Effect of Hemodialysis on Total and Free Lenvatinib Concentrations in a Patient With Metastatic Renal Cell Carcinoma

ABSTRACT

Introduction

Lenvatinib (LEN) concentrations in patients undergoing hemodialysis (HD) have not been examined. Herein, we report the effect of HD on total and free LEN concentrations in a patient with mRCC.

Case Presentation

The hemodialyzed patient was a 55‐year‐old Japanese male who was treated with 20 mg LEN daily. The area under the plasma concentration–time curve for LEN from 0 to 24 h (AUC_0–24) was calculated on Day 8 (off HD) and Day 9 (on HD) after starting administration of LEN. For total LEN on Days 8 and 9, the AUC_0–24 was 2553 and 2783 ng × h/mL, respectively. The free LEN concentration just after HD on Day 9 was 40% lower than that at the same time on Day 8 (1.8 vs. 3.0 ng/mL).

Conclusion

Although the free LEN concentration is reduced just after HD, LEN will have sufficient pharmacological activity on HD days for patients undergoing HD.

Summary.

• We report the effect of hemodialysis on total and free lenvatinib concentrations.

• The free lenvatinib concentration just after hemodialysis on Day 9 was 40% lower than that at the same time on Day 8 (off hemodialysis day).

• The exposure of total lenvatinib was little affected by hemodialysis.

1. Introduction

Lenvatinib (LEN), an inhibitor of multiple receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGFR) [1], is used in combination with pembrolizumab for first‐line treatment of metastatic renal cell carcinoma (mRCC) [2]. However, about 70% of patients require dose reduction in LEN due to severe adverse events [3]. Dose‐limiting toxicity and tumor shrinkage have been associated with the total LEN trough concentration [4, 5], and dose adjustment based on therapeutic drug monitoring is required.

LEN is administered to many different patients in the daily clinical setting. A phase III trial has examined the use of LEN in patients with adequate renal function [3], but experience with LEN in patients undergoing hemodialysis (HD) is limited [6]. Evaluation of free and total drug concentrations is critical because only the free form is relevant for pharmacological activity. Analytical methods for the assessment of both total and free LEN concentrations have been described using liquid chromatography–tandem mass spectrometry (LC–MS/MS) combined with equilibrium dialysis [7] and using ultrafiltration [8]. However, LEN concentrations in patients with HD have not been examined. Herein, we report the effect of HD on total and free LEN concentrations in a patient with mRCC.

2. Case Presentation

A 55‐year‐old Japanese male patient with mRCC was enrolled. The patient started chronic HD because of focal segmental glomerulosclerosis in 2001. Computed tomography performed in November 2024 revealed the presence of a mass lesion in the right kidney, suspected to be renal cancer with multiple bone metastases. The stage of the tumor was determined to be cT3bN0M1. The patient underwent tumor biopsy in December 2024 and was histopathologically diagnosed with clear cell renal cell carcinoma. The combination therapy of LEN (20 mg orally once daily) plus pembrolizumab was started as a first‐line therapy for mRCC in January 2025. HD was performed for 4 h, three times weekly. An APS‐21SA polysulfone dialyzer (Asahi Kasei Medical, Tokyo, Japan) was used. The blood flow rate was 250 mL/min. Blood samples were collected just before LEN administration (0 h) and then 2, 6, 12, and 24 h after LEN administration on Day 8 (off HD) and Day 9 (on HD). HD was performed 2 to 6 h after LEN administration, when LEN plasma concentrations were expected to be relatively high. The blood samples were centrifuged (1900g at 20°C for 15 min), and then an aliquot of the obtained plasma was immediately ultrafiltered. The area under the plasma concentration–time curve for LEN from 0 to 24 h (AUC_0–24) was calculated using the trapezoidal rule.

Free LEN was fractionated from 200 μL of plasma samples using an ultrafiltration device for 30 min at 2000g at 37°C. Total LEN was purified from 50 μL of non‐filtrated plasma samples. Both total and free LEN concentrations were determined using LC–MS/MS. The multiple reaction monitoring transition of LEN was m/z 427.0 > 370.0 [9]. The detection was linear at concentrations ranging from 30 to 500 ng/mL for total LEN (r = 0.999, p < 0.001), and from 1 to 25 ng/mL for free LEN (r = 1.000, p < 0.001). The data obtained met the criteria required by the US Food and Drug Administration [10].

