Odalade Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Thrombopoietin (TPO) is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-receptor.
Eltrombopag is a TPO-receptor agonist which interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades similar but not identical to that of endogenous TPO, inducing proliferation and differentiation of megakaryocytes and bone marrow progenitor cells.
Pharmacodynamics: Eltrombopag differs from TPO with respect to the effects on platelet aggregation. Unlike TPO, eltrombopag treatment of normal human platelets does not enhance adenosine diphosphate (ADP)-induced aggregation or induce P-selectin expression. Eltrombopag does not antagonize platelet aggregation induced by ADP or collagen.
Pharmacokinetics: In clinical trials, eltrombopag resulted in dose-dependent increases in platelet count following repeat daily dosing and reached a maximum in approximately 2 weeks, and returned to baseline within approximately 2 weeks after the last dose. Steady-state was achieved after approximately 1 week with once daily dosing.
Absorption: After oral administration to healthy volunteers, the Cmax of eltrombopag occurred at a Tmax between 2 and 6 hours. Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects.
Compared with the fasted state, the administration of eltrombopag with a high-fat, high-calcium meal decreased the AUC by 59%, decreased the Cmax by 65%, and delayed the Tmax by 1 hour in an open label, randomized crossover study. The decrease in exposure was primarily due to the high calcium content. A meal low in calcium (up to 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.
Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure.
The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in feces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52%.
Distribution: Eltrombopag is greater than 99.9% protein bound to albumin. Eltrombopag is a substrate for BCRP, but not a substrate for P-glycoprotein or OATP1B1.
Biotransformation: Eltrombopag is extensively metabolized via cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest oxidation of eltrombopag is via CYP1A2 and CYP2C8 and UGT1A1 and UGT1A3 are responsible for glucuronidation.
Excretion: The main route of excretion of eltrombopag is through feces. 59% of the dose is excreted via this route with 20% of the dose excreted as unchanged drug. Approximately 31% of metabolized eltrombopag is excreted in the urine. Unchanged eltrombopag is not found in the urine.
The elimination half-life of eltrombopag is 21 to 32 hours.
Special populations: Gender: The steady state AUC of eltrombopag was found to be 50% higher in female patients compared with male patients according to a population pharmacokinetic analysis in healthy subjects and patients with idiopathic thrombocytopenic purpura.
Race/Ethnicity: Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with idiopathic thrombocytopenic purpura or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects.
The steady state AUC of eltrombopag was found to be 87% higher in East Asian patients as compared with non-East Asian patients (primarily Caucasian) in a population pharmacokinetic analysis in healthy subjects and patients with idiopathic thrombocytopenic purpura.
Renal impairment: Following administration of a single dose of eltrombopag 50 mg, the AUC was 32% to 36% lower in patients with mild to moderate renal impairment and 60% lower in patients with severe renal impairment compared with healthy patients. The relationship between renal impairment and unbound (active) eltrombopag exposure has not been evaluated.
Hepatic impairment: Following administration of a single dose of eltrombopag, the AUCinf was increased by 41% in patients with mild hepatic impairment (Child-Pugh A) and by approximately two-fold in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) compared with subjects with normal hepatic function. In another population pharmacokinetic analysis in patients with thrombocytopenia and chronic liver disease, the AUCtau was increased by 87% to 110% in patients with mild hepatic impairment and 141% to 240% in patients with moderate hepatic impairment compared with healthy volunteers after repeated doses of eltrombopag.
Toxicology: Preclinical safety data: Safety pharmacology and repeat dose toxicity: Treatment-related cataracts were detected in rodents and were dose and time-dependent. At times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 3 times the human clinical exposure based on AUC in HCV patients at 100 mg/day, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At ≥4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in HCV patients at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses in pre-weaning juvenile rats dosed from Days 4-32 (approximately equating to a 2-year, old human at the end of the dosing period), ocular opacities were observed (histology not performed) at 9 times the maximum human clinical exposure in pediatric ITP patients at 75 mg/day, based on AUC. However, cataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinical exposure in pediatric ITP patients, based on AUC. Cataracts have not been observed in dogs after 52 weeks of dosing at 2 times the human clinical exposure in ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC.
Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2 year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterized by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.6 times the human clinical exposure based on AUC in HCV patients at 100 mg/day. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times the human clinical exposure in ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC.
Carcinogenicity and mutagenicity: Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 and 5 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in HCV patients at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure, based on Cmax in ITP patients at 75 mg/day and 7 times the human clinical exposure in HCV patients at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and in vivo findings suggest that eltrombopag does not pose a genotoxic risk to humans.
Reproductive toxicity: Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).
Juvenile animal studies: At non-tolerated doses in pre-weaning rats, ocular opacities were observed. However, at tolerated doses, no ocular opacities were observed. There are no findings in juvenile rats to suggest a greater risk of toxicity with eltrombopag treatment in pediatric vs. adult patients.