Inotuzumab ozogamicin is an ADC composed of a CD22-directed monoclonal antibody that is covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide. Inotuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody that specifically recognises human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic product.
N-acetyl-gamma-calicheamicin is covalently attached to the antibody via an acid-cleavable linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumour cells, followed by internalisation of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
In patients with relapsed or refractory ALL treated with inotuzumab ozogamicin at the recommended starting dose of 1.8 mg/m²/cycle, steady-state exposure was achieved by Cycle 4. The mean (SD) maximum serum concentration (Cmax) of inotuzumab ozogamicin was 308 ng/mL (362). The mean (SD) simulated total area under the concentration-time curve (AUC) per cycle at steady state was 100 mcg·h/mL (32.9).
In vitro, the binding of the N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp). In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L.
In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolised via nonenzymatic reduction. In humans, serum N-acetyl-gamma-calicheamicin dimethylhydrazide levels were typically below the limit of quantitation (50 pg/mL), but sporadic measurable levels of unconjugated calicheamicin up to 276 pg/mL occurred in some patients.
Inotuzumab ozogamicin pharmacokinetics were well characterised by a 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h, and the terminal elimination half-life (t1⁄2) at the end of Cycle 4 was approximately 12.3 days. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was observed between Cycles 1 and 4.
Based on a population pharmacokinetic analysis in 765 patients, body surface area was found to significantly affect inotuzumab ozogamicin disposition. The dose of inotuzumab ozogamicin is administered based on body surface area.
Based on a population pharmacokinetic analysis, age, race, and gender did not significantly affect inotuzumab ozogamicin disposition.
No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients with hepatic impairment.
Based on a population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab ozogamicin in patients with hepatic impairment defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG) category B1 (total bilirubin ≤ ULN and AST > ULN; n=133) or B2 (total bilirubin >1.0-1.5 × ULN and AST any level; n=17) was similar to patients with normal hepatic function (total bilirubin/AST ≤ ULN; n=611). In 3 patients with hepatic impairment defined by NCI ODWG category C (total bilirubin >1.5-3 × ULN and AST any level) and 1 patient with hepatic impairment defined by NCI ODWG category D (total bilirubin >3 × ULN and AST any level), inotuzumab ozogamicin clearance did not appear to be reduced.
No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients with renal impairment.
Based on population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab ozogamicin in patients with mild renal impairment (CLcr 60-89 mL/min; n=237), moderate renal impairment (CLcr 30-59 mL/min; n=122), or severe renal impairment (CLcr 15-29 mL/min; n=4) was similar to patients with normal renal function (CLcr ≥90 mL/min; n=402). Inotuzumab ozogamicin has not been studied in patients with end-stage renal disease.
Population pharmacokinetic/pharmacodynamic evaluation suggested a correlation between increasing inotuzumab ozogamicin serum concentrations and prolongation of QTc intervals in ALL and non-Hodgkin’s lymphoma (NHL) patients. The median (upper bound of the 95% CI) for the change in QTcF at a supratherapeutic Cmax concentration was 3.87 msec (7.54 msec).
In a randomised clinical study in patients with relapsed or refractory ALL (Study 1), maximum increases in QTcF interval of ≥30 msec and ≥60 msec from baseline were measured in 30/162 (19%) and 4/162 (3%) patients in the inotuzumab ozogamicin arm, respectively, versus18/124 (15%) and 3/124 (2%) in the Investigator’s choice of chemotherapy arm, respectively. Increases in QTcF interval of >450 msec and >500 msec were observed in 26/162 (16%) and none of the patients in the inotuzumab ozogamicin arm versus 12/124 (10%) and 1/124 (1%) patients in the Investigator’s choice of chemotherapy arm, respectively.
In animals, the primary target organs included the liver, bone marrow and lymphoid organs with associated haematological changes, kidney, and nervous system. Other observed changes included male and female reproductive organ effects (see below) and preneoplastic and neoplastic liver lesions (see below). Most effects were reversible to partially reversible except for effects in the liver and nervous system. The relevance of the irreversible animal findings to humans is uncertain.
Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice. This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin dimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in an in vitro bacterial reverse mutation (Ames) assay.
Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In toxicity studies, rats developed oval cell hyperplasia, altered hepatocellular foci, and hepatocellular adenomas in the liver at approximately 0.3 times the human clinical exposure based on AUC. In 1 monkey, a focus of hepatocellular alteration was detected at approximately 3.1 times the human clinical exposure based on AUC at the end of the 26-week dosing period. The relevance of these animal findings to humans is uncertain.
Administration of inotuzumab ozogamicin to female rats at the maternally toxic dose (approximately 2.3 times the human clinical exposure based on AUC) prior to mating and during the first week of gestation resulted in embryo-foetal toxicity, including increased resorptions and decreased viable embryos. The maternally toxic dose (approximately 2.3 times the human clinical exposure based on AUC) also resulted in foetal growth retardation, including decreased foetal weights and delayed skeletal ossification. Slight foetal growth retardation in rats also occurred at approximately 0.4 times the human clinical exposure based on AUC.
Inotuzumab ozogamicin is considered to have the potential to impair reproductive function and fertility in men and women based on non-clinical findings. In repeat dose toxicity studies in rats and monkeys, female reproductive findings included atrophy of ovaries, uterus, vagina, and mammary gland. The no observed adverse effect level (NOAEL) for the effects on female reproductive organs in rats and monkeys was approximately 2.2 and 3.1 times the human clinical exposure based on AUC, respectively. In repeat dose toxicity studies in rats, male reproductive findings included testicular degeneration, associated with hypospermia, and prostatic and seminal vesicle atrophy. The NOAEL was not identified for the effects on male reproductive organs, which were observed at approximately 0.3 times the human clinical exposure based on AUC.
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