; ROC, receiver operating characteristics; TEAE, treatment-emergent adverse event. Cited from Tamai et al [15]. …”

“…AUC, area under the plasma concentration-time curve at steady state; TTP, time to progression. Cited from Tamai et al [15] …”

“…Following the phase I and II studies, population pharmacokinetics was analyzed in 65 HCC patients enrolled in these trials and in 155 patients with solid cancer and 232 healthy individuals enrolled in other clinical studies [15]. A relationship between body weight and plasma lenvatinib level (represented by the area under the blood concentration-time curve [AUC]) was detected, indicating that exposure to lenvatinib increased as body weight decreased (Fig.…”

Lenvatinib May Drastically Change the Treatment Landscape of Hepatocellular Carcinoma

“…Close examination of the patients' background suggested that body weight and serum lenvatinib levels were associated with dose reduction or early treatment withdrawal. More precisely, patients who had dose reduction or early withdrawal within 30 days of lenvatinib treatment were significantly lighter (median weight, 54.1 vs. 67.6 kg) and had a significantly higher minimum plasma concentration of lenvatinib (trough concentration [C1D15C trough ], 62.4 vs. 33.9 ng/mL) [36,37].…”

“…Following the phase I and II trials, population pharmacokinetics were analyzed in 65 HCC patients enrolled in those trials, and in 155 patients with solid cancer and 232 healthy individuals enrolled in other clinical trials [36]. A relationship was observed between body weight and plasma lenvatinib level (represented by the area under the blood concentration time curve [AUC]), indicating that exposure to lenvatinib increased as body weight decreased [36,37].…”