Uterine fibroid therapy: the pharmacokinetic considerations

KEYWORDS:

• Leiomyoma
• liver injury
• oral GnRH antagonist
• pharmacokinetics
• SPRMs
• uterine fibroids

1. Introduction

Uterine fibroids (UFs, AKA; leiomyoma) are the most prevalent benign neoplastic threat in reproductive age women. Ultrasound based epidemiological studies disclosed that 70−80% of these women will develop UFs by age of 50. Although inherently benign, this enigmatic disease constitutes a major health and financial burden worldwide, also, it presents a major health disparity challenge for being at least four times more common in women of color [1].

UFs associated symptoms negatively impact daily living as well as overall quality of life of approximately 20–30% of afflicted patients. This includes abnormal uterine bleeding with subsequent anemia, bulk symptoms, obstetrical complications and recently possible infertility [1,2].

Despite the high prevalence and health significance of UFs, we know surprisingly little about its underlying cause or pathogenesis. This reflects the limited availability of safe long-term anti-UF treatment options. Historically, Hysterectomy has been the most common treatment option for symptomatic UFs. Yet, many factors halt that preference including, its invasive nature as well as uterus and consequently fertility deprivation [1,2]. In regard to alternatives like pharmacological treatment, unfortunately, majority of the current therapies offer inadequate or short-term control of symptoms and cannot be used for long term because of safety concerns [3]. In this editorial we will glimpse the important medical treatment options for UF, either approved or in the pipeline, with emphasis on their pharmacokinetic (PK) features that certainly can shape the future of UF treatment development.

2. UF therapies

UF growth is hormonal dependent on estrogen and most importantly progesterone. Therefore, current treatments aim to suppress or modulate these ovarian sex hormones [1]. Herein we will focus on the most commonly used treatment options, other possible treatment options include aromatase inhibitors, oral contraceptives, Levonorgestrel-releasing intrauterine system, Selective estrogen receptor modulators, localized treatments (gene therapy and collagenase), and alternative medicine (green tea and Vitamin D) can be found in more details in literature [1,3].

2.1. Gonadotropin-releasing hormone (GnRH) agonists

Leuprolide acetate (LA) is the only FDA approved treatment of UF associated bleeding for sake of preoperative hematologic improvement. Pharmacologically, LA constantly stimulates pituitary GnRH receptors with subsequent desensitization, this is translated clinically with initial 1–2 weeks hormonal flare followed by profound hormonal suppression and consequently bleeding cessation. LA absorption is characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL after 4 h of dosing followed by plateau within 2 days and remained relatively stable for about 4 to 5 weeks with plasma concentrations of about 0.30 ng/mL [4]. LA is formulated as depot subcutaneous injection of 3.75 mg monthly administrated. LA associated hypoestrogenic side effects are hot flashes, mood swings, headache and bone density loss, they can be reduced with concomitant administration of add back therapy with limited use up to 3–6 months and 12 months follow-up [5]. After drug discontinuation, both estrogen level, and so UF symptoms, will recur. If additional treatment is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits [4].

2.2. GnRH antagonists

GnRH agonist are peptides so they can’t be taken orally due to destruction by gastric peptidases, but nonpeptide antagonists such as Elagolix, Relugolix, and OBE2109 are orally administrated, they are currently investigated for anti-UF utility in phase III studies with added advantage of bypassing the initial flare effect of the agonists besides, they induced a dose dependent hormonal suppression [6]. Phase I studies showed that Elagolix is rapidly absorbed with peak plasma concentration reached in 30–60 min. and relatively short plasma half-life changed from 2.4 to 6.3 h across a range of dosage regimens. However, repeated daily administrations do not result in significant accumulation [6]. Elagolix suppressed estradiol by 24 h in doses higher than 50 mg, while 100 mg twice daily showed a consistent significant suppression compared to placebo. Notably, Elagolix induced estrogen suppression is still less than the corresponding suppression of depot GnRH agonists, therefore, its side-effect profile is better. However, add back therapy is still important to improve patient quality of life and tolerability during treatment although it can affect the therapeutic outcome. Phase I study of Relugolix showed similar finding concerning rapid absorption while limited data is known about PK of OBE2109 so far.

