The present prospective study investigated the associations of plasma aprepitant and its metabolite with cachexia progression, antiemetic efficacy, and adverse effects in oral aprepitant-treated head and neck cancer patients. Our findings suggest that these head and neck cancer patients who had a progressive cachectic condition have elevated plasma aprepitant. In contrast, elevated plasma free ND-AP reduces the incidence of delayed nausea caused by high-dose cisplatin-based chemotherapy. To the best of our knowledge, this is the first report to characterize plasma aprepitant and ND-AP from the viewpoint of cachexia progression and antiemetic efficacy in a clinical setting.
The interindividual variation in plasma concentration of total aprepitant was similar to that of total ND-AP based on their IQR values. In contrast, plasma free ND-AP was more variable than plasma free aprepitant in the present population. A previous study also showed similar interindividual variability in plasma total aprepitant in a different population . The plasma protein binding rate of aprepitant was more than 90% [11, 12], whereas that of ND-AP has not been reported. In the present study, the free fraction proportion of ND-AP also had a larger interindividual variability. Cancer-related factors potentially contribute to the variability in plasma free ND-AP.
A lower serum level of albumin was negatively associated with the higher plasma concentrations of total and free aprepitant, but not ND-AP in this study. In contrast, the free fraction kinetics and metabolism of aprepitant were only slightly associated with the serum albumin level. Patients with cancer, especially head and neck cancer, tend to suffer from hypoalbuminemia due to undernutrition caused by parenteral feeding . Inadequate oral intake with supplemental parenteral nutrition was present in 63% of the patients in our population. Our data indicate that albumin dynamics and poor oral intake may be indirectly associated with oral aprepitant clearance. The oral bioavailability of aprepitant was reported to be approximately 60% . Cytotoxic chemotherapy or intestinal edema caused by low serum albumin may lead to a higher absorption of aprepitant because of intestinal barrier breakdown. Other cancer-related factors may also be involved in the pharmacokinetic variation of aprepitant and ND-AP.
The inflammatory marker and serum CRP levels had no associations with the plasma aprepitant and ND-AP levels in the present study population. Inflammation reduces CYP3A4 activity and the oral clearance of CYP3A4-substrate drugs [23, 24]. However, the inflammatory state based on serum CRP did not have a direct correlation to plasma aprepitant. Cancer-related inflammation is responsible for the reduction of CYP3A4 activity through a complex mechanism [25, 26]. The present patients had a low total protein level (median level, 6.2 g/dL). Our data suggest that the alteration of serum protein mobilization during cancer progression affects the clearance of plasma aprepitant in advanced cancer patients.
Cancer patients with progressive cachexia had high plasma concentrations of total and free aprepitant in this study. Several studies have demonstrated that the progression of cachexia results in reduced CYPs activity [17–19, 27]. The present cancer patients with progressive cachexia tended to have a lower metabolic ratio of aprepitant. Aprepitant is metabolized predominantly by CYP3A4 , while CYP3A5 was not involved in aprepitant metabolism using recombinant enzymes (Online Resource 5). Our previous report also demonstrated that the CYP3A5 genotype did not alter the plasma aprepitant level . These data suggest that cachexia progression increases plasma aprepitant through the reduction of CYP3A4 activity.
Our cancer patients with progressive cachexia had a higher plasma level of IL-6. IL-6 is a pro-inflammatory cytokine that causes cachexia and is directly involved in the reduction of CYP3A4 activity . In the present population, the median value of plasma IL-6 in patients with GPS 1 or 2 was 7.7 pg/mL. Diagnostic criteria for cachexia in adults include a serum IL-6 level of more than 4 pg/mL . The half maximal inhibitory concentration (IC50) of CYP3A4 activity by IL-6 was reported to be 8.3 pg/mL . CYP3A4 activity may be suppressed in our study population. In addition, serum IL-6 promotes systemic protein degradation and release through cortisol and catecholamine secretion . Our data suggest that plasma aprepitant is elevated via plasma IL-6 in patients with progressive cachexia.
The antiemetic effect of aprepitant was strongly associated with the absolute plasma concentration of free ND-AP but not aprepitant in this study. The IC50 of aprepitant for the NK1 receptor was 0.1 nmol/L, while that for ND-AP was 0.5 nmol/L . In plasma, the free concentration of aprepitant was similar to that of ND-AP. A higher distribution of ND-AP compared to aprepitant to brain was observed in ferrets . These data support that the brain concentration of ND-AP is higher than that of aprepitant, indicating a higher inhibitory activity against brain NK1 receptors. Although most patients had a plasma concentration of total aprepitant above 100 ng/mL, which occupies more than 90% of the NK1 receptors in the brain , nausea occurred in approximately 50% of the patients in the present study. Aprepitant is a substrate of P-glycoprotein , whereas if ND-AP is also a substrate remains unknown. Since ND-AP with its detriazolone ring is structurally more basic and more likely to become a cation, it can more easily cross the BBB. The antiemetic effect of oral aprepitant may be determined by plasma ND-AP and its degree of brain migration.
The incidences headache, constipation, and hiccups were 21%, 48%, and 57%, respectively. In earlier studies using a regimen including aprepitant, the incidences of headache, constipation, and hiccups were 4–15%, 12–43%, and 10–33%, respectively [34–37]. The incidences of headache and constipation were similar to these earlier studies, while that of hiccups was higher. Cisplatin, which was administered to the enrolled patients, frequently induces hiccups . No association was observed between the plasma absolute concentrations of free aprepitant or ND-AP and the adverse effects observed. To date, few reports have been published on the association between plasma aprepitant and adverse effects. Radiation therapy in addition to any concomitant drugs potentially had a positive impact on the occurrence of adverse effects in our study population.
The present study has several limitations that should be addressed. First, we enrolled head and neck cancer patients who received high-doses of cisplatin. The type of cancer did not alter the plasma aprepitant level in a previous study . Patients who had moderate or severe hepatic dysfunction were not included. Application of our findings to a population without high-dose cisplatin-based chemotherapy or with hepatic dysfunction should be undertaken with care. Second, cachexia was assessed using GPS. Inflammation-based GPS classification potentially differs from symptom-based classification . Inflammation-based GPS 0 or 1 is classified as pre-cachexia in the symptom-based classification. The impact of the early stage of cachexia on plasma aprepitant can be evaluated using GPS classification. The GPS could be partially substituted for a clinical symptom-based cachexia score . Cachexia scoring methods may not make a major impact on our findings. Third, the present study assessed the drug concentration at a single point on day 4. Since the plasma aprepitant level at 24 hours after the last dosing is considered to have reached the elimination phase, the observed plasma concentration reflects the drug exposure. Further studies, including systemic drug exposure analyses, would lead to better understanding of the interindividual variations in clinical responses to aprepitant.
Although cancer cachexia raised the plasma aprepitant level in this study, the clinical implication of plasma aprepitant monitoring and cachexia scoring remains to be fully clarified. Cancer cachexia had no impact on plasma free ND-AP. However, the clinical implications of plasma free ND-AP monitoring during the first cycle would enable clinicians to make a decision on additional drug dosing for patients who are predicted to respond inadequately. Based on a plasma free ND-AP level of less than 18.9 ng/mL, the additional dosing of aprepitant on days 4 and 5, or other antiemetic drugs such as olanzapine can be prophylactically prescribed during the subsequent cycle. The patient factors that can determine the plasma free ND-AP level may allow us to predict the development of CINV before starting anticancer treatment.