(068) Low Drug-Drug interaction risk of Estetrol (E4), a Promising New Estrogen for the Treatment of Menopausal Symptoms
Authors: Sweat M , Foidart J , Utian W , Gerard C , Chatel G , Gaspard U , Taziaux M , Lobo R 
Published: May 2023

Introduction

Polypharmacy is common among postmenopausal women and exposes them to the risks of inappropriate drug use and drug-drug interactions (DDI). Most estrogens are influenced metabolically by drugs which affect key metabolic enzymes.

Objective

To investigate the DDI potential of E4, several in vitro studies with metabolizing enzymes were performed. A clinical study was also conducted to evaluate the consequence of inhibiting the main enzyme responsible for E4 metabolism.

Methods

In vitro studies on human hepatocytes or human liver microsomes and recombinant enzymes were conducted to evaluate the role of drug metabolizing enzymes on E4 metabolism [cytochrome P450 enzymes (CYP), UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT)]. We also assessed the potential of E4 to inhibit or induce these enzymes. Finally, we performed a clinical study to determine the effect of UGT inhibition on the pharmacokinetics (PK) of E4. In this open-label two period, two-way cross-over study, 24 healthy female volunteers received two single doses of a product containing E4 15 mg once alone and once in combination with valproic acid 500 mg twice daily, a strong UGT inhibitor. The consequence of UGT inhibition was quantified by serial plasma measurements of E4 up to 168h after drug administration.

Results

Effects of other drugs on E4 (E4 as a substrate) CYP enzymes, a superfamily of enzymes that functions as monooxygenases did not play a significant role in the metabolism of E4. Consequently, E4 does not interact with drugs that inhibit or induce CYP enzymes. In vitro and in vivo studies showed that UGT2B7 was the main enzyme involved in E4 glucuronidation and that SULT1 was the dominant enzyme for sulfation of E4. The clinical phase 1 study confirmed the role of UGT in the metabolism of E4. UGT inhibition by valproic acid increased total E4 exposure and maximum concentration only by 1.13 and 1.36-fold, respectively. Because the effect of UGT inhibition on E4 pharmacokinetics is minimal, no clinically relevant effects are expected during coadministration of drugs that inhibit UGT activity. Effect of E4 on other drugs (interference by E4) Studies on the effect of E4 on other drugs showed that E4 neither induces nor inhibits CYP or UGT enzymes, except for a very minimal inhibition of CYP3A4, UGT1A9 and UGT2B7 isoforms. The half maximal inhibitory concentration (IC50) of these in vitro effects were several hundred times above the anticipated clinical maximum concentrations, indicating a low potential for clinically relevant DDIs. Also, there was no evidence of time-dependent inhibition of CYP enzymes.

Conclusions

Based on these in vitro and in vivo drug interaction studies on metabolizing enzymes, E4 is not expected to have a potential risk for DDI. Unlike other estrogens, CYP enzymes do not play a major role in the metabolism of E4 and can therefore be combined with drugs that inhibit or induce CYP or UGT enzymes without compromising its safety or efficacy.

Disclosure

Yes, this is sponsored by industry/sponsor: Estetra an affiliate company of Mithra Pharmaceuticals

Clarification: Industry initiated, executed and funded study

Any of the authors act as a consultant, employee or shareholder of an industry for: Estetra an affiliate company of Mithra Pharmaceuticals.