Linzagolix is a selective, non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signalling by binding competitively to GnRH receptors in the pituitary gland, thereby modulating the hypothalamic-pituitary-gonadal axis.
Administration of linzagolix results in dose-dependent suppression of luteinizing hormone and follicle-stimulating hormone, leading to decreased blood concentrations of estradiol and progesterone. In the phase 3 studies, full suppression of serum estradiol (median <20 pg/mL) was observed with linzagolix 200 mg from 4 to 24 weeks. Partial suppression was observed with linzagolix 100 mg, 100 mg with concomitant ABT (referred to as “with ABT”) and 200 mg with ABT from 4 to 52 weeks, with median serum estradiol levels in the range of 20 to 60 pg/mL. Progesterone levels were maintained ≤3.1 ng/mL in 83% of women receiving linzagolix 200 mg for 24 weeks and 68% of women receiving linzagolix 100 mg for 52 weeks, and about 90% of women receiving linzagolix 100 mg with ABT or 200 mg with ABT for 52 weeks.
One randomised, placebo- and positive-controlled, open-label, single-dose, crossover thorough-QTc study evaluated the effect of linzagolix on the QTc interval. Forty-eight healthy women received a 200 mg dose of linzagolix (therapeutic target exposure), a 700 mg dose of linzagolix (supratherapeutic target exposure), a 400 mg dose of moxifloxacin (positive control), or placebo with an appropriate washout. A marginal effect with linzagolix 200 mg and 700 mg doses on the prolongation of the heartrate corrected QT interval was identified, with a maximum observed mean at 3 hours post dose of 8.34 msec (90% CI 6.44-10.23) and 9.92 msec (90% CI 8.03-11.81), respectively. Based on the magnitude of the QTc prolongation, subsequent concentration effect modelling and QT subinterval (JTpeakc), the observed effects are not considered clinically relevant. The highest anticipated steady state concentration in the QT study was estimated in healthy subjects, not accounting for increases in unbound linzagolix exposure due to existing disorders.
Fasting lipid levels (HDL, LDL and total cholesterol, and triglycerides) were assessed every three months from start of linzagolix treatment up to 3 months post treatment. There were increases in LDL cholesterol, HDL cholesterol, and triglycerides across all linzagolix arms (typically less than 15% in the case of LDL, and less than 20% in the case of triglycerides) and generally increases were higher for the linzagolix only regimes. These increases were evident from week 12 and lipid parameters had generally stabilised after 52 weeks of treatment. After stopping linzagolix, lipid levels showed signs of returning towards baseline by 12 weeks after stopping treatment, but still remained slightly elevated relative to baseline.
Following oral administration of a single dose of 100 mg or 200 mg, linzagolix is swiftly absorbed, with Cmax occurring approximately 2 h after administration. Linzagolix shows dose-linear pharmacokinetics and no relevant accumulation at steady state.
Administration of linzagolix (200 mg) with a high fat meal appeared to delay and to slightly decrease peak plasma concentrations, consistent with delayed gastric emptying after the high fat meal but had no effect on the extent of exposure. It is not considered to be of clinical significance.
Linzagolix was highly bound (>99%) to plasma proteins, in particular to albumin, and did not partition into red blood cells. The volume of distribution (Vd/F) following 7 consecutive days of oral linzagolix 100 mg or 200 mg administration was 11.067 L (CV: 20.4%) and 11.178 L (CV: 11.8%), respectively.
Metabolite profiling and identification of linzagolix quantified up to 7 metabolites across plasma, urine, and faeces. The predominant component in the human plasma profiles was unchanged linzagolix. Similarly, linzagolix was the predominant component in urine and one of the major components in faeces. All plasma metabolites were present at less than 10% of the total linzagolix related exposure.
Following multiple doses of linzagolix, linzagolix t1/2 was approximately 15 hours. Linzagolix was mainly excreted in urine and approximately one third was eliminated via faeces. Following administration of multiple doses of linzagolix 100 mg and 200 mg, the linzagolix geometric mean apparent clearance (CL/F) was 0.522 L/h (CV: 20.1%) and 0.499 L/h (CV: 15.2%), respectively.
