Ignite Creation Date:
2024-05-06 @ 2:55 PM
Last Modification Date:
2024-10-26 @ 1:39 PM
Study NCT ID:
NCT04463680
Status:
COMPLETED
Last Update Posted:
2023-05-16
First Post:
2020-07-06
Brief Title:
Rifampin and the Contraceptive Implant
Sponsor:
University of Colorado Denver
Organization:
University of Colorado Denver
Study Overview
Official Title:
The Effect of Rifampin on Etonogestrel Concentrations in Contraceptive Implant Users
Status:
COMPLETED
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
It is important for women taking rifampin to be aware if they are at greater risk of an unintended pregnancy while on the implant An unintended pregnancy has many social emotional and financial impacts on women and society Rifampin is also a Class C medication for pregnancy and could have potential negative effects on a developing fetus Additionally women considering rifampin for treatment of LTBI face additional risks with an unintended pregnancy making the reliability of contraception even more important for these women The results of this study can directly inform counseling on a national and international basis for women who use the contraceptive implant and are considering their treatment options for LTBI
Detailed Description:
Rifampin is an antibiotic historically prescribed as part of a treatment regimen for active tuberculosis TB infection Though active TB infections have become rarer over time in the US it is estimated that up to 13 million people in the US may have latent TB infections LTBIs with even greater numbers of LTBIs worldwide1 In efforts to combat the persistent rate of LTBI the US Centers for Disease Control and Prevention CDC released updated treatment guidelines for LTBI in 20181 This recommended treatment guideline consists of four treatment regimens varying in duration from 3 to 9 months The CDC recommends utilization of the shorter regimens when possible to achieve higher patient compliance and infection clear rates The second shortest duration treatment regimen 4 months consists of daily rifampin only1
In addition to its antitubercular properties rifampin is a known strong cytochrome P-450 CYP 3A4 enzyme inducer2 Similar to other strong CYP3A4 enzyme inducers eg carbamazepine rifampin can affect the serum concentrations of exogenous steroid hormones found in hormonal contraception2 The only published literature on the interaction between rifampin and hormonal contraception has focused on combined oral contraceptives3 Five studies that investigated the pharmacokinetics of combined oral contraceptives all found significant reductions in serum ethinyl estradiol and progestin concentrations with rifampin co-administration3 This pharmacokinetic effect is significant enough to warrant a category 3 recommendation theoretical or proven risks usually outweigh the advantages from the CDC Medical Eligibility Criteria MEC for Contraceptive Use for concomitant rifampin and combined hormonal contraceptive methods4 This pharmacokinetic effect is large enough to raise concerns for combined hormonal contraceptive method efficacy and recommendation of alternative methods One of those alternative methods is the etonogestrel ENG implant Nexplanon which has a category 2 recommendation in the CDC MEC for concomitant rifampin use4 However in the clarifications for this recommendation the CDC MEC warns that rifampin is likely to reduce the effectiveness of the ENG implant with no supporting evidence provided4
Prior work found that a strong CYP3A4 inducer carbamazepine caused clinically significant reductions in serum etonogestrel concentrations among contraceptive implant users5 The investigators found a median decrease in serum ENG of 61 range 25-87 with 810 participants having serum ENG concentrations 90pgmL after concomitant carbamazepine5 Though there is currently no published data on the pharmacokinetic interaction between rifampin and the ENG implant given its similar enzyme induction properties there is concern that the CDC MEC recommendation for rifampin and the ENG implant may underestimate the potential risk for contraceptive failure
Given the social financial and healthcare costs of unintended pregnancies it is imperative that the investigators better understand the drug-drug interaction between rifampin and the ENG implant Especially in light of the contradictory category 2 recommendation and clarification in the CDC MEC4 more data are needed to determine if rifampin has a significant enough pharmacokinetic effect on the ENG implant to potentially cause contraceptive failure This information would allow healthcare providers around the world the ability to provide improved counseling to patients needing treatment for LTBI in regards to both their TB treatment regimen and their concurrent contraceptive options
Specific Aim
To evaluate the pharmacokinetic effect of rifampin on serum etonogestrel concentrations in contraceptive implant users at the dose of rifampin used for latent tuberculosis infection LTBI treatment 600mg per day
Exploratory Aim - to evaluate the effect of rifampin on serologic measures of ovulatory suppression estradiol and progesterone in contraceptive implant users
Hypothesis
The investigators hypothesize that rifampin will have a significant pharmacokinetic effect on participants etonogestrel levels resulting in etonogestrel concentrations at least 35 decreased from baseline measurements
Methods
The investigators propose a prospective pre and post study to evaluate the pharmacokinetic effect of rifampin on serum ENG levels in contraceptive implant users The investigators will enroll healthy women using an ENG implant for at least 12 months and no greater than 36 months
Participants will then begin a 2 week regimen of rifampin at 600mg per day This dose is the recommended dose for treatment of LTBI and duration of 2 weeks will achieve steady state rifampin levels with adequate time for liver enzyme induction All participants will then return at the end of the second week for a repeat blood draw The investigators will again obtain serum as described above for planned measurement of serum ENG concentrations The investigators will also obtain blood samples for repeat measurements of serum estradiol and progesterone The investigators will also measure a serum rifampin level at the time of the second ENG blood draw to confirm compliance Serum estradiol serum progesterone and serum rifampin levels will all be measured at the UCH Clinical Laboratory At the conclusion of enrollment all stored serum samples will be de-identified and shipped to a Merck laboratory for serum ENG concentration measurement Batch analysis will be performed using a liquid chromatography mass-spectrometry method that has been previously validated Participants will serve as their own controls for this study
