DALLAS – Numerous prescription drugs inhibit the metabolism of 17-alpha hydroxyprogesterone caproate, or 17P, and could impact its efficacy for the prevention of preterm delivery, according to findings from a study evaluating the effects of 25 specific medications.
Of the 25 medications tested, 16 were found to inhibit the metabolism of 17P, Dr. Courtney Cuppett reported at the annual meeting of the Society for Maternal-Fetal Medicine.
Those with the strongest inhibitory effects were the asthma drug montelukast (Singulair), and the protease inhibitors nelfinavir (Viracept) and ritonavir (Norvir), which were associated with 90%-100% inhibition of 17P.
Drugs associated with moderate (50%-80%) inhibition of 17P were fluconazole (Diflucan), itraconazole (Sporanox), diltiazem, esomeprazole (Nexium), tacrolimus, and bergamottin. Those with weak (30%-50%) inhibitory effects included fluticasone, voriconazole (Vfend), nifedipine, erythromycin, sertraline (Zoloft), haloperidol (Haldol), and trazodone, and those with negligible (less than 20%) inhibitory effects included midazolam (Versed), quetiapine (Seroquel), venlafaxine (Effexor), citalopram (Celexa), clarithromycin (Biaxin), metronidazole (Flagyl), cyclosporine, sirolimus (Rapamune), and ondansetron (Zofran), said Dr. Cuppett, a fellow in the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh’s Magee-Women’s Hospital.
The hormonal agent 17P has been shown to reduce the incidence of recurrent preterm birth by 33% in a high risk population of women. In 2011, it became the first medication to receive Food and Drug Administration approval for prevention of preterm birth. Its use has become widespread, and it is currently indicated in patients with a history of spontaneous preterm birth. It is administered at a weekly dosage of 250 mg given intramuscularly at 16-36 weeks’ gestation, Dr. Cuppett noted.
"Although this drug is routinely prescribed, there is so much we don’t understand," including the optimal dose and dosing interval and the definition of therapeutic concentration; in addition, "importantly, both the site and mechanism of action are still largely unknown," she said.
One thing that is known, however, is that there is very large interindividual variability in plasma concentrations (range, 5-40 ng/mL) in those receiving a standard dose, she said, noting that such variability can potentially affect efficacy, and may be one reason why only a third of the target population benefited from treatment in trials.
She and her colleagues also found that 17P is metabolized by the drug-metabolizing enzyme CYP3A4, which is primarily found in the liver, but is also found in other tissues, including the placenta, uterus, and cervix. CYP3A4 also is responsible for the metabolism of more than half of all prescription medications.
"Thus, we hypothesized that prescription medications may alter the metabolism of 17P," she said.
Using ideal drug concentrations and incubation conditions identified as part of the study, they incubated pooled human CYP3A4 microsomes with 17P alone and with each of the 25 medications known to be substrates and or inhibitors of CYP3A4.
The finding that the metabolism of 17P is significantly inhibited by several of the prescription medications suggests that these drug-drug interactions may contribute to the large interindividual variability in 17P plasma concentrations observed in patients treated with the standard 17P dose, Dr. Cuppett said.
The clinical implications of the findings are unclear, as the therapeutic window for 17P has not been defined.
"However, if in the future we are able to define the therapeutic window for 17P, the dose and/or dosing interval may be adjusted in women who also take medications that are substrates, inhibitors, and/or inducers of CYP3A4," she said.
Importantly, it should also be considered that if prescription medications inhibit 17P, the converse also could be true.
In the future, it will be important to look for the converse drug-drug interactions and potential for 17P to inhibit prescription medications – particularly those with narrow therapeutic windows – because inhibition of metabolism of such drugs could lead to toxicity.
An example is the protease inhibitors that were shown in this study to inhibit 17P by 90%-100%. If the converse interaction proved true, patients using these drugs would need to be monitored more closely for signs of toxicity, and doses may potentially require adjustment, Dr. Cuppett said.
This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Cuppett said she had no relevant financial disclosures.