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Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism

BMC Cancer volume 24, Article number: 1131 (2024) Cite this article

Abstract

Background

Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort.

Methods

The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro.

Results

Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0→t), AUC(0→∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib.

Conclusions

Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.

Peer Review reports

Introduction

As an oral multi-targeted receptor tyrosine kinase inhibitor (TKI), sunitinib primarily functions by inhibiting the split-kinase domain group of TKIs. It also prevents formation of tumor-disordered vasculature and induces vascular normalization [1,2,3]. Sunitinib was received initial FDA approval in 2006 for managing advanced renal cell carcinoma (RCC). Subsequently, it was authorized for individuals with advanced pancreatic neuroendocrine tumors and gastrointestinal mesenchymal cancers who were not responsive to imatinib [4]. Sunitinib is predominantly metabolized by the enzyme cytochrome P450 3A4 (CYP3A4) (Fig. 1A), which produces N-desethyl sunitinib (Fig. 1B), its principal metabolite [5]. N-desethyl sunitinib exhibits comparable potency to sunitinib in biochemical and cellular studies [6], indicating that monitoring the plasma concentrations of both sunitinib and N-desethyl sunitinib can guide rational dosing and help prevent adverse effects.

Fig. 1
figure 1

Chemical structures of sunitinib (A) and N-desethyl sunitinib (B), and the chromatographic information of sunitinib, N-desethyl sunitinib and dasatinib (IS) (C)

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In 2015, isavuconazole, a novel triazole antifungal, received approval for the management of invasive mucormycosis (IM) and invasive aspergillosis (IA) [7]. Furthermore, isavuconazole has shown efficacy in treating invasive candidiasis (IC), particularly in rare cases of invasive fungal disease (IFD) [8]. Additionally, because of its broader spectrum of antimicrobial activity and fewer adverse effects, isavuconazole has also been utilized to treat COVID-19-associated mucormycosis (CAM), among other conditions [9]. A clinical study involving healthy volunteers revealed that isavuconazole functions both as a substrate and a moderate inhibitor of the enzyme CYP3A4 in vivo. When administered concurrently with isavuconazole, the mean AUC(0→∞), AUClast, and Cmax values of midazolam were raised to 203%, 206%, and 172%, respectively, indicating that isavuconazole markedly enhanced the exposure of midazolam, a substrate highly sensitive to CYP3A4 metabolism [10]. Additionally, another study observed a moderate elevation in the concentration/dose ratio of tacrolimus and sirolimus in patients who had undergone hematopoietic stem cell transplantation and were receiving isavuconazole [11].

Drug-drug interaction (DDI) is one of the various factors influencing drug plasma exposure. Moreover, changes in medication efficacy may result from the inhibition or activation of drug and substance metabolizing enzymes [12]. DDI may elevate the risk of therapeutic failure or increase the incidence of adverse events (AEs), with cytochrome P450-based drug metabolism plays a major role in DDI [12, 13]. Immunodeficiency limits the prevention, therapy, and clearance of the viruses. Consequently, the use of combination therapy during cancer treatment, particularly during the COVID-19 pandemic, heightens the likelihood of respiratory viral infections in cancer patients and other immunocompromised individuals [14]. The likelihood of concomitant antifungal use of isavuconazole in cancer patients taking sunitinib is significantly elevated. Since isavuconazole inhibits CYP3A4, increased plasma levels of sunitinib may result from the combination of isavuconazole and sunitinib. To date, no relevant DDI studies have been conducted on the combination of sunitinib and isavuconazole.

Therefore, we evaluated how isavuconazole influences the pharmacokinetics profile of sunitinib and its primary metabolite N-desethyl sunitinib in rats, using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The effects of isavuconazole on sunitinib metabolism and its underlying mechanism in rat liver microsomes (RLM) and in human liver microsomes (HLM) were also investigated in vitro. The findings from this study may contribute to a deeper understanding of optimal sunitinib dosing, thereby supporting rational and individualized clinical dosing strategies.

Materials and methods

Chemicals and reagents

Sunitinib, isavuconazole, internal standard (IS) dasatinib, and N-desethyl sunitinib were obtained from Shanghai Canspec Scientific Instruments Co., Ltd (Shanghai, China). HLM was sourced from iPhase Pharmaceutical Services Co., Ltd. (Beijing, China). The mobile phase methanol and acetonitrile were purchased from Merck (Darmstadt, Germany). Shanghai Aladdin Biochemical Technology Co., Ltd. (Shanghai, China) provided reduced nicotinamide adenine dinucleotide phosphate (NADPH).

UPLC-MS/MS detection conditions

The concentrations of sunitinib, N-desethyl sunitinib, and IS were quantified using a Waters Acquity UPLC system (Milford, MA, USA) fitted with an Acquity BEH C18 column (2.1 mm × 50 mm, particle size 1.7 μm) operated at 40 °C. 0.1% formic acid in water (A) and acetonitrile (B) were used as the mobile phase. The flow rate was adjusted to 0.40 mL/min and maintained consistently over a period of 2.0 min. 80% A was eluted for 0 to 0.5 min, followed by 80–20% A for 0.5 min to 1.0 min, 20% A for 1.0 min to 1.4 min, 20–80% A for 1.4 min to 1.5 min, and 80% A for 1.5 min to 2.0 min. For every running procedure, the auto-sampler was configured to maintain a temperature of 10 °C and an injection volume was 0.2 µL. A Waters XEVO TQS triple quadruple mass spectrometer was used for quantification. Multiple reaction monitoring (MRM) was then chosen to identify the analytes in positive mode. The ion transitions selected for sunitinib, N-desethyl sunitinib, and the IS were m/z 399.30 → 282.96, m/z 371.03 → 282.95, and m/z 488.03 → 401.10, respectively.

RLM preparation

After weighing the rat liver, phosphate-buffered saline (PBS) containing 0.25 mM sucrose was added and homogenized at the ratio of 1 g of liver to 2.5 mL of pre-cooled PBS-0.25 mM sucrose buffer. The homogenate was centrifuged at 11,000 rpm for 15 min. The supernatant was then collected and subjected to a second centrifugation under the same conditions. This supernatant was subsequently centrifuged at 75,600 × g for another 2 h at 4℃. Then, three times the volume of PBS buffer was added to the precipitate and thoroughly mixed. Finally, a BCA protein assay kit (Thermo Scientific) was used to determine the protein concentration [15].

Kinetic study of sunitinib using HLM and RLM

To explore the Km (Michaelis-Menten constant) in RLM, a total reaction volume of 200 µL was prepared, including 1 M PBS, 0.3 mg/mL RLM, 1 mM NADPH, and 1–200 µM sunitinib. Similarly, the HLM incubation system was consisted of 1 M PBS, 0.3 mg/mL HLM, 1 mM NADPH, and 1–200 µM sunitinib. Prior to the reaction, the mixture was pre-incubated at 37 °C for 5 min, and the reaction was initiated by adding 1 mM NADPH. After 30 min of incubation at 37 °C, 20 µL IS working solution and 2-fold volume of acetonitrile relative to the reaction mixture were added to terminate the reaction. The mixture was then centrifuged for 10 min at 13,000 rpm after being vortexed for 2 min. After that, the supernatant was transferred for analysis by analytical instruments.

Mechanism and inhibitory impact of isavuconazole on sunitinib in vitro

To assess potential DDI between sunitinib and inhibitors, sunitinib was maintained at a concentration of 32.08 µM in RLM, corresponding to its Km value, and the inhibitors were used at 100 µM. A parallel experiment was conducted if the metabolic rate fell below 20%.

In order to ascertain the half maximal inhibitory concentration (IC50) of isavuconazole, its concentrations in RLM and HLM were varied at 0, 0.01, 0.1, 1, 10, 25, 50, and 100 µM. Concurrently, the concentrations of sunitinib in RLM and HLM were set at 32.08 µM and 36.45 µM, respectively, corresponding to the matching Km values. Moreover, according to the corresponding Km values, sunitinib concentrations were respectively adjusted to 8.02, 16.04, 32.08, and 64.16 µM in RLM and 9.12, 18.23, 36.45, and 72.90 µM in HLM to investigate the possible mechanism for DDI between isavuconazole and sunitinib. And according to the corresponding IC50 values, the concentrations of isavuconazole were adjusted to 0, 0.33, 0.67, 1.33, and 2.66 µM in RLM and 0, 1.33, 2.65, 5.30, and 10.60 µM in HLM, respectively. The processing processes that followed were as the same as those described earlier.

