Molecular mass: 151,500 g/mol
Gemtuzumab ozogamicin is a CD33-targeted ADC. Gemtuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognises human CD33. The antibody portion binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of myeloid leukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoietic stem cells. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic semisynthetic natural product. N-acetyl gamma calicheamicin is covalently attached to the antibody via an AcBut (4-(4-acetylphenoxy) butanoic acid) linker. Non-clinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumour cells, followed by internalisation of the ADC-CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of calicheamicin to leukaemic blast cells. Several single agent studies measured target (CD33) saturation post-gemtuzumab dose in patients with relapsed and refractory AML. Across all studies, near maximal peripheral CD33 saturation was observed post-gemtuzumab dose at all dose levels of 2 mg/m² and above, suggesting that a low dose of gemtuzumab ozogamicin is sufficient to bind all available CD33 sites.
Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of CD33-directed monoclonal antibody (hP67.6) that is covalently linked to the cytotoxic agent N-acetyl-gamma calicheamicin. The pharmacokinetics (PK) of gemtuzumab ozogamicin is described by measuring PK characteristics of the antibody (hP67.6) as well as total and unconjugated calicheamicin derivatives. Given that the hP67.6 portion renders target selectivity on the intact molecule, and that gemtuzumab ozogamicin dosages are reported in terms of milligrams of protein (hP67.6), the hP67.6 concentration results are reported as the primary PK measures. After gemtuzumab ozogamicin binds to the target it is internalised and N-acetyl calicheamicin is released by hydrolytic cleavage. Determination of PK parameters for unconjugated calicheamicin was limited due to the low systemic concentration levels.
No clinical PK data have been collected using the fractionated regimen; however, the PK have been simulated using the population PK model. Although the total dose of the fractionated dosing regimen is half of that of the original dosing regimen (9 versus 18 mg/m²), the predicted total AUC of hP67.6 over the course of treatment is 25%, and Cmax is 24%, of the values for original 9 mg/m² dosing regimen, since the PK is nonlinear. When gemtuzumab ozogamicin is administered at 3 mg/m² on Days 1, 4, and 7, the Cmax of hP67.6, which would occur at the end of infusion, is predicted to be 0.38 mg/L following the first dose and increased to 0.63 mg/L after the third dose.
In vitro, the binding N-acetyl gamma calicheamicin dimethyl hydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is a substrate of P-glycoprotein (P-gp). In patients, the total volume of distribution of hP67.6 antibody (sum of V1 [10 L] and V2 [15 L]) was found to be approximately 25 L.
The primary metabolic pathway of gemtuzumab ozogamicin is anticipated to be hydrolytic release of N acetyl gamma calicheamicin dimethyl hydrazide. In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolised, primarily via nonenzymatic reduction of the disulphide moiety. The activity (cytotoxicity) of the resultant metabolites is expected to be significantly attenuated. In patients, unconjugated calicheamicin plasma levels were typically low, with a predicted mean Cmax of 1.5 ng/mL following the third dose.
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is primarily metabolised via nonenzymatic reduction. Therefore, coadministration of gemtuzumab ozogamicin with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug metabolising enzymes are unlikely to alter exposure to N-acetyl gamma calicheamicin dimethyl hydrazide.
Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin with hydroxyurea, DNR, and AraC is not predicted to cause clinically meaningful changes in the PK of hP67.6 or unconjugated calicheamicin.
Effect on CYP substrates: In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to inhibit the activities of CYP1A2, CYP2A6 (tested only using gemtuzumab ozogamicin), CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 at clinically relevant concentrations. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to induce the activities of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.
Effect on UGT substrates: In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 at clinically relevant concentrations.
Effect on drug transporter substrates: In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance associated protein (MRP) 2, multidrug and toxin extrusion protein (MATE)1 and MATE2K, organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)1 and OCT2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3 at clinically relevant concentrations.
Effect on co-administered chemotherapeutic agents: Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin with DNR and AraC is not predicted to cause clinically meaningful changes in the PK of these agents.
