Drug Interaction Report

GENERALLY AVOID: Macimorelin can cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a dedicated thorough QT study consisting of 60 healthy subjects, a mean baseline- and placebo-adjusted change in QTcF of 9.6 msec was observed 4 hours following administration of a supratherapeutic dose of macimorelin 2 mg/kg (4 times the recommended dose), which occurred after the mean maximum macimorelin plasma concentration (0.5 hour). A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels: 0.5 mg/kg; 1 mg/kg (2 times the recommended dose); and 2 mg/kg (4 times the recommended dose). All three doses levels produced a similar magnitude of QTcF prolongation as reported in the thorough QT study, suggesting an absence of dose-dependent changes. The mechanism for the observed QTcF prolongation is unknown. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of macimorelin with other drugs that can prolong the QT interval should generally be avoided. A sufficient washout period following discontinuation of these drugs is recommended prior to macimorelin administration. Patients treated with any medication that can cause QT prolongation should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant. A high degree of intersubject variability in the grapefruit juice effect was also observed. The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown. However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability. Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.

ADJUST DOSING INTERVAL: Food reduces the oral bioavailability of macimorelin. According to the product labeling, administration with a liquid meal decreased macimorelin peak plasma concentration (Cmax) and systemic exposure (AUC) by 55% and 49%, respectively, compared to administration under fasting conditions (i.e., for at least 8 hours).

MANAGEMENT: Macimorelin should be administered after fasting for at least 8 hours.