Population pharmacokinetics and individualized lobaplatin regimen for the treatment of Chinese small cell lung cancer in the elderly

Abstract

Background: Lobaplatin (LBP) is a third-generation platinum compound.

Material and methods: This prospective study was performed in 7 institutions in 2014-2016. Elderly small cell lung cancer (SCLC) patients (≥65 years old) were divided into 2 groups to receive LBP regimens according to endogenous creatinine clearance rate (Ccr). LBP was administered at 30 and 20 mg/m in groups A (Ccr ≥ 80 ml/min) and B (60 ml/min ≤ Ccr < 80 ml/min), respectively. The primary endpoint was plasma LBP concentrations. Secondary endpoints were safety and efficacy parameters, including progression-free survival (PFS) and overall survival (OS).

Results: One-hundred patients were enrolled. Median PFS and OS in groups A and B were 155 vs170 days and 306 vs 272 days, respectively. The rates of grade III/IV AEs in groups A and B were 60.8% (n = 31) and 51.0% (n = 25), respectively. In population pharmacokinetics, the area under the curve (AUC) value for group B was 39% lower than that of group A. With LBP administration based on body surface area (BSA), AUC differences between individuals were small.

Conclusion: With Ccr ≥ 60 ml/min, BSA based administration is necessary. Meanwhile, LBP-based regimens are reliable in treating elderly patients with SCLC.

Figure 1

Study flowchart.

Figure 2

Final goodness of fit evaluation for the Pop PK model. Upper left, observed value versus individual predictive value; upper right, observed value vs group predictive value; bottom left, conditional weighted error vs group predictive value; bottom right, conditional weighted error versus point-in-time. The dotted line represents accuracy (diagonal), and the solid one is the Lowess trend line. PK = pharmacokinetic.

Figure 3

Visual predictive testing of the Final Pop PK Model. Gray points are measured values. The solid line is the median of 1000 simulations in the final model of plasma LBP concentrations, indicating the 2.5th and 97.5th quantiles. The shading represents the 95% confidence interval for each quantile. LBP = lobaplatin, PK = pharmacokinetic.

Figure 4

(A) Simulation chart of patients treated at a fixed dose. Left panel, patients with Ccr < 80 ml/min; right panel, patients with Ccr ≥ 80 ml/min. The different colored lines represent populations with distinct BSAs, respectively, and the corresponding median AUCs are plotted. (B) Simulation chart of patients with different Ccr values using BSA-based administration of 30 mg/m². Left, patients with a BSA of 1.24 m²; middle, patients with a BSA of 1.675 m²; right, patients with a BSA of 2.09 m². The different colored lines represent populations with distinct BSAs, respectively, and the corresponding median AUCs are plotted. (C) Simulation chart of patients with LBP administration based on the experimental regimens. Left, patients with a BSA of 1.24 m²; middle, patients with a BSA of 1.675 m²; right, patients with a BSA of 2.09 m². The different colored lines represent populations with distinct BSAs, and the corresponding median AUCs are plotted. (D) Simulation chart of patients with LBP administration based on adjusted experimental regimens. Left, patients with a BSA of 1.24 m²; middle, patients with a BSA of 1.675 m²; right, patients with a BSA of 2.09 m². The different colored lines represent populations with distinct BSAs, respectively, and the corresponding median AUCs are plotted. AUC = area under the curve, BSA = body surface area, Ccr = creatinine clearance rate, LBP = lobaplatin.