Based on Population PK analyses, the predicted clearance (CL) value of hP67.6 from plasma was 3 L/h immediately after the first dose and then 0.3 L/h. The terminal plasma half-life (t1⁄2) for hP67.6 was predicted to be approximately 160 hours for a typical patient at the recommended dose level (3 mg/m²) of gemtuzumab.
Based on a population PK analysis, age, race, and gender did not significantly affect gemtuzumab ozogamicin disposition.
No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with hepatic impairment.
Based on a population PK analysis, the clearance of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is not expected to be affected by mild hepatic impairment status, as defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG). The analysis included 405 patients in the following NCI ODWG impairment status categories: mild (B1, n=58 and B2, n=19), moderate (C, n=6), and normal hepatic function (n=322).
No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with renal impairment.
Based on a population PK analysis in 406 patients, the clearance of gemtuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr ] 60-89 mL/min; n=149) or moderate renal impairment (CLcr 30-59 mL/min; n=47), was similar to patients with normal renal function (CLcr ≥90 mL/min; n=209). The PK of gemtuzumab ozogamicin has not been studied in patients with severe renal impairment.
The results of the population modelling showed that the PK behaviour of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is similar between adult and paediatric AML patients following the 9 mg/m² dosing regimen.
The main toxicities occurred in the liver, bone marrow and lymphoid organs, haematology parameters (decreased RBC mass and WBC counts, mainly lymphocytes), kidney, eye and male and female reproductive organs. Effects on liver, kidney and male reproductive organs in rats, and on lymphoid tissues in monkeys (approximately 18 times for rats, and 36 times for monkeys, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168) were not reversible. Effects on female reproductive organs and the eye in monkeys were adverse in the 12-week study (approximately 193 and 322 times, respectively, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). The relevance of the irreversible animal findings to humans is uncertain. Nervous system effects have not been observed in animals after administration of gemtuzumab. Nervous system alterations were identified in rats with other antibody-calicheamicin conjugates.
Gemtuzumab ozogamicin was found to be clastogenic. This is consistent with the known induction of DNA breaks by calicheamicin and other enediyne antitumour antibiotics. N-acetyl gamma calicheamicin DMH (the released cytotoxin) was found to be mutagenic and clastogenic.
Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin. In toxicity studies, rats developed preneoplastic lesions (minimal to slight oval cell hyperplasia) in the liver approximately 54 times, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). There were no preneoplastic or neoplastic lesions observed in monkeys up to approximately 115 times the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). The relevance of these animal findings to humans is uncertain.
In a female rat fertility study slightly lower numbers of corpora lutea and increased embryolethality were observed in the presence of maternal toxicity (approximately 9.7 times, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). Effects on the reproductive tract of female monkeys were observed in the 12-week study (atrophy of the ovary, oviduct, uterus, and cervix; approximately 193 times the human clinical exposure after the third dose of 3 mg/m²).
In a male fertility study, effects on male reproduction included lower spermatogonia and spermatocytes, decreases in testicular spermatids and epididymal sperm, vacuolation of the nucleus in spermatids, and/or appearance of giant cells. Additional findings included effects on the testes, epididymides and mammary gland as well as fertility. When male rats were mated again after a 9-week non-dosing period, effects on sperm and fertility were worse but there was partial recovery of the lower spermatogonia and spermatocytes in the testes. Effects on male rat reproductive organs were partially reversible or not reversible. Male reproductive effects (testes, epididymides, seminal vesicles) in monkeys were observed at approximately 66 times the human clinical exposure after the third dose of 3 mg/m²).
In an embryo-foetal toxicity study lower foetal body weight, higher incidence of foetal wavy ribs, and lower incidence of foetal skeletal ossification were observed. Increased embryolethality and foetal morphological anomalies included digital malformations, absence of the aortic arch, anomalies in the long bones in the forelimbs, misshapen scapula, absence of a vertebral centrum, and fused sternebrae. Increased embryolethality was also observed in the presence of maternal toxicity. The lowest dose with embryo-foetal effects correlated with 9.7 times the human clinical exposure after the third human dose of 3 mg/m², based on AUC168.
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