Chemical formula: C₂₄H₂₈F₄N₆ Molecular mass: 476.231 g/mol PubChem compound: 134453496
Camizestrant is an oral selective oestrogen receptor degrader (SERD) and oestrogen receptor (ER) antagonist.
Camizestrant binds to the ligand binding domain of ERα, antagonising the activity of ERα encoded by both wild-type ESR1 and mutated ESR1, and inducing proteasome-dependent degradation of ERα, without agonising ERα.
Exposure response analysis of potential QTcI prolongation of daily 75 mg to 300 mg of camizestrant monotherapy was assessed in 30 patients. The predicted drug related mean QTcI prolongation was 2.99 msec (95% CI: (-0.75, 6.73)) at the mean steady state Cmax with an upper bound of 6.09 msec (90% CI) following 75 mg camizestrant daily. At the recommended 75 mg dose of camizestrant, a mean increase in QTcI >10 msec was not observed.
Camizestrant pharmacokinetic parameters have been characterized in healthy patients and breast cancer patients. Based on population pharmacokinetic (popPK) analysis, the pharmacokinetics of camizestrant at the 75 mg dose are characterized by an apparent plasma clearance of 69.1 L/h, apparent volume of distribution (Vss/F) at steady state of 26.97 L/kg and a terminal half-life of approximately 23 hours. The camizestrant 75 mg dose oral bioavailability is 43% and steady state is reached by Day 5 following once daily dosing.
Following oral administration, camizestrant is absorbed with median peak plasma concentrations achieved between approximately 2 to 4 hours after dosing.
Similar exposures were observed following administration with a high fat meal or fasted overnight supporting camizestrant being taken with or without food. Following a high fat meal, the fed to fasted Cmax and AUC geometric mean ratios (90% CI) were 106.2% (90% CI: 94.3%, 119.7%) and 109.8% (90% CI: 104.4%, 115.5%), respectively.
Based on popPK analysis, camizestrant is distributed in the tissues with an apparent peripheral volume of distribution of 8.69 L/kg. The apparent volume of distribution of camizestrant at steady state is 26.97 L/kg.
Plasma protein binding of camizestrant is 75.3% (24.7% free). There is no evidence of concentration dependent plasma protein binding. The blood to plasma ratio was 0.99.
Metabolism results from in vitro hepatocytes studies suggest that camizestrant undergoes multiple oxidation reactions in addition to direct N-glucuronidation and is primarily metabolised by CYP3A4/5 and UGT1A4. Human metabolites of camizestrant were detected and quantified in pharmacokinetic samples from healthy female volunteers receiving a single oral dose of 75 mg [14C]-camizestrant (0.67 MBq). The major drug-related circulating materials were the N-glucuronide conjugate of camizestrant, the N-glucuronide of the acid metabolite and camizestrant which accounted for 20.1%, 11.2%, and 13.6% of the circulating radioactivity in plasma. The other eight minor metabolites in plasma, each of which had a relative abundance lower than 10% of the total drug-related materials in plasma, were either oxidative metabolites or glucuronides of oxidative metabolites. No active metabolites have been identified.
In vitro: Camizestrant does not inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 or CYP2E1 and is a weak (IC50 >100 μM) inhibitor of UGT1A1 and UGT2B7. Camizestrant does not cause time-dependent inhibition of CYP1A2, CYP2D6 and CYP3A4/5. Camizestrant has low potential to cause induction of CYP1A2, CYP2B6, and CYP3A4/5. For the drug transporters, camizestrant does not inhibit OATP1B3, OCT2, OAT1, OAT3, MATE1, and MATE2K and is not a substrate of BCRP, OATP1B1 or OATP1B3.
Following single oral administration of 75 mg [14C]-camizestrant, mean of 82% of the radioactivity administered was recovered in urine and faeces. Mean total radioactivity (65.1%) was recovered in faeces indicating faecal excretion was the main route of elimination following oral dosing; with 16.8% of the total radioactivity being recovered from the urine.
Camizestrant AUC and Cmax showed greater than dose-proportional increase over the dose range of 25 to 450 mg.
Based on popPK analyses (n=756), no clinically significant relationships were identified between model predicted steady-state exposure, area under the curve at steady state (AUCss) and the following covariates: baseline median age 61 years (29 to 89 years) and racial groups. PopPK analysis showed baseline median body weight was 69.9 kg (34.2 to 150 kg) and it affected apparent volume of distribution (V2/F), but this was not clinically relevant; it did not significantly impact apparent total body clearance (CL/F) or AUCss. No dose adjustments for camizestrant are required based on age, gender, race, or body weight.
The popPK analysis used continuous creatinine clearance. Baseline creatinine clearance (CrCL) was calculated using the Cockcroft-Gault equation to evaluate the effect of renal function on camizestrant PK; the median CrCL was 86.2 mL/min (range 22.8-303 mL/min). The analysis showed no clinically meaningful impact of mild and moderate renal impairment at baseline on camizestrant PK, indicating that no dose adjustment is necessary for patients with mild to moderate renal impairment.
There were limited patients with severe renal impairment and no patients on dialysis or with CrCL <15 mL/min were included in the clinical studies of camizestrant. Therefore, an appropriate dose of camizestrant has not been established for severe renal impairment patients and patients on dialysis.
Based on a pharmacokinetic study in patients following a single 75 mg dose, camizestrant exposure geometric mean Cmax and AUC0-INF in patients with moderate (Child-Pugh B) hepatic impairment was 2.4-fold and 2.7-fold, respectively, compared to patients with normal hepatic function. Camizestrant exposure geometric mean Cmax and AUC0-INF in patients with severe (Child-Pugh C) hepatic impairment was 3.1-fold and 3.8-fold, respectively, compared to patients with normal hepatic function.
