Pertuzumab and trastuzumab are recombinant humanised IgG1 monoclonal antibodies which target the human epidermal growth factor receptor 2 (HER2). Both substances bind to distinct HER2 subdomains without competing and have complementary mechanisms for disrupting HER2 signalling:
Additionally, both substances mediate antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, both pertuzumab and trastuzumab ADCC are exerted preferentially on HER2-overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
The PK results for the primary endpoint of pertuzumab Cycle 7 Ctrough (i.e., pre-dose cycle 8), showed non-inferiority of pertuzumab within pertuzumab/trastuzumab (geometric mean 88.7 mcg/mL) compared to intravenous pertuzumab (geometric mean 72.4 mcg/mL) with a geometric mean ratio of 1.22 (90% CI: 1.14-1.31). The lower boundary of the two-sided 90% confidence interval for the geometric mean ratio of pertuzumab within pertuzumab/trastuzumab and intravenous pertuzumab was 1.14, i.e., greater than the predefined margin of 0.8.
The PK results for the secondary endpoint, trastuzumab Cycle 7 Ctrough (i.e., predose Cycle 8), showed non-inferiority of trastuzumab within pertuzumab/trastuzumab (geometric mean 57.5 mcg/mL) compared to intravenous trastuzumab (geometric mean 43.2 mcg/mL) with a geometric mean ratio of 1.33 (90% CI: 1.24-1.43).
The median maximum serum concentration (Cmax) of pertuzumab within pertuzumab/trastuzumab and time to maximal concentration (Tmax) were 157 mcg/mL and 3.82 days, respectively. Based on population PK analysis, the absolute bioavailability was 0.712 and the first-order absorption rate (Ka) is 0.348 (1/day).
The median Cmax of trastuzumab within pertuzumab/trastuzumab and Tmax were 114 mcg/mL and 3.84 days, respectively. Based on population PK analysis, the absolute bioavailability was 0.771 and the Ka is 0.404 (1/day).
Based on population PK analysis, the volume of distribution of the central (Vc) compartment of pertuzumab within pertuzumab/trastuzumab in the typical patient, was 2.77 litres.
Based on population PK analysis, the Vc compartment of subcutaneous trastuzumab in the typical patient, was 2.91 litres.
The metabolism of pertuzumab/trastuzumab has not been directly studied. Antibodies are cleared principally by catabolism.
Based on population PK analysis, the clearance of pertuzumab within pertuzumab/trastuzumab was 0.163 L/day and the elimination half-life (t½) was approximately 24.3 days.
Based on population PK analysis, the clearance of trastuzumab within pertuzumab/trastuzumab was 0.111 L/day. Trastuzumab is estimated to reach concentrations that are <1 mcg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% washout) in at least 95% patients 7 months after the last dose.
No studies have been conducted to investigate the pharmacokinetics of pertuzumab/trastuzumab in elderly patients.
In population PK analyses of pertuzumab within pertuzumab/trastuzumab and intravenous pertuzumab, age was not found to significantly affect PK of pertuzumab.
In population PK analyses of subcutaneous or intravenous trastuzumab, age has been shown to have no effect on the disposition of trastuzumab.
No studies have been conducted to investigate the pharmacokinetics of pertuzumab/trastuzumab in patients with renal impairment.
Based on population PK analyses of pertuzumab within pertuzumab/trastuzumab and intravenous pertuzumab, renal impairment was shown not to affect pertuzumab exposure; however, only limited data from patients with severe renal impairment were included in population pharmacokinetic analyses.
In a population PK analysis of subcutaneous and intravenous trastuzumab, renal impairment was shown not to affect trastuzumab disposition.
No formal PK study has been conducted in patients with hepatic impairment. Based on population PK analyses of pertuzumab within pertuzumab/trastuzumab, mild hepatic impairment was shown not to affect pertuzumab exposure. However, only limited data from patients with mild hepatic impairment were included in population PK analyses. IgG1 molecules such as pertuzumab and trastuzumab are catabolised by widely distributed proteolytic enzymes not restricted to hepatic tissue. Therefore, changes in hepatic function are unlikely to have an effect on the elimination of pertuzumab and trastuzumab.
No dedicated studies were conducted with the combination of subcutaneous pertuzumab, trastuzumab, and vorhyaluronidase alfa.
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No definitive conclusion on adverse effects can be drawn on the male reproductive organs in cynomolgus monkey repeated dose toxicity.
Reproductive toxicology studies have been conducted in pregnant cynomolgus monkeys (Gestational Day (GD) 19 through to GD 50) at initial doses of 30 to 150 mg/kg followed by bi weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human subcutaneous dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-foetal death between GD25 to GD70. The incidences of embryo-foetal loss were 33, 50, and 85% for pregnant female monkeys treated with bi weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (4- to 35-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. In addition, consistent with foetal growth restrictions, secondary to oligohydramnios, lung hypoplasia (1 of 6 in 30 mg/kg and 1 of 2 in 100 mg/kg groups), ventricular septal defects (1 of 6 in 30 mg/kg group), thin ventricular wall (1 of 2 in 100 mg/kg group) and minor skeletal defects (external -3 of 6 in 30 mg/kg group) were also noted. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.
Subcutaneous pertuzumab (250 mg/kg/week for 4 weeks) and intravenous pertuzumab (up to 150 mg/kg weekly for up to 26 weeks) was well tolerated in cynomolgus monkeys (binding species), except for the development of diarrhoea. With intravenous pertuzumab doses of 15 mg/kg and higher, intermittent mild treatment-associated diarrhoea was noted. In a subset of monkeys, chronic dosing (26 weekly doses) resulted in episodes of severe secretory diarrhoea. The diarrhoea was managed (with the exception of euthanasia of one animal, 50 mg/kg/dose) with supportive care including intravenous fluid replacement therapy.
Reproduction studies have been conducted in Cynomolgus monkeys via the intravenous route at doses up to 16 times that of the human maintenance trastuzumab dose of 600 mg and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal development period was observed.
There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer studies. Trastuzumab is not genotoxic. A study of trehalose, a major formulation excipient did not reveal any toxicities.
No long-term animal studies have been performed to establish the carcinogenic potential of trastuzumab, or to determine its effects on fertility in males.
A study conducted in lactating Cynomolgus monkeys administered intravenous trastuzumab doses up to 16 times that of the human maintenance dose of 600 mg trastuzumab demonstrated that trastuzumab is secreted in the milk post partum. The exposure to trastuzumab in utero and the presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age.
Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant human hyaluronidase reveal no special hazard for humans based on conventional studies of repeated dose toxicity including safety pharmacology endpoints. Reproductive toxicology studies with vorhyaluronidase alfa revealed embryofetal toxicity in mice at high systemic exposure, but did not show teratogenic potential.
A single dose study in rabbits and a 13-week repeat dose toxicity study in Cynomolgus monkeys were conducted with trastuzumab subcutaneous formulation. The rabbit study was performed to specifically examine local tolerance aspects. The 13-week study was performed to confirm that the change to the subcutaneous route of administration and the use of the excipient vorhyaluronidase alfa did not have an effect on the trastuzumab safety characteristics. Trastuzumab subcutaneous formulation was locally and systemically well tolerated.
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