The Effect of Protease Inhibitors on the Pharmacokinetics of Oral Norethindrone Contraception

BACKGROUND/RATIONALE : It is recognized that there is a dearth of clinically applied,
population based, empiric data to guide contraceptive recommendations in HIV + women on
ARVs.(1) Protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI
) induce micro enzyme systems such as CYP 3a4, which in turn alters the bio-availability and
pharmacokinetics of other concurrently administered medications.(2) Empiric trials from
small samples, often of 10-20 HIV negative subjects, have demonstrated that concurrent
administration of combined oral contraceptives (COC) and a PI or a NNRTI have been
associated with decreased plasma ethinyl estradiol (EE) levels. These pharmacokinetic
findings have raised concern that decreased bio-availability of EE may result in decreased
contraceptive efficacy, with possible increased unintended pregnancy. Some of these COC
studies have demonstrated that there is no change in the serum levels of norethindrone (NET)
on ARVs.(3-16) However, there are no published trials focused on oral NET or oral
progestin-only pills (POP) to guide management in HIV+ women.(17)

OBJECTIVES:

Primary objective of this study is:

To detect a ±40% difference in AUC of serum NET in HIV+ women taking ATV/RTV as compared to
AUC of NET in HIV+ women taking an ARV regimen that has demonstrated no interaction with NET
in the past.

Primary endpoint: Natural log-transformed NET PK parameter AUC from 0 to 72 hours following
oral administration, with multiple discrete serum data points for each subject on ATV/RTV.
This will be compared to natural log-transformed NET PK AUC from 0 to 72 hours following
oral administration, with multiple discrete serum data points for controls HIV+ women taking
an ARV regimen that has demonstrated no interaction with NET in the past.

The secondary objectives of this study are:

To evaluate the effect of ATV/RTV on other PK exposure endpoints and parameters of NET (with
natural log transformation). The sample and control groups mentioned above will again be
compared. Endpoints include:

minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), time to Cmax
(Tmax), and half-life (T1/2).

SAMPLE SIZE: Recruitment of 16 participants in each arm, with the goal of attaining 32
evaluable HIV-1-seropositive female subjects in total.

POPULATION/STUDY ARMS: HIV-1-infected female subjects 18-44 years of age

METHODOLOGY/INTERVENTIONS/FOLLOW-UP: A two-arm, open-label, prospective, steady state trial
to characterize the pharmacokinetics (PK) of oral norethindrone (NET) as a progestin only
contraceptive pill (POP) in HIV+ women receiving atazanavir and ritonavir therapy (ATV/RTV).
The investigators will identify a control group of HIV+ women who are taking ARV regimens
that have not significantly altered oral NET levels in prior trials. Subjects will be
enrolled in the trial for approximately 4 weeks A 28 day continuous packet of NET 0.35 mg
will be provided to all enrolled volunteers for 21 days of continuous administration. Women
who participate in this study will demonstrate a means of continuing their ARV regimens for
the duration of the study, ARV therapy will not be provided by this study. On day 22
subjects will be admitted for serial pharmacokinetic (PK) specimens collection following the
final study dose of NET.

Subjects will be enrolled into one of the 2 arms based on their current ARV regimen.

Study group: Women on stable ARV/RTV (300/100mg daily) with additional ARV regimens that
have not significantly altered oral NET levels in prior trials. (n=12).

Control group: Stable on current ARV, no protease inhibitors (PI), ARV regimens that have
not significantly altered oral NET levels in previous research.

OUTCOMES: Intensive PK sampling for NET will be performed in those in intervention and
control arms after 21 days of NET administration. To determine side effect profile of NET by
self-administered daily questionnaire during the 3-4 week study enrollment period

STATISTICS: Area under the concentration-time curve (AUC), peak plasma concentration, and
the lowest plasma concentration for NET in HIV+ women receiving this PI therapy will be
determined and compared to similar values in HIV positive control subjects who are not
taking PI therapy. Statistical consultation will be obtained from the USC Keck School of
Medicine Department of Bio statistics and Laboratory of Applied Pharmacokinetics

Inclusion Criteria:

Ages: 18-44 years Gender: female Accepts: healthy volunteers and HIV-1 infected women
Acceptable medications include: no other medications, NRTI combinations, entry inhibitors,
integrase inhibitors, and CCR5 agonists. NRTI combinations may include but are not limited
to: zidovudine (ZDV), lamivudine (3TC), emtricitabine (FTC), didanosine (ddl), stavudine
(d4T), abacavir (ABC), and tenofovir disoproxil fumarate (TDF). NNRTI: etravirine, and
rilpivirine.

Exclusion criteria:

History of bilateral oophorectomy, ovarian dysfunction or no regular periods. CD4+ cell
count <200 cells/mm3 No current or uncontrolled thyroid, liver, or renal disease BMI <40
kg/m^2 Current pregnancy, breastfeeding or pregnancy within 30 days of enrollment.
Depomedroxyprogesterone acetate injection (DMPA) within 180 days prior to study entry.

Other hormonal therapies (e.g. oral contraceptive agents, Provera, vaginal ring,
contraceptive patch, monthly contraceptive injection, hormone replacement therapy,
anabolic therapies, including nandrolone decanoate or megestrol acetate) within the 21
days prior to study entry.