Informing the selection of clinically relevant pharmacokinetic target range for Therapeutic Drug Monitoring (TDM) of sunitinib: a pharmacometric simulation framework
Han Liu (1), Maddalena Centanni (1), Lena E. Friberg (1)
(1) Department of Pharmacy, Uppsala University, Sweden
Objectives:
Sunitinib is commonly used to treat gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma (mRCC). With sunitinib exposure related to both survival and adverse events (AEs) [1], therapeutic drug monitoring (TDM) based on pharmacokinetic (PK) measurements is suggested to reduce exposure variability and improve treatment outcomes [2]. For mRCC, a target range of 50-100 ng/mL for total Ctrough of sunitinib and its active metabolite SU12662 has been suggested for the 50 mg daily 4/2 (4 weeks, 2 weeks off) regimen [3]. However, this range was initially proposed based on animal studies [4] and supported by limited clinical knowledge [5]. For GIST, the target range has not been established, and therefore the same thresholds as for mRCC are recommended. Due to the limited evidence on which the exposure targets are based, the clinical benefits of TDM remain unclear. The aim of this simulation study is to quantify the expected clinical outcomes of proposed Ctrough-based therapeutic ranges for TDM of sunitinib in GIST, based on an earlier established simulation framework [6], and explore if alternative ranges may be more beneficial.
Methods:
The simulation framework for dose individualization of sunitinib includes an integrated PK model of sunitinib and SU12662 [7], linked with models describing the relationship between sunitinib daily area under the curve (AUC), sVEGFR, overall survival (OS), and undesired effects (fatigue, hand-foot syndrome [HFS], platelet count [PC], absolute neutrophil count [ANC], diastolic blood pressure [dBP]), informed by 303 GIST patients from 4 phase I-III trials [8,9].
A virtual population (n=10,000) received a 50 mg 4/2 regimen for 102 weeks as the base scenario. Observed measures of PC, ANC, and dBP were simulated at weeks 2, 4, 6, 8, 12, 16 and once every 12 weeks thereafter, and graded following the CTCAE criteria v5.0 for AEs of thrombocytopenia, neutropenia, and hypertension. Fatigue and HFS were evaluated on a daily basis. Dosing was temporarily suspended in case of grade 3 AEs, and resumed at 50 mg after resolution to grade 1 (grade 2 for neutropenia and hypertension) for the first-time occurrence of grade 3 AEs, or lowered by 12.5 mg for each additional incidence of grade 3 AEs.
The Ctrough was measured at weeks 2, 4, and 8, as proposed by Lankheet et al. [10]. Individuals with Ctrough below the efficacy threshold and without previous grade 3 AEs had their dose increased by 12.5 mg, while individuals with Ctrough above the toxicity threshold had their dose decreased by 12.5 mg. The possible sunitinib doses ranged from 12.5 to 75 mg, in 12.5 mg increments. Different TDM scenarios (n=321) were simulated with different combinations of efficacy (30 to 60 ng/ml, by 2.5 increments) and toxicity thresholds (70 to 170 ng/ml, by 5 increments).
Results:
At the target range of 50-100 ng/ml, 72.3% of individuals received an adjusted dose. Compared to the base scenario without TDM, the OS increased in 33.6% of individuals, on average by 5.30 weeks, with the majority (74.0%) having unchanged number of ≥ grade 3 AEs. However, OS also decreased in 26.9% of individuals, on average by 7.48 weeks, with the majority of these individuals having unchanged number or decreased by 1 event of ≥ grade 3 AEs (31.2% and 51.3%, respectively). OS was the same in 39.4% of patients, with the majority (53.9%) having unchanged AEs. On a population level, median OS was decreased compared to the base scenario without TDM (19.1 vs. 19.3months), and the total cumulative number of ≥ grade 3 AEs was decreased by 936 events across the 10,000 individuals (-620, -261, -50, -8, +3 for hypertension, thrombocytopenia, HFS, fatigue, and neutropenia, respectively). Alternative therapeutic windows for TDM could result in improved median OS with a similar or higher risk of AE events compared to the base scenario, e.g. a target range of 52.5-115 ng/ml increased median OS by 1.57 weeks and ≥ grade AEs by 66, or decreased median OS with lower risk of AEs, e.g. 40-90 ng/ml decreased both median OS by 3.57 weeks and number of ≥ grade AEs by 2341.
Conclusions:
These findings could be used in clinical practice to select an optimized therapeutic window, based on the most desired clinical outcomes. Further sensitivity analysis could help to define the impact of parameter uncertainty.
References:
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