2.3. Selective progesterone receptor modulators (SPRMs)

Considering the high expression level of progesterone receptors in UF compared to adjacent myometrium, SPRMs family offered a promising globally recognized treatment option with a tissue selective mixed progesterone agonist/antagonist effect [1]. In the past recent years, much interest has emerged around this family members and have been investigated for UF treatment including the forefront Ulipristal acetate (UPA), Vilaprisan, Asoprisnil, and Telapristone (Proellex). The last two were suspended in phase III trials due to abnormal changes in the endometrial lining of patients’ uteri and significant elevation of liver enzymes respectively, UPA is approved in Europe and Canada as long-term treatment (up to four treatment courses of 3 months, separated by a drug-free period until the start of the second menstruation following the end of the previous treatment course), it is currently under FDA review in United states [3,7]. Vilaprisan is currently in many Phase 3 clinical studies.

Later the perceived endometrial safety issues raised previously with Asoprisnil were known to be common to all SPRMs as benign reversible progesterone associated endometrial changes (PAECs) [1].

2.3.1. Ulipristal acetate

To date, it is estimated that UPA has been utilized globally by more than half a million women with UFs [7]. PK studies showed that UPA has a good oral bioavailability with elimination half-life of 35 to 43 h, which allows once daily dosage. C_max increased in linear dose dependent manner up to 100 mg [8]. UPA is extensively metabolized in the liver by cytochrome p450 (CYP) 3A4 via N-demethylation of its dimethyl-amino phenyl group to form aniline-like metabolites and 73% of administrated dose is eliminated in feces [9]. Elevated levels of liver enzymes in few clinical studies, suggestive of undesired liver effects, have been observed for UPA [10]. Recently, the Pharmacovigilance Risk Assessment Committee (PRAC) of European Medicines Agency (EMA) announced an ongoing review procedure regarding potential liver-related safety signal with UPA following four reports of serious liver injury, three of which ended in liver transplantation, in patients treated with UPA [11]. Other SPRMs as Mifepristone and Telapristone have dimethyl-amino phenyl group as UPA and mainly metabolized by N-demethylation to form an aniline-like metabolite as well.

2.3.2. Vilaprisan

Vilaprisan is a novel highly potent SPRM currently under evaluation for long-term treatment of symptomatic UFs [12]. Phase I studies showed that daily Vilaprisan doses of 0.5 mg or higher were able to reduce mean maximum serum concentrations of LH and FSH and 1 mg doses or higher decreased mean maximum estradiol concentrations. However, estradiol concentrations never decreased below 40 pg/ml. Progesterone concentration was persistently low in most of participants during treatment with 1 mg [13]. Vilaprisan peak plasma concentration was achieved 1–2 h after oral dose, and the half-life is about 35 h which permit once daily administration with linear PK in the expected therapeutic dose range [12,13]. Vilaprisan chemical structure, as well as Asoprisnil, is slightly different from UPA in lacking the N-dimethyl-amino-phenyl group in the position 11 of the steroid. Therefore, hepatic biotransformation doesn’t result in aniline-like metabolite neither pharmacologically active metabolites [11].

Phase II studies emphasized the rapid bleeding control (3 days) compared to 7 days of UPA. Phase III studies aim to enroll more than 3600 women worldwide to evaluate the efficacy and safety of Vilaprisan 2 mg at different regimens as compared to control or UPA.

A transient elevation in liver enzymes was found in six subjects, regardless of the study drug dose used, however, values returned to normal range during ongoing treatment in all cases [12]. Table 1 summarizes the PK features of the aforementioned anti-UF medications.