The population PK analysis suggests that age does not have a meaningful effect on linzagolix exposure. The analysis showed that Black subjects had a 22.5% decrease in CL/F relative to Caucasian subjects; however, the safety profile of linzagolix between Black and Caucasian subjects was similar.
Based on the population PK analysis, weight was found to influence linzagolix PK. The CL/F in patients weighing 52.7 kg (5th percentile) was predicted to be about 19.2% lower, and in patients weighing 112 kg (95th percentile), about 42% higher than in patients weighing 70 kg. However, subgroup analyses of data from the pivotal phase 3 studies did not indicate any clinically relevant differences with respect to safety and efficacy, and no dose adjustment is recommended.
A clinical study conducted in female subjects with hepatic impairment (mild Child-Pugh A, moderate: Child-Pugh B and severe: Child-Pugh C) revealed no relevant effect on total plasma linzagolix exposure following administration of a single 200 mg dose of linzagolix. The unbound fraction of linzagolix was not affected by mild and moderate hepatic impairment; no dose adjustments with linzagolix in patients with mild and moderate hepatic impairment are required. Linzagolix should not be used in women with severe hepatic impairment (Child-Pugh C) as 2- to 3-fold higher unbound linzagolix mean exposures were recorded.
A clinical study conducted in female subjects with renal impairment (mild, moderate, severe and end-stage renal disease) where glomerular filtration rate (GFR) was assessed using creatine clearance, revealed no relevant effect on total plasma linzagolix exposure following administration of a single 200 mg dose of linzagolix. Unbound plasma linzagolix Cmaxu, AUCu0-t, and AUCu0-inf were increased by 30%, 32%, and 33%, in women with mild renal impairment as compared to healthy subjects with normal renal function. As a potential safety concern with long-term use cannot be excluded, prescribers are recommended to monitor for adverse reactions in women with mild renal impairment. However, no dose adjustment is required. Linzagolix should not be used in women with moderate or severe renal impairment or end-stage renal disease as approximately 1.5-fold (in moderate) and 2-fold (in severe renal impairment and ESRD) higher unbound linzagolix mean exposures were observed.
Due to its mechanism of action, linzagolix prevented conception and reduced implantation in rat fertility studies and resulted in embryo-foetal mortality, total litter loss or abolished pregnancy in rat and rabbit embryo-foetal studies.
No teratogenic effects and no adverse effect on the pre- and postnatal development were observed in a rat study. Dose levels of 100 mg/kg and 3 mg/kg linzagolix were shown to be the No observed adverse effect level (NOAEL) for reproductive function and embryo-foetal development in the main embryodevelopment studies in rat and rabbit, respectively (corresponding to respectively 5.9 and 0.004 times the maximum recommended human dose based on AUC).
Linzagolix was shown to be excreted in milk of rats. Up to 96 h after administration, the radioactivity concentration was lower in milk than in plasma (less than 0.3 times).
A standard battery of in vitro and in vivo tests revealed no evidence of mutagenic or clinically relevant genotoxic potential of the drug.
Carcinogenic properties of linzagolix were assessed in a 26-week carcinogenicity study in transgenic Tg RasH2 mice. There was no evidence of linzagolix-induced carcinogenicity up to the highest dose of 500 mg/kg (corresponding to 13.2 times the maximum recommended dose in humans based on AUC).
In a 2-year carcinogenicity study in rats, an increased incidence of uterine endometrial adenocarcinoma was observed in the mid- (50 mg/kg) and high-dose (500 mg/kg) groups (corresponding to respectively 6.8 and 9.6 times the maximum recommended human dose based on AUC) and a marginal increase in the frequency of mammary gland adenocarcinoma was observed at the mid-dose (50 mg/kg) only (6.8 times the maximum recommended human dose based on AUC). The clinical relevance of these findings remains unknown.
Non-carcinogenic histopathological findings in the ovary and uterus (mouse) or ovary and female mammary gland (rat) were considered to be related to the pharmacological action of linzagolix.
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