Axitinib is a tyrosine kinase inhibitor approved in the second-line treatment of metastatic renal cell carcinoma (mRCC). Its pharmacokinetics is characterized by rapid absorption (peak plasma concentrations at 2–6 h after intake), short half-life (t1/2 = 2–5 h), and metabolic elimination through cytochrome metabolism. Moreover, axitinib presents an important inter-individual pharmacokinetic variability, including the risk of under-exposure. Therefore, its dosing may be titrated according to clinical tolerance, mainly hypertension which correlates with clinical outcomes [1]. Importantly, this drug is currently investigated in combination with anti-PD1/anti-PDL1 antibodies in mRCC with promising results [2]. Pharmacologic therapeutic monitoring (PTM) could support dose adjustments and drug exposure in such combinations.

Fifteen patients treated in 3 University Hospital in Paris between 2014 and 2016 had available routine axitinib dosages. Median age was 65 years [range: 42.1–86.2]. All dosages were centralized in the Pharmacology Laboratory of Henri Mondor University Hospital. Axitinib quantification used a validated liquid chromatography-tandem mass spectrometry method. Internal quality controls were regularly performed. Overall, concentrations ranged between 1 to 500 ng/mL (lower limit of quantification: 1 ng/mL). Six patients had very low/undetectable trough concentrations. In view of the short half-life of axitinib, our pharmacokinetic analysis focused on Cmax dosages which is usually performed 1 to 6 h after oral intake. Nine patients had Cmax measurements.

According to published data in patients exposed to axitinib titration, mean Cmax was 28.6 ng/ml (CI95% [20.5–39.9]) [2]. Five patients had Cmax concentration ≥ 20.5 ng/mL at 5 mg bid while 4 patients had Cmax concentrations below 20.5 ng/mL. Patients with Cmax < 20.5 ng/mL had no axitinib-related hypertension and were subsequently managed by axitinib titration on the basis of clinical tolerance, according to French and international routine guidelines. Cmax measurements were performed at each axitinib dose modification.

Three out of the four patients with Cmax < 20.5 ng/mL had successful Cmax increase within range after titration. The last patient (Patient D, Fig. 1a) remained at undetectable plasma axitinib Cmax concentration.

Fig. 1
figure 1

Axitinib exposure at baseline and after titration. a. Titration efficiency after dose escalation. For each patient (A to D), axitinib maximal concentration (Cmax) at each dose level before (white bars) and after (grey bars) dose increase. N + N indicates axitinib bid intakes for each dose level. b. Pharmacokinetic analysis for patient D. Axitinib doses were 10 mg bid for black dots (H12 (trough concentration), H1, H2), and 5 mg and 7 mg bid for grey dots (H4:45 and H6, respectively)

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This 43 years-old woman, with ECOG performance status 0, without any previous medical or surgical condition, was diagnosed of mRCC and was initially treated with frontline sunitinib. At progression seven months later, she received axitinib 5 mg bid and was subsequently monitored in the Henri Mondor Hospital routine PTM program. Good compliance was confirmed by interview and pill count. No potential drug interaction was found, with the exception of active tobacco use (one pack per day). She did not use estroprogestative contraception. Figure 1b summarizes all dosages performed for this patient. Two dosages were performed during titration, revealing undetectable plasma axitinib concentrations. In-hospital controlled oral intake was realized at 10 mg bid (maximum recommended dose). Dosages were performed in fasting condition before oral intake, and after one and two hours. We observed only a very slight concentration increase, which remained out of the published range ([20.5–39.9] ng/mL [2]). This pattern suggested a poor absorption of axitinib and/or rapid metabolizing phenotype. This patient had early progressive disease as best response.

We report here one patient with titration failure, implying concerns about a potential subsequent lack of antitumor efficacy. Axitinib is metabolized primarily in the liver by cytochrome P450 (CYP) 3A4/5 and, to a lesser extent (<10%), by CYP1A2, CYP2C19, and uridine diphosphate glucuronosyltransferase (UGT) 1A1. One previous case of poor axitinib exposure was reported and suggested involvement of intestinal CYP3A4 into axitinib poor absorption, corrected with the use of CYP3A4 inhibitor [3]. Poor absorption related to intestinal metabolism is probably the main cause of low exposure in the present case but active smoking, as a CYP1A2 inductor may also be involved.

Pharmacokinetic considerations appear to be of interest in axitinib-treated mRCC patients and should be considered in further development of combination therapies with anti-PD1/PD-L1. Of note, axitinib doses are for now fixed at 5 mg bid in combination with avelumab [2], which may result in a higher risk of axitinib under-exposure, and a potential lack of efficacy. Further pharmacokinetic studies are warranted to confirm these data and prospectively validate PTM for axitinib.