Chemical formula: C₂₉H₃₄Cl₂N₆O₃S₂ Molecular mass: 649.65 g/mol PubChem compound: 9852519
Avatrombopag is an orally active, small molecule thrombopoietin (TPO) receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in increased production of platelets. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.
The plasma concentration-time profiles following the oral administration of avatrombopag were characterised by a short lag time (0.5–0.75 hours) with peak exposure at 6–8 hours post dose. In a multiple-dose pharmacokinetic study in healthy volunteers, steady state was reached by day 5 of dosing. Open label, randomised, cross-over replicate design clinical trials were conducted in healthy subjects to assess the effects of high-fat and low-fat food on the bioavailability and pharmacokinetic variability of avatrombopag. Administration with either type of food did not have any clinically important effects on rate (Cmax) or extent (AUC) of avatrombopag exposure. However, there was a significant reduction (by approximately 50%) in the between- and within -subject variability of avatrombopag AUC and Cmax when administered with food.
Coadministration of avatrombopag with either a high-fat or low-fat meal did not result in clinically important changes in rate or extent of absorption of avatrombopag. However, administration of avatrombopag with both a high and low-fat meal reduced intersubject and intrasubject pharmacokinetic variability of avatrombopag by approximately 50%. Therefore, avatrombopag is recommended to be administered with food.
In vitro studies suggest that avatrombopag is highly bound to human plasma proteins (>96%). The apparent volume of distribution of avatrombopag in patients with thrombocytopenia and chronic liver disease based on population pharmacokinetic analysis is approximately 180 L, and the apparent volume of distribution with patients with chronic immune thrombocytopenia is approximately 235 L, suggesting that avatrombopag is extensively distributed.
The oxidative metabolism of avatrombopag is mainly mediated by CYP2C9 and CYP3A4/5. Avatrombopag is a substrate for p-glycoprotein (P-gp) mediated transport, although no clinically important differences in platelet count elevations are expected when avatrombopag is co-administered with a strong P-gp inhibitor. Based on in vitro studies, no other transporting proteins (OATP1B1, OATP1B3, OCT2, OAT1, and OAT3) are expected to play a significant role in the disposition of avatrombopag.
Drug interactions: Changes in pharmacokinetics of avatrombopag in the presence of co-administered drug:
| Co-administered drug* | Geometric mean ratio [90% CI] of avatrombopag PK with/without co administered drug (No Effect = 1.00) | |
|---|---|---|
| AUC0-inf | Cmax | |
| Strong CYP3A inhibitor | ||
| Itraconazole | 1.37 (1.10, 1.72) | 1.07 (0.86, 1.35) |
| Moderate CYP3A and CYP2C9 inhibitor | ||
| Fluconazole | 2.16 (1.71, 2.72) | 1.17 (0.96, 1.42) |
| Moderate CYP2C9 and strong CYP3A inducer | ||
| Rifampin | 0.57 (0.47, 0.62) | 1.04 (0.88, 1.23) |
| P-gp inhibitor | ||
| Cyclosporine | 0.83 (0.65, 1.04) | 0.66 (0.54