We report our experience with anamorelin-induced QT interval prolongation in an obese woman. QT prolongation induced by anamorelin occurred on the 12th day after initiation of anamorelin, consistent with existing reports. Patients with cancer cachexia are often underweight, but even in obese patients, we should be aware of the potential side effect of stimulant conduction system depression with anamorelin. Anamorelin is a highly lipophilic drug, with a distribution coefficient (1-octanol/water) of 2.98 [3]. Therefore, in obese patients, there is a possibility of a more extended prolongation of the QT interval over an extended duration due to the increased distribution of anamorelin in the body, as it remains in the body for a long time after discontinuation.

In this patient, we considered that anamorelin inhibits sodium channels, resulting in the prolongation of the QRS complex and QT interval. There has been a case report of wide QRS complex tachycardia induced by anamorelin [11]. In our case, on the third day after anamorelin discontinuation, the QT interval was maximal at 557 ms, and a mild prolongation of the QRS duration of 106 ms was observed.

Many cases of drug-induced QT prolongation are caused by the inhibition of potassium channels [12]. One type of potassium channel is the IKr channel, the pore-forming subunit of which is encoded by the human ether-a-go-go-related gene (hERG). Drug-induced QT prolongation is caused by an inhibitory effect on the hERG channel. In this case, the patient developed immune-related adverse events due to atezolizumab, and initially, we also considered QT interval prolongation as one of its effects. However, it has been reported that monoclonal antibodies, including atezolizumab, have a very low potential to interact with extracellular or intracellular domains on the hERG channel [13]. In addition, similar to other immune checkpoint inhibitors, atezolizumab has not been shown to have a significant effect on the QT profile [14]. In the phase III trial (IMpower130) combining atezolizumab with carboplatin plus nab-paclitaxel chemotherapy as first-line treatment for non-small cell lung cancer, QT interval prolongation was not observed as an adverse event across all grades [15]. Therefore, we considered the contribution of atezolizumab to QT interval prolongation to be minimal. Further, since the patient’s troponin I levels were below the reference value upon admission, we considered myocarditis due to atezolizumab unlikely. In contrast, the inhibitory effect of anamorelin on the hERG channel is broad, with an IC50 ranging from 4.3 to 34 μmol/L [16]. The inhibitory effect of anamorelin on hERG channel currents in human cardiomyocytes was reported to have an IC50 of 4.3 μmol/L. In contrast, under conditions using HEK293 cells transfected with the hERG gene, it was reported to be 34 μmol/L. The risk of causing TdP is reported to be low when the IC50 of drugs exhibiting hERG inhibition exceeds 30 times the maximum plasma concentration of the drug (unbound free drug concentration) [17]. In the case of the anamorelin, with a maximum drug concentration of 629 ng/mL and a protein binding rate of 97.3%–98.3% [3], there is a difference of over 100 times compared with the IC50 of 4.3 μmol/L (2350 ng/mL). Therefore, the risk of developing TdP is considered low. Anamorelin, a substrate of the metabolic enzyme cytochrome P450 3A4, may increase blood concentrations in cases of hepatic dysfunction. Okidono and colleagues reported two cases of wide QRS complex tachycardia in patients with Child–Pugh class B hepatic function [11]. The patient had normal liver function at anamorelin initiation and no history of liver disease, such as cirrhosis or cholangitis. However, upon admission (day 12), the patient’s hepatic function was classified as Child–Pugh class B. Therefore, we suggest that the metabolism of anamorelin was impaired, leading to a temporary increase in blood concentration, which led to the prolongation of the QT interval. Anamorelin is a highly lipophilic drug with a distribution coefficient of 2.98. In the halothane-anesthetized guinea pig model, the lipophilicity (logP) of drugs that may prolong the QT interval (e.g., haloperidol, bepridil) is known to correlate well with the heart-to-plasma concentration ratio [18]. These highly lipophilic drugs have been reported to prolong the QT interval in humans [19, 20]. Therefore, given that anamorelin also has high lipophilicity, it is possible that it may cause QT prolongation. The ratio of myocardium to plasma concentrations for antipsychotic drugs known to cause QT prolongation, arrhythmias, and sudden death (such as haloperidol and risperidone) is higher than 4 [21]. The ratio of radioactive concentrations in the heart to plasma 72 h (3 days) after a single oral dose of 14C-anamorelin is 4.5 [22]. This suggests that anamorelin has a notable impact on the heart, indicating a substantial tissue distribution to the heart by the third day post-administration. Obesity is recognized as a predictor for sudden cardiac death, further contributing to increased QTc and QT or QTc dispersion [23]. Therefore, obesity poses a potential risk of QTc prolongation. Risk factors for drug-induced TdP involve hypokalemia and hypomagnesemia [24], although they were not observed in the blood tests conducted upon admission. The day after discontinuation of anamorelin, hydrocortisone infusion via intravenous drip was initiated for secondary adrenal insufficiency, leading to a decrease in potassium levels and a tendency toward QT interval prolongation. This is considered to be due to a decrease in extracellular potassium concentration, leading to prolonged ventricular repolarization time. Moreover, diarrhea, a thyrotoxic symptom caused by atezolizumab, may have contributed to the decreased potassium levels. Various risk factors for QTc prolongation include BMI ≥ 30 kg/m2, hypokalemia (K ≤ 3.5 mmol/L), female gender, age ≥ 65 years, and smoking [25]. Therefore, narrowing down the cause of the QTc prolongation observed in this patient was difficult.

In this case, it took 16 days for the patient's QT interval to return to within normal limits. Anamorelin, being highly lipophilic, may have accumulated in the body over an extended period of time. In patients with higher body weight, the excretion rate of anamorelin tends to increase. However, in obese patients, anamorelin may accumulate in adipose tissue and distribute within the adipose tissue over an extended period of time. It has been reported that obesity contributes to an increase in the volume of distribution (Vd) of drugs in obese patients [26]. Therefore, because the patient was obese, it is possible that the high partition coefficient of anamorelin resulted in a larger distribution volume, leading to prolonged accumulation in the body. Consequently, this may have influenced the time to improve the QT interval.

In the present case, initiating anamorelin during outpatient treatment made it difficult to track detailed changes in lean body mass indicative of treatment effects. In additional, due to the short duration of administration, the treatment effects remained unclear.

In conclusion, we report a case of drug-induced QT interval prolongation due to anamorelin. In obese patients with cancer cachexia, there is a risk of potential QT interval prolongation due to the increased Vd of anamorelin, and these patients may experience stimulatory conduction system depression even after discontinuation of anamorelin. Therefore, it is essential to monitor obese patients, as well as underweight patients, by ECG from the early stages of anamorelin administration.