Drug Interactions between daridorexant and hydroxyprogesterone

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of daridorexant, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. Per physiologically based pharmacokinetic (PBPK) analysis, concomitant use of itraconazole, a potent CYP450 3A4 inhibitor, increased daridorexant systemic exposure (AUC) by more than 400%. When a 25 mg daridorexant dose was coadministered with multiple 240 mg doses of diltiazem, a moderate CYP450 3A4 inhibitor, daridorexant peak plasma concentration (Cmax) and AUC increased by 1.4- and 2.4-fold, respectively. 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 daridorexant may increase the risk of adverse reactions such as central nervous system (CNS) depression, sleep paralysis, hallucinations, complex sleep behaviors, worsening of depression or suicidal ideation, or headache.

After administration of a high-fat, high-calorie meal, daridorexant Cmax decreased by 16% (no effect on AUC) and the time to maximum concentration (Tmax) was delayed by 1.3 hours.

GENERALLY AVOID: Alcohol may potentiate the pharmacologic effects of daridorexant. Coadministration of daridorexant (50 mg) with alcohol led to additive effects on psychomotor performance. Use in combination may result in an increased risk of complex sleep-related behaviors (e.g., "sleep driving"), additive central nervous system (CNS) depression, and/or impairment of psychomotor performance.

MANAGEMENT: Consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with daridorexant should generally be avoided. Some authorities suggest avoiding grapefruit or grapefruit juice consumption specifically in the evening. Patients should avoid the consumption of alcohol during treatment with daridorexant. The manufacturer makes no recommendation regarding administration with food; however, the time to sleep onset may be delayed if taken with or soon after a meal.

MONITOR: Coadministration with hydroxyprogesterone may decrease the plasma concentrations of drugs that are metabolized by CYP450 1A2, 2A6, and/or 2B6. An in vitro study using human liver microsomes and CYP isoform-selective substrates indicated that hydroxyprogesterone caproate can increase the metabolic rate of CYP450 1A2, 2A6, and 2B6 by approximately 80%, 150%, and 80%, respectively. The clinical significance has not been determined.

MANAGEMENT: Pharmacologic effects and/or serum concentrations of the coadministered drug should be monitored more closely whenever hydroxyprogesterone is added to or withdrawn from therapy, and the dosage adjusted if an interaction is suspected.