The exposure to camizestrant is higher than dose-proportional and increases with time until steady state. The increase in exposure to camizestrant from single dose to steady state is not known in subjects with hepatic impairment (Child-Pugh). PopPK modelling did not indicate mild hepatic impairment (NCI) as a significant covariate for camizestrant exposure. As precautionary measures, camizestrant should be avoided in subjects with moderate and severe hepatic impairment. Patients with mild hepatic impairment are allowed to take camizestrant.
In repeat-dose toxicity studies in mice, rats and dogs, the reproductive tract was identified as a target organ with histopathological findings occurring at exposures significantly below (female) or at 2-fold (male) human exposure at Maximum Recommended Human Dose (MRHD). There were related findings in the adrenals (rats and mice) and pituitary (mice) glands. Findings were hormone-driven, based on the pharmacological action of camizestrant and therefore not relevant for post-menopausal women or pre- or peri menopausal women or men administered an LHRH agonist. Findings in the male reproductive tract of clinical relevance are described in the fertility section.
Macrophage aggregation (lung, spleen, thymus and mesenteric lymph nodes) and vacuolation (biliary epithelium of the liver) were noted in the rat and/or mouse. This was confirmed as phospholipidosis in the lung of rat, was reversible following 1-month dosing but was considered adverse in female rats in the 6-month study at a total plasma exposure (AUC) of approximately 60-fold human exposure at MRHD.
In mechanistic studies, camizestrant caused rod bipolar cell dysfunction in the retina of rats at clinically relevant exposures (approximately 5-fold human exposure at MRHD). The retina effects in rats were reversible and are consistent with the transient visual effects observed in humans.
Cardiovascular effects were observed across species (i.e. dogs and rats) and supported by mechanistic studies. Heart rate reduction, related to decreased sinoatrial node pacemaker current activity via HCN4 ion channels, was observed in animals and confirmed clinically. In dogs and rats, additional delayed-onset cardiovascular functional effects included dose- and time-dependent decreases in diastolic blood pressure, QA interval and PR interval, with increases in pulse pressure, QT/QTc intervals and left ventricular parameters (dP/dt+ and dP/dt-). When assessed in dogs, QTc prolongation persisted for at least 3 days up to 4 weeks. The QTc prolongation was of unknown mechanism, independent of heart rate and unrelated to hERG inhibition and observed at maximum unbound plasma concentrations ≥ 4-fold those at human MRHD. Additional atrial premature complexes (APCs) were observed in one telemetry and one toxicology dog at maximum free plasma levels 12-fold and 33-fold human MRHD, respectively. Cardiomyopathy was observed in female rats following dosing for 6 months at total plasma exposures ≥ 11-fold the human AUC exposure at human MRHD.
In dogs, combination dosing of camizestrant with atropine resulted in a significant increase in plasma and brain exposure of atropine considered to be due to inhibition of atropine metabolism and, therefore, likely dog specific.
Camizestrant was negative in the in vitro Ames and micronucleus assays, and the in vivo micronucleus study. Findings in the ovaries in chronic repeat-dose studies included hyperplasia at total plasma exposures (AUC) ≥2-fold (rat granulosa cell) and 52-fold (dog sex cord stromal) relative to human exposure at MRHD and benign granulosa cell tumours at total plasma exposures (AUC) of approximately 60-fold (rats) and 3.5-fold (dogs) relative to human exposure at MRHD. An interstitial (Leydig) cell adenoma was observed in the testis of a single dog at 13-fold human exposure at MRHD. Findings are considered hormone-driven, based on the pharmacological action of camizestrant and therefore not relevant for post-menopausal women or in pre- or peri menopausal women or men administered an LHRH agonist.
Administration of camizestrant in a modified embryofoetal development study in rats resulted in a complete lack of implantation in females when dosing at 0.1 mg/kg/day commenced prior to implantation. When administration was restricted to the phase of organogenesis, camizestrant had no effect on embryofoetal survival or development, but when dosed from implantation through parturition and into lactation, camizestrant resulted in increased length of gestation, dystocia, impaired offspring survival and growth. Maternal exposures in this study were far below human exposure at MRHD.
In a fertility study in female rats, camizestrant negatively affected oestrous cycles, mating behaviour, fertility and early embryonic survival which fully reversed following 1 month off dose. Effects were observed at maternal exposures below human exposure at MRHD.
In male rats and dogs, atrophy of the prostate gland, seminal vesicle and seminiferous tubules, tubular dilation of testis and changes in the epididymis (decreased sperm in rats and cell debris in dog) were evident from the lowest dose in chronic studies at exposures ≥2-fold (rat) or ≥3.5-fold (dog) human exposure at MRHD and were considered of clinical relevance. In male rats following 9 weeks of dosing there were lower spermatid/sperm counts, a higher percentage of sperm abnormalities, lower sperm motility, and lower mating and pregnancy rates indicating an effect on male fertility. Effects were observed at a total plasma exposure (AUC) ≥2-fold that observed at a clinical dose of 75 mg, but a no-effect level was not established. In that study, implantation loss and a decrease in number of live foetuses was observed in non-dosed females paired with dosed males suggesting male-mediated reproductive toxicity at a total plasma exposure (AUC) 27-fold the human exposure at MRHD. Reversibility of male fertility findings was not assessed.
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