Bliss Kaneshiro Pharmacokinetics of oral contraceptives and sub-antimicrobial doxycycline

kaneshiro

Unintended pregnancy is a major public health concern that results in direct health care costs of $5 billion dollars and more than 1.2 million abortions in the United States every year (1-3). Oral contraceptives (OCs) are the most commonly used method of reversible birth control in the United States, but unwanted side effects contribute to a high failure rate (8.7% per year) and discontinuation rate (32% per year) (1, 4, 5). Our long-range goal is to reduce the personal, societal, and economic burden of unintended pregnancy by decreasing the side effects associated with OC use thereby improving continuation and compliance.

Our approach focuses on continuous administration of OCs in which hormonally active pills are taken every day without a placebo week to avoid a hormonal withdrawal bleed (6-8). New studies indicate that shortening the hormone-free interval increases contraceptive effectiveness (9). Additionally, decreasing or eliminating bleeding is preferred to monthly bleeding by most women (7). The major downside and primary reason for discontinuation of continuous OCs is unscheduled, irregular bleeding which affects more than 84 percent of women in the first three months of use (10). In a randomized placebo-controlled trial, we demonstrated that prophylactic administration of sub-antimicrobial doxycycline (40 mg daily) allowed women taking a low-dose OC in a continuous manner to achieve menstrual suppression sooner (11). While doxycycline’s inhibitory effect on matrix metalloproteinases (MMPs) is believed to be responsible for decreased endometrial bleeding (12, 13), the effect of sub-antimicrobial doxycycline on MMP expression in continuous OC users is unknown. The current study seeks to identify the pathophysiology behind our clinically significant results and will allow us to optimize doxycycline dosing and the duration of treatment.

We plan to quantify MMP activity in the endometrium of women using continuous OCs and describe the effect of sub-antimicrobial doxycycline on MMP activity in continuous OC users. Specifically, we will describe MMP activity in 14 subjects using endometrial biopsies (EMB). Subjects will have a biopsy prior to initiating OCs (control, biopsy 1) and while taking a cyclic OCs (biopsy 2). All subjects will then start continuous OCs and will be randomized to placebo or sub-antimicrobial doxycycline. The third biopsy will be performed after subjects have been on continuous doxycycline and doxycycline or placebo for four weeks. An important part of this study is the collaboration between Dr. Bliss Kaneshiro at the University of Hawaii (UH) and Dr. James Hildreth and Dr. Chandravanu Dash at Meharry Medical College (MMC). Dr. Kaneshiro will continue to collaborate with Dr. Alison Edelman and Dr. Jeffrey Jensen at Oregon Health & Science University (OHSU).