Rifampin and the Contraceptive Implant
Condition: Contraception; Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 4

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 (e.g.
      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 8/10
      participants having serum ENG concentrations <90pg/mL 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 Women's Health Clinic in Lowry.
    

Intervention name(s): Rifampin 600 MG
Intervention type(s): Drug
Intervention description(s): Administered daily for 2 weeks
Intervention MeSH terms: Rifampin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science