For total LEN on Days 8 and 9, the maximum plasma concentration (C _max) was 167.4 and 189.1 ng/mL, and AUC_0–24 was 2553 and 2783 ng × h/mL, respectively (Figure 1A). For free LEN on Days 8 and 9, C _max was 3.0 and 2.6 ng/mL, and AUC_0–24 was 50.5 and 44.6 ng × h/mL, respectively (Figure 1B). The free LEN concentration just after HD on Day 9 was 40% lower than that at the same time on Day 8 (1.8 vs. 3.0 ng/mL). Protein binding rates of LEN on Days 8 and 9 were 97.8%–98.7% and 97.6%–99.0% (range), respectively (Figure 1C).

FIGURE 1.

Change of (A) total lenvatinib concentration, (B) free lenvatinib concentration, and (C) protein binding rate on Day 8 (off hemodialysis) and Day 9 (on hemodialysis). Arrows show administration of 20 mg of lenvatinib. The 4‐h hemodialysis started 2 h after administration on Day 9. HD, hemodialysis.

Grade 3 neutropenia, grade 2 oral mucositis, and grade 2 thrombocytopenia developed after 5 weeks, necessitating a 1‐week interruption of LEN. LEN administration was resumed at a dose of 14 mg/day. Due to grade 2 thrombocytopenia and neutropenia, the LEN dose was further reduced to 10 mg/day 7 weeks after treatment initiation. The dose intensity of LEN was 13.7 mg/day. Three months after the initiation of the treatment, the tumor had decreased in size, which was judged to be a partial response (Figure 2).

FIGURE 2.

Computed tomography images of the right kidney lesion: (A) before treatment with lenvatinib plus pembrolizumab and (B) 3 months after initiation of the treatment.

3. Discussion

The pharmacokinetic pattern of free LEN on Day 9 differed slightly from that on Day 8 in this case. Interestingly, the free LEN concentration just after HD on Day 9 was 40% lower than that at the same time on Day 8 (Figure 1B). This suggests that free LEN was partially eliminated during HD. The half maximal inhibitory concentration of LEN for VEGFR‐2 phosphorylation in endothelial cells is 0.83 nmol/L [1], which is approximately equivalent to a plasma‐free concentration of 0.4 ng/mL. The free LEN trough concentrations in our case on Days 9 and 10 were above 1.1 ng/mL, suggesting that LEN will have sufficient pharmacological activity on HD days. In fact, the systemic exposure to free LEN as AUC_0–24 on Day 9 was similar to that on Day 8 (44.6 vs. 50.5 ng × h/mL), and this patient showed a partial response after 3 months (Figure 2).

The AUC_0–24 of total LEN was little affected by HD (Figure 1A). LEN has been reported to have a high protein binding rate (96.6%–98.2%) [11], consistent with the high binding observed in this patient (Figure 1C). Thus, LEN in plasma may only rarely be removed during HD because the large plasma protein–LEN complex is unable to pass through the HD membrane.

The AUC_0–24 of total LEN on Day 9 was 2783 ng × h/mL, which is comparable with that in patients with normal renal function receiving 20 mg of LEN [12]. The reported AUC_0–24 values of total LEN are 2500 ± 647 and 3690 ± 1790 ng × h/mL (mean ± standard deviation) on Days 1 and 15, respectively [12]. This suggests that the pharmacokinetic properties of total LEN are not affected by renal function.

This study is limited in that it refers to a single patient on HD, and thus, a study in a larger number of patients is needed to validate the results. Since the steady state of LEN has been reported to be achieved in 8 days [12], we adopted Days 8 and 9 as the blood sampling days in this case. This patient was discharged on the morning of Day 10, which made it difficult to perform frequent blood sampling afterward. Given the possible interpatient variability, it would be preferable to perform blood sampling at a later time point. Within these limitations, we conclude that, although the free LEN concentration is reduced just after HD, LEN will have sufficient pharmacological activity on HD days for patients with mRCC undergoing HD.

Ethics Statement

This study was approved by the Wakayama Medical University Ethics Committee (No. 4332).

Consent

Written informed consent was obtained from the patient for the publication of this case report.

Conflicts of Interest

Yasuo Kohjimoto is an Editorial Board member of the International Journal of Urology Case Report and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.