Table 1. Summary of pharmacokinetics features of most commonly studied medications against Uterine Fibroids

Drug	Used dose	Terminal half life	Peak concentration	Route of administration/frequency
Ulipristal acetate	5 mg	35–43 h	23.5 ± 14.2 ng/mL	Oral once daily
Vilaprisan	1–30 mg	31–38 h	3.74 – 68.6 µg/L	Oral once daily
Elagolix	200 mg	5.4 ± 1.4 h	707 ± 211 ng/mL	Oral twice daily
Relugolix	40 mg	49.4 h	20.8 ng/mL	Oral once daily
Leuprolide acetate	3.75 mg	3 h	4.6 to 25.3 ng/mL	Intramuscular/subcutaneous monthly

In conclusion, UFs can significantly impair patient’s quality of life leading to absenteeism or decreased productivity in the workplace, annoying symptoms, and eventually exert a tremendous health toll with costs up to hundreds of billions of health care dollars worldwide. There is unmet need for medical therapies that could provide a long-term treatment option for women with UFs who wish to preserve their future fertility. Emerging treatments currently under development in the United States, such as SPRMs and oral GnRH antagonists, might offer that. Research focused on comparative effectiveness is essential to achieve that goal.

3. Expert opinion

Pharmacological therapy for UFs used to be a preoperative ancillary to improve surgical outcomes by reducing the size of tumor and/or hematological improvement. Moreover, it can stand-alone as short-term therapy only. Lately, evidences regarding efficacy of long-term use of some medications as Ulipristal acetate are available. This can usher the era of medical myomectomy that aims to remove the UFs while preserving the uterus, the same as in surgical myomectomy, yet avoid its risks and high cost.

Despite FDA approval of GnRH agonists, the high cost, rapid regrowth after cessation, and hypoestrogenic side effects as bone demineralization after long-term use, limit their use only as short-term adjuvant therapy in most patients. Although there were attempts to decrease their side effects by using hormonal add-back therapies [5], they were associated with larger uterine volume as an adverse effect.

Oral GnRH antagonists are promising and overcome the burden of injectable agonists, besides a dose-dependent suppression of sex steroids can be achieved; however, their consumption as monotherapy will suffer the same limitation of conventional agonists as LA; this explains why add-back hormonal therapy is included in most of ongoing clinical trials to limit the undesired hypoestrogenic side effect. Conversely, these additives might affect the tumor shrinking effect of those novel compounds. Development of novel formulations or derivatives of those antagonists with longer half-life is encouraged to decrease their administration frequency and consequently improve patients’ compliance.

Modern SPRMs as UPA and Vilaprisan can offer long-term treatment options. Regarding the specific modification of endometrium in response to SPRMs and known as PAECs, public domain data showed that they do not seem to be precursors of precancerous lesions and reversible within 6 months after medication discontinuation. Recently, due to liver injury incidents in four patients treated with UPA, PRAC published a recommendation for temporary measures while their review on UPA is ongoing. These include regular 4-weekly liver monitoring for women taking UPA, Additionally no new patients should be started on and no patients who have completed a course of treatment should start another one [14].

Metabolism of SPRMs with dimethyl-amino phenyl group as UPA and Telapristone results in formation of aniline substructures that have been reported to represent a ‘structural alert’ and could cause the undesired liver effects by the formation of reactive intermediates [15]. Available data from clinical studies with SPRMs that lack this dimethyl-amino phenyl group as Vilaprisan and Asoprisnil have provided no evidence for such clinically relevant drug-related change in liver enzyme activity. The absence of hepatic biotransformation of Vilaprisan to aniline-like metabolites, in addition to a faster action than UPA, seems to suggest, once its studies have been completed, that the need for frequent monitoring of liver enzymes that is currently required with the use of UPA will no longer be needed. Further long-term safety studies are needed to delineate this issue. Modification of molecule structure or drug formulation can overcome this issue if confirmed to cause any undesirable outcome.

Declaration of interest

A Al-Hendy is a consultant for Allergan, Bayer, Repros and Myovant Sciences, as well as AbbVie. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by a grant from the National Institute of Health [Grant no. R01 ES 028615-01].