Time-dependent inhibition in RLM was evaluated by various isavuconazole concentrations from 0 to 100 µM with or without 1 mM NADPH over a 30-min incubation at 37 °C. Subsequently, sunitinib was introduced and incubated for an additional 30 min [16]. Sample processing was adhered to the previously outlined method.

Metabolic stability of sunitinib and N-desethyl sunitinib

The metabolic stability of sunitinib and its primary metabolite, N-desethyl sunitinib, were evaluated in RLM with or without isavuconazole. The stability assay performed in RLM system, was referred to the reaction system and the experimental conditions in a previous report, where 1 µM sunitinib or 1 µM N-desethyl sunitinib, 0.3 mg/mL RLM, 1 mM NADPH, and isavuconazole were incubated in PBS buffer [17]. After 5 min of pre-incubation, NADPH was added, and the reaction was terminated at multiple time points: 0, 20, 30, 45, 60, and 90 min. Post-treatment was performed as previously described for the enzyme reaction, followed by analysis of the collected supernatant using analytical instruments. To quantify the metabolic stability, the concentrations at each time point were normalized relative to the initial concentration at time zero. The resulting ratios were multiplied by 100 to express the values as ‘% Remaining’. Based on the obtained data, the natural logarithm (ln) of ‘% Remaining’ of sunitinib and N-desethyl sunitinib were plotted against incubation time, and linear regression was applied to obtain the metabolic stability profiles. The parameters half-time (t1/2) and intrinsic clearance (CLint) were obtained from the following equations, where ke represents the elimination rate constant derived from the slopes of the linear regression curves in the experiments [18].

$${t_{1/2}} = 0.693/{k_e}$$
$$\begin{aligned}{{\text{CL}}_{\text{int}}} (\text{mL/min/mg protein}) = & 0.693/t_{1/2}\\& \times{\text{volume\,of\,incubation\,(mL)}} /{\text{protein}}\\&\,{\text{in}}\, {\text{the\;incubation\,(mg)}}.\end{aligned}$$

The effect of isavuconazole on sunitinib in rats

Ten male Sprague-Dawley (SD) rats (200 ± 10 g), acquired from Animal Experiment Center of The First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China) were divided into two groups at random: the control group (Group A, 5 mg/kg sunitinib orally alone), and the experimental group (Group B, 20 mg/kg isavuconazole with 5 mg/kg sunitinib) [19]. Corn oil was used to prepare the solution of isavuconazole and sunitinib. The rats were given free access to water but were fasted for 12 h before to the experiment. Group B were received 20 mg/kg isavuconazole at the start of the experiment, while Group A were received an equivalent volume of the corn oil solution. After 30 min, 5 mg/kg of sunitinib was given to rats in both groups. The tail vein blood was drawn at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h following sunitinib administration, respectively. After centrifuging the blood sample at 13,000 rpm for 5 min, 100 µL of plasma was then mixed with 300 µL of acetonitrile and 20 µL of IS working solution (200 ng/mL). The mixture was vortexed for 2 min, followed by centrifugation at 13,000 rpm for 10 min. The supernatant obtained from this step was subsequently prepared for analysis.

Euthanasia of the experimental animals was carried out according to the anesthesia protocol outlined in the AVMA Guidelines for the Euthanasia of Animals. Upon the conclusion of the experiment, each animal was euthanized via intravenous administration of pentobarbital (150 mg/kg). Once the cessation of vital signs was confirmed, the animals were appropriately packaged and subjected to cremation.

Statistical analysis

With GraphPad Prism (GraphPad, San Diego, CA), the Km, IC50, Lineweaver–Burk plot, metabolic stability curves, and mean plasma concentration–time curves were generated. The pharmacokinetic parameters of sunitinib and N-desethyl sunitinib, in rats were computed by non-compartmental analysis approach. This analysis was conducted with the aid of the Drug and Statistics (DAS) software (version 3.0, Mathematical Pharmacology Professional Committee of China, Shanghai). Additionally, SPSS 19.0 (IBM Corp., Armonk, NY, USA) was utilized to perform statistical analyses, including the independent sample t-test, to compare the metabolic stability across different experimental groups and the pharmacokinetic parameters in rats. P < 0.05 was considered statistically significant.

Results

Method validation

As seen in Fig. 1C, the UPLC-MS/MS technique for quantifying sunitinib and its primary metabolite, N-desethyl sunitinib in plasma was successfully established. Importantly, the UPLC-MS/MS chromatograms revealed no interference with the retention periods of the compounds. The retention times for N-desethyl sunitinib (m/z 371.03 → 282.95), sunitinib (m/z 399.30 → 282.96), and IS (m/z 488.03 → 401.10) were approximately 1.17 min, 1.19 min, and 1.16 min, respectively.

