TABLE 1

Drug interactions with AUC changes ≥5 in the victim drugs

Maximum AUCR is presented for the same mechanism; for each section, DDIs are arranged based on the AUCR; all studies were conducted in healthy subjects unless otherwise specified (this information was not available for elugolix in the NDA review or the drug label).

Substrate (Dosage)Precipitant (Dosage)NME Therapeutic ClassAUCRCmax RatioEnzyme or Transporter Primarily InvolvedLabel ImpactReference
Inhibition DDIs with AUCRs ≥5, NMEs as substrates
Avapritinib (300 mg QD at steady state)Itraconazole (200 mg QD at steady state)Antineoplastic Agents7.00 (PBPK in healthy subjects), 7.90 (PBPK in patients)6.21 (PBPK in healthy subjects), 6.91 (PBPK in patients)CYP3AAvoid strong CYP3A inhibitors(FDA, 2020b)
Relugolix (20 mg SD)Erythromycin (NP)Antineoplastic Agents6.256.18P-gpaAvoid oral P-gp inhibitors; if unavoidable, separate dose of at least 6 hours(FDA, 2020i)
Lonafarnib (50 mg SD)Ketoconazole (200 mg QD for 5 days)Otherb5.073.60CYP3Accontraindicated with strong or moderate CYP3A inhibitors; avoid weak CYP3A inhibitors, if unavoidable, reduce dose of lonafarnib; monitor for adverse reactions, such as arrhythmias, and events, such as syncope and heart palpitations(FDA, 2020p)
Induction DDIs with AUCRs ≤0.2, NMEs as substrates
Lonafarnib (50 mg SD with ritonavir 100 mg)Rifampin
(600 mg QD for 8 days)
Other0.020.08CYP3AcContraindicated with strong or moderate CYP3A inducers(FDA, 2020p)
Avapritinib (400 mg SD)Rifampin
(600 mg QD for 18 days)
Antineoplastic Agents0.080.29CYP3AAvoid strong CYP3A inducers(FDA, 2020b)
Selpercatinib (160 mg SD)Rifampin
(600 mg QD for 11 days)
Antineoplastic Agents0.130.30CYP3AcAvoid strong CYP3A inducers(FDA, 2020a)
Pemigatinib (13.5 mg SD)Rifampin
(600 mg QD for 9 days)
Antineoplastic Agents0.150.38CYP3AcAvoid strong CYP3A inducers(FDA, 2020j)
Fostemsavir (1200 mg SD)Rifampin
(600 mg QD for 7 days)
Anti-infective Agents0.18 (temsavir)0.24 (temsavir)CYP3AcContraindicated with strong CYP3A inducers(FDA, 2020k)
Rimegepant (75 mg SD)Rifampin
(600 mg QD for 11 days)
Migraine Treatments0.200.38CYP3A4cAvoid strong or moderate CYP3A4 inducers(FDA, 2020g)
Inhibition DDIs with AUCRs ≥5, NMEs as precipitants
Decitabine (20 mg SD)Cedazuridine (100 mg QD for 4 days)Antineoplastic Agents12.00dNPCytidine deaminaseAvoid coadministration of cedazuridine and decitabine with drugs that are metabolized by cytidine deaminase(FDA, 2020d)
Midazolam (3 mg SD)Lonafarnib
(100 mg BID for 5 days)
Other7.392.80CYP3Acontraindicated with midazolam and the HMG CoA reductase inhibitors lovastatin, simvastatin, and atorvastatin; avoid other sensitive CYP3A substrates, if unavoidable, monitor for adverse reactions and reduce the dose of those sensitive CYP3A substrates according to their product labeling; for certain CYP3A substrates where minimal concentration changes may lead to serious or life-threatening toxicities, monitor for adverse reactions and reduce the dose of the CYP3A substrate in accordance with the product labeling(FDA, 2020p)
Midazolam (2 mg SD)tucatinib
(300 mg BID for 10 days)
Antineoplastic Agents5.743.01CYP3Aavoid CYP3A substrates wherein minimal concentration changes may lead to serious or life-threatening toxicities; if unavoidable, reduce dose of the CYP3A substrate in accordance with its approved product labeling(FDA, 2020n)
  • BID, twice daily; MD, multiple doses; NP, not provided; QD, once daily; SD, single dose.

  • aInhibiton of CYP3A may be also involved. However, compared with the DDI study result with CYP3A inhibitors, the increase in relugolix exposure is likely primarily driven by the increase in oral bioavailability due to inhibition of intestinal P-gp efflux by erythromycin. A postmarketing commitment was issued to conduct a pharmacokinetic study to evaluate the effect of P-gp inhibitors administered after relugolix to further inform dosing strategy.

  • bOther refers to a new class of drug, indicated to reduce the risk of death due to rare genetic diseases that cause premature aging.

  • cIn vitro, the NME was a substrate of P-gp. Inhibiton or induction of P-gp may also contribute to the NME exposure change.

  • dThe study was conducted in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia.