Integrated semi‐physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662

Abstract

AIMSPreviously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice. METHODSOne thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using non-linear mixed effects modelling (NONMEM). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens. RESULTSSunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h −1 and 17.1 (RSE 7.4%) l h −1 , respectively for 70 kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy. CONCLUSIONSA semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in many aspects. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The necessity and evidence of therapeutic drug monitoring has been reported for sunitinib and its active metabolite SU12662.• Pharmacokinetic modelling has proved its utility in therapeutic drug monitoring.• Limitations existed for a previous published pharmacokinetic model for sunitinib and SU12662 in the application of therapeutic drug monitoring. WHAT THIS STUDY ADDS• We presented a superior pharmacokinetic model for sunitinib and SU12662 including pre-systemic metabolism.• The simulation of the current model obtained the correct concentration range for sunitinib and SU12662.• The model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy in clinic observations.

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

“…9 Of note, the plasma sunitinib concentration with the low dose of sunitinib was comparable with the concentration measured in patients treated with a standard dose of sunitinib of 50 mg per day. 15 However, the concentration of its active metabolite N-desethyl sunitinib was markedly higher, indicating increased metabolism of the parent compound in rats, as reported previously. 18 Glomerular endotheliosis, sometimes accompanied by thrombi, is a hallmark of angiogenesis inhibition-induced renal injury.…”

“…The plasma concentration of sunitinib at the lowest dose was comparable with the systemic concentrations reached in patients treated with a standard daily dose of sunitinib of 50 mg. 15 Sunitinib is metabolized by cytochrome P450 3A4 to the active compound N-desethyl sunitinib. Even at the lowest dose of sunitinib, the plasma concentration of this compound in rats was much higher than in patients during standard dosing.…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…TDM for sunitinib is generally performed using the sum of concentrations (total C min ) of both sunitinib and SU12662 71. Dose‐limiting and Grade ≥3 toxicities of sunitinib have been associated with total C min ≥100 ng/mL 17, 72.…”

Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours

“…The pharmacokinetics of sunitinib have been well characterised in several compartmental models [8,9]. Exposure-response relationships have also been established for several clinical outcome measures, such as time to tumour progression (TTP) and overall survival [6].…”

“…Here, we combined the results from three published papers on the pharmacokinetics, efficacy and dose-limiting toxicity of sunitinib into a single simulation model [6,7,9]. Based on initial simulations, we decided to focus on the clinically relevant endpoint of TTP in patients with GIST.…”