The regression equations for the calibration plot were y = 0.885945*x + 0.259535 with r2 = 0.998 for sunitinib, while y = 1.3871*x + 0.349049 with r2 = 0.995 for N-desethyl sunitinib. The ranges of the concentration covered by these calibration equations were 0.5–500 ng/mL for both sunitinib and N-desethyl sunitinib. Additionally, both analytes had the lower limit of quantification (LLOQ) of 0.5 ng/mL, with a respectable degree of precision and accuracy.

Kinetic study of sunitinib using HLM and RLM

The Michaelis-Menten curves of sunitinib in RLM and HLM were presented in Fig. 2A and B, respectively. As shown in Table 1, the Km values for sunitinib were 32.08 µM in RLM and 36.45 µM in HLM, respectively.

Fig. 2
figure 2

Michaelis-Menten plots of sunitinib in RLM (A) and HLM (B). Data are presented as the mean ± SD, n = 3

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Table 1 The IC50 values and inhibitory effects of isavuconazole on sunitinib metabolism in RLM and HLM
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Potential drugs interact with sunitinib

We conducted an investigation into the effects of 85 drugs on the metabolism of sunitinib and identified those with significant inhibitory effects (Fig. 3A). Among these, the drugs with more than 80% inhibition were isavuconazole, vortioxetine, tropifexor and ritonavir (Fig. 3B). In this study, isavuconazole demonstrated a lower IC50 value of 1.33 µM for sunitinib in RLM, resulting in an inhibition rate of 83.47% compared to the control.

Fig. 3
figure 3

Screen drugs that may interact with sunitinib potentially. (A) Inhibition rates of the 85 drugs screened. (B) Inhibitors with an inhibition rate of more than 80% of control. The IC50 of isavuconazole in RLM (C) and HLM (D). Data are presented as the mean ± SD

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Isavuconazole potently inhibited sunitinib metabolism in RLM and HLM

Figure 3C and D showed the inhibitory effect of isavuconazole on sunitinib metabolism, with observed IC50 values of 1.33 µM in RLM and 5.30 µM in HLM (Table 1). Since all IC50 values were less than 10 µM, it could be concluded that isavuconazole moderately inhibited sunitinib metabolism in vitro. Lineweaver-Burk plots revealed that isavuconazole inhibited sunitinib metabolism in RLM via a combination of non-competitive and competitive inhibition mechanisms (Fig. 4A), and in HLM through a competitive inhibition mechanism (Fig. 4B). The Ki values were 1.27 µM in RLM and 3.71 µM in HLM, respectively, and the α value was 2.37 µM in RLM (Table 1). The IC50 (-NADPH): IC50 (+ NADPH) ratio was 1.36, as illustrated in Fig. 4C. According to research, a compound is commonly classified as a time-dependent inhibitor if its ratio (“shift”) is greater than 1.5 [20]. As a result, in RLM, isavuconazole did not act as a time-dependent inhibitor of sunitinib.

Fig. 4
figure 4

The potential mechanism of isavuconazole’s effect on sunitinib. (A) Lineweaver–Burk plot, the secondary plot for Ki, and the secondary plot for αKi in the inhibition of sunitinib metabolism by isavuconazole with various concentrations in RLM. (B) Lineweaver–Burk plot and the secondary plot for Ki in the inhibition of sunitinib metabolism by isavuconazole with various concentrations in HLM. (C) The inhibition curves of isavuconazole in RLM with or without NADPH. Data are presented as the mean ± SD, n = 3

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Metabolic stability

The elimination rates of sunitinib with or without isavuconazole in RLM were displayed in Table 2; Fig. 5 (A). The results showed that the t1/2 of sunitinib was 76.99 ± 12.46 min, while isavuconazole prolonged it to 99.76 ± 6.22 min, which was significantly different (P < 0.05). CLint was decreased from 0.0306 ± 0.0055 to 0.0236 ± 0.0021 mL/min/mg, and it was consistent with the in vivo pharmacokinetic results. Meanwhile, the impact of isavuconazole on the metabolic stability of N-desethyl sunitinib, the major metabolite of sunitinib, was indicated in Table 3; Fig. 5 (B). The findings similarly demonstrated that isavuconazole significantly prolonged the t1/2 of N-desethyl sunitinib (from 679.21 ± 172.47 to 1345.61 ± 95.84 min), and also significantly reduced CLint from 0.0036 ± 0.0010 to 0.0017 ± 0.0001 mL/min/mg. It was suggested that isavuconazole affected the metabolism of both sunitinib and N-desethyl sunitinib in vitro.

