Drug Interactions between adenosine and pralsetinib

ADJUST DOSING INTERVAL: Food significantly increases the oral bioavailability of pralsetinib. According to the product labeling, administration of pralsetinib (200 mg) with a high-fat meal (approximately 800 to 1000 calories; 50% to 60% from fat) increased mean pralsetinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 104% and 122%, respectively. The median time to maximum concentration (Tmax) was delayed from 4 hours to 8.5 hours, when compared to the fasted state.

GENERALLY AVOID: The juice of grapefruit and/or Seville oranges may increase the plasma concentrations of pralsetinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to pralsetinib may increase the risk of adverse effects such as interstitial lung disease/pneumonitis, liver transaminase elevations, hypertension, and hemorrhage. Some clinical trials have also observed prolongation of the QT interval in patients on pralsetinib, though this was not observed in a study of 34 patients with rearranged during transfection (RET)-altered solid tumors on pralsetinib at the recommended dosage.

MANAGEMENT: Pralsetinib should be administered on an empty stomach, with no food intake recommended for at least 2 hours before and at least 1 hour after taking the medication. Patients should avoid consumption of grapefruit, grapefruit juice, Seville oranges, or Seville orange juice during treatment with pralsetinib.

ADJUST DOSING INTERVAL: Caffeine and other xanthine derivatives (e.g., theophylline) are nonspecific, competitive antagonists of adenosine receptors and may interfere with the hemodynamic effects of adenosine. There have been case reports of patients receiving theophylline who required higher than normal dosages of adenosine for the treatment of paroxysmal supraventricular tachycardia. In studies of healthy volunteers, caffeine and theophylline have been shown to reduce the cardiovascular response to adenosine infusions (i.e., heart rate increases, vasodilation, blood pressure changes), and theophylline has also been shown to attenuate adenosine-induced respiratory effects and chest pain/discomfort.

MANAGEMENT: Clinicians should be aware that adenosine may be less effective in the presence of xanthine derivatives including caffeine. Patients should avoid consumption of caffeine-containing products for at least 12 hours, preferably 24 hours, prior to administration of adenosine for myocardial perfusion imaging.

ADJUST DOSING INTERVAL: Methylxanthines (e.g., caffeine, theophylline) are nonspecific, competitive antagonists of adenosine receptors. As such, they may interfere with the pharmacologic effects of adenosine and other adenosine receptor agonists such as dipyridamole and regadenoson. There have been case reports of patients receiving theophylline who required higher than normal dosages of adenosine for the treatment of paroxysmal supraventricular tachycardia. In studies of healthy volunteers, caffeine and theophylline have been shown to reduce the cardiovascular response to adenosine infusions (i.e., heart rate increases, vasodilation, blood pressure changes), and theophylline has also been shown to attenuate adenosine-induced respiratory effects and chest pain/discomfort. Similarly, caffeine has been found to reduce the hemodynamic response to dipyridamole, and both caffeine and theophylline have been reported to cause false-negative results in myocardial scintigraphy tests using dipyridamole. In a placebo-controlled study that assessed the effects of oral caffeine on regadenoson-induced increase in coronary flow reserve (CFR), healthy subjects who took caffeine 200 mg orally two hours prior to regadenoson administration exhibited a median CFR that was 92% that of subjects who took placebo. The study was done using positron emission tomography with radiolabeled water.

MANAGEMENT: Clinicians should be aware that adenosine and other adenosine receptor agonists may be less effective in the presence of methylxanthines. Methylxanthines including caffeine should be withheld for 12 to 24 hours (or five half-lives) prior to administration of adenosine receptor agonists for myocardial perfusion imaging. However, parenteral aminophylline should be readily available for treating severe or persistent adverse reactions to adenosine receptor agonists such as bronchospasm or chest pain.

Nicotine may enhance adenosine-associated tachycardia and chest pain. The mechanism is not known. No special precautions appear to be necessary.