All participants will be required to use either a back-up non-hormonal method of birth control or abstain from intercourse during the study and for 2 weeks after the last dose of rifampin Rifampin has a half-life of 3-4 hours and thus will be eliminated within 1-2 days of the last dose but the investigators will allow a full 2 weeks of buffer to ensure that the contraceptive effect of the implant has reinitiated before recommending resuming unprotected intercourse
All study visits will occur at the Comprehensive Womens Health Clinic in Lowry
In addition to its antitubercular properties rifampin is a known strong cytochrome P-450 CYP 3A4 enzyme inducer2 Similar to other strong CYP3A4 enzyme inducers eg carbamazepine rifampin can affect the serum concentrations of exogenous steroid hormones found in hormonal contraception2 The only published literature on the interaction between rifampin and hormonal contraception has focused on combined oral contraceptives3 Five studies that investigated the pharmacokinetics of combined oral contraceptives all found significant reductions in serum ethinyl estradiol and progestin concentrations with rifampin co-administration3 This pharmacokinetic effect is significant enough to warrant a category 3 recommendation theoretical or proven risks usually outweigh the advantages from the CDC Medical Eligibility Criteria MEC for Contraceptive Use for concomitant rifampin and combined hormonal contraceptive methods4 This pharmacokinetic effect is large enough to raise concerns for combined hormonal contraceptive method efficacy and recommendation of alternative methods One of those alternative methods is the etonogestrel ENG implant Nexplanon which has a category 2 recommendation in the CDC MEC for concomitant rifampin use4 However in the clarifications for this recommendation the CDC MEC warns that rifampin is likely to reduce the effectiveness of the ENG implant with no supporting evidence provided4
Prior work found that a strong CYP3A4 inducer carbamazepine caused clinically significant reductions in serum etonogestrel concentrations among contraceptive implant users5 The investigators found a median decrease in serum ENG of 61 range 25-87 with 810 participants having serum ENG concentrations 90pgmL after concomitant carbamazepine5 Though there is currently no published data on the pharmacokinetic interaction between rifampin and the ENG implant given its similar enzyme induction properties there is concern that the CDC MEC recommendation for rifampin and the ENG implant may underestimate the potential risk for contraceptive failure
Given the social financial and healthcare costs of unintended pregnancies it is imperative that the investigators better understand the drug-drug interaction between rifampin and the ENG implant Especially in light of the contradictory category 2 recommendation and clarification in the CDC MEC4 more data are needed to determine if rifampin has a significant enough pharmacokinetic effect on the ENG implant to potentially cause contraceptive failure This information would allow healthcare providers around the world the ability to provide improved counseling to patients needing treatment for LTBI in regards to both their TB treatment regimen and their concurrent contraceptive options
Specific Aim
To evaluate the pharmacokinetic effect of rifampin on serum etonogestrel concentrations in contraceptive implant users at the dose of rifampin used for latent tuberculosis infection LTBI treatment 600mg per day
Exploratory Aim - to evaluate the effect of rifampin on serologic measures of ovulatory suppression estradiol and progesterone in contraceptive implant users
Hypothesis
The investigators hypothesize that rifampin will have a significant pharmacokinetic effect on participants etonogestrel levels resulting in etonogestrel concentrations at least 35 decreased from baseline measurements
Methods
The investigators propose a prospective pre and post study to evaluate the pharmacokinetic effect of rifampin on serum ENG levels in contraceptive implant users The investigators will enroll healthy women using an ENG implant for at least 12 months and no greater than 36 months
Participants will then begin a 2 week regimen of rifampin at 600mg per day This dose is the recommended dose for treatment of LTBI and duration of 2 weeks will achieve steady state rifampin levels with adequate time for liver enzyme induction All participants will then return at the end of the second week for a repeat blood draw The investigators will again obtain serum as described above for planned measurement of serum ENG concentrations The investigators will also obtain blood samples for repeat measurements of serum estradiol and progesterone The investigators will also measure a serum rifampin level at the time of the second ENG blood draw to confirm compliance Serum estradiol serum progesterone and serum rifampin levels will all be measured at the UCH Clinical Laboratory At the conclusion of enrollment all stored serum samples will be de-identified and shipped to a Merck laboratory for serum ENG concentration measurement Batch analysis will be performed using a liquid chromatography mass-spectrometry method that has been previously validated Participants will serve as their own controls for this study
All participants will be required to use either a back-up non-hormonal method of birth control or abstain from intercourse during the study and for 2 weeks after the last dose of rifampin Rifampin has a half-life of 3-4 hours and thus will be eliminated within 1-2 days of the last dose but the investigators will allow a full 2 weeks of buffer to ensure that the contraceptive effect of the implant has reinitiated before recommending resuming unprotected intercourse
All study visits will occur at the Comprehensive Womens Health Clinic in Lowry
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None