Table 2 The comparison of in vitro metabolic parameters of sunitinib in RLM with or without isavuconazole (mean ± SD, n = 3)
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Fig. 5
figure 5

In vitro metabolic stability of sunitinib (A) and N-desethyl sunitinib (B) in RLM with or without isavuconazole, n = 3

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Table 3 The comparison of in vitro metabolic parameters of N-desethyl sunitinib in RLM with or without isavuconazole (mean ± SD, n = 3)
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The exposure of sunitinib was greatly elevated in rats by isavuconazole

Figure 6 showed the average concentration-time curves of sunitinib and N-desethyl sunitinib in rats, and Tables 4 and 5 provided an overview of the primary pharmacokinetic parameters in two groups. The AUC(0→t), AUC(0→∞), and Tmax of sunitinib were increased to approximately 211.38%, 203.92%, and 288.89%, respectively, compared to the control group. The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib showed no statistically significant differences when compared to those of the control group.

Fig. 6
figure 6

Mean concentration–time curves of sunitinib (A), and N-desethyl sunitinib (B) in rats. Data are presented as the mean ± SD, n = 5

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Table 4 The main pharmacokinetic parameters of sunitinib in two groups of SD rats (n = 5)
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Table 5 The main pharmacokinetic parameters of N-desethyl sunitinib in two groups of SD rats (n = 5)
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Discussion

Cytochrome P450 (CYP450), originally discovered in liver microsomes, is a multifunctional protein superfamily present in all biological evolutionary processes. CYP3A4 is the most abundantly expressed enzyme in human liver, primarily found in liver (about 95%), where it makes up an average of 14–24% of total microsomal CYP450. Studies have shown that CYP3A4 is responsible for metabolizing about 50% of clinical medications [21,22,23]. Therefore, given the clinical importance of CYP3A4 in human for metabolism, emphasis should be paid on its active function in medication and exogenous chemical metabolism.

Sunitinib is metabolized to the active metabolite N-desethyl sunitinib, primarily via CYP3A4. According to a preclinical study, sunitinib is efficacious at 50–100 ng/mL of total plasma [24]. In a separate clinical trial, researchers observed that with a daily dosage of 50 mg, the total concentration of sunitinib ranged from 50 to 100 ng/mL [5]. An observational study further revealed that several patients with sunitinib concentrations exceeding 100 ng/mL were hospitalized due to severe toxicity during outpatient treatment, and that one of these patients needed to be permanently taken off sunitinib after two cycles due to intestinal perforation. The investigators identified DDI as a significant factor contributing to the high drug concentrations observed in the patient. During sunitinib treatment, this patient took azelastine, a CYP3A4 inhibitor, concomitantly. This resulted in high levels of sunitinib in the patient [25]. Given the frequent practice of combining drugs in cancer therapy, studying the DDI associated with sunitinib becomes increasingly necessary.

After 85 drugs were investigated, isavuconazole was chosen in this research. Isavuconazole, a novel triazole antifungal drug, has been shown to be effective against COVID-19-associated CAM due to its broader antimicrobial spectrum and lower adverse effects, with an increased use especially in immunocompromised cancer patients [9]. However, isavuconazole moderately inhibits CYP3A4, potentially influencing the concentrations of other drugs metabolized by this enzyme [7, 26]. Therefore, investigating the impact of isavuconazole on sunitinib metabolism is essential.

Based on the in vitro results of RLM, isavuconazole did not inhibit the metabolism of sunitinib in a time-dependent manner. Additionally, isavuconazole exhibited a variety of potential mechanisms of inhibition. For instance, it demonstrated a mixed mechanism of inhibition in RLM with Ki = 1.27 µM, αKi = 3.02 µM, and α = 2.37 µM, whereas it showed a competitive mechanism of inhibition in HLM with Ki = 3.71 µM.

The in vivo experiments showed the alterations in the pharmacokinetic parameters of sunitinib, providing evidence for potential DDI between isavuconazole and sunitinib in rats. Following co-administration, the AUC(0→t) and AUC(0→∞) values of sunitinib showed significant increases, suggesting that isavuconazole enhanced the oral bioavailability of sunitinib. Additionally, isavuconazole caused a significant prolongation of Tmax. In vitro metabolic stability experiments indicated that isavuconazole suppressed the metabolism of both sunitinib and N-desethyl sunitinib. According to a study, when erdafitinib was combined with isavuconazole, Cmax, AUC(0→t) and t1/2 of erdafitinib were increased to 123.13%, 154.46%, and 106.04%, respectively. The findings implied that isavuconazole could affect the pharmacokinetics of erdafitinib, potentially raising its plasma levels. Isavuconazole inhibited CYP3A4, leading to reduce the metabolism of erdafitinib [27]. Therefore, we hypothesized that isavuconazole might inhibit CYP3A4 activity, then inhibit the metabolism of sunitinib. However, it is worth noting that CYP3A4 is the predominant hepatic enzyme in humans, whereas in male rats, CYP3A1/2 are considered the primary CYP3A isoforms [28]. Previously, it has been shown that the structures of rat CYP3A1/2 and human CYP3A4 are highly similar, and their amino acid sequence homology has been calculated to be 73% [29, 30]. Meanwhile, CYP3A1/2 catalyze similar types of reactions in rats as human CYP3A4, including oxidative metabolism of several drugs. This functional similarity allows rats to mimic the drug metabolism process of human CYP3A4 [31]. Since CYP3A1/2 in rats are able to metabolize drugs similar to those metabolized by human CYP3A4, drug interaction studies using SD rats can provide clinically meaningful predictive data. However, in vivo studies in rats do not completely and accurately predict the situation in humans, and this result remains to be confirmed by further clinical studies.

Therapeutic drug monitoring (TDM), which involves optimizing doses based on observed plasma concentrations, is useful for medications with narrow therapeutic windows, clear exposure-response relationships, and considerable inter-patient PK variation. Sunitinib falls into this category. TDM helps minimize toxic side effects and provides a valuable laboratory support for diagnosing and managing drug overdose toxicity, thereby advancing clinical dosing from a traditional empirical model to a more scientific approach. Our work provides fundamental data on the metabolic properties of the combination of sunitinib and isavuconazole. Timely identification of individual genotype and interaction characteristics, establishment of sunitinib TDM, and early intervention may improve sunitinib efficacy and reduce potential DDI and adverse effects.

Conclusion

Both in vitro and in vivo, isavuconazole decreased sunitinib metabolism. Given the widespread clinical use of this combination, our findings offered evidence for their proper and rational use, helping to reduce adverse effects and support the advancement of personalized medicine.

Data availability

Data is provided within the manuscript files.

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Authors and Affiliations

  1. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Jinyu Hu, Hailun Xia, Xiaohai Chen, Xinhao Xu, Hua-Lu Wu, Yuxin Shen, Ren-ai Xu & Wenzhi Wu

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  1. Jinyu Hu
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  2. Hailun Xia
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  3. Xiaohai Chen
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  4. Xinhao Xu
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  5. Hua-Lu Wu
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  6. Yuxin Shen
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  7. Ren-ai Xu
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  8. Wenzhi Wu
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Contributions

Jinyu Hu and Hailun Xia performed the experiments; Xiaohai Chen and Xinhao Xu analyzed the data; Hua-Lu Wu and Yuxin Shen wrote the paper; Ren-ai Xu conceived the experiments; Wenzhi Wu designed the experiments. All authors read and approved the final manuscript.

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Correspondence to Ren-ai Xu or Wenzhi Wu.

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Animal experiments were demonstrated to be ethically acceptable and were carried out according to the Guidelines of the Experimental Animal Care and Use of Laboratory Animals of The First Affiliated Hospital of Wenzhou Medical University. All animal procedures and experimental protocols were approved by the Laboratory Animal Ethics Committee of The First Affiliated Hospital of Wenzhou Medical University (Ethics approval number: WYYY-IACUC-AEC-2023-033). And the study was reported in accordance with ARRIVE guidelines.

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Hu, J., Xia, H., Chen, X. et al. Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism. BMC Cancer 24, 1131 (2024). https://doi.org/10.1186/s12885-024-12904-4

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Keywords

BMC Cancer

ISSN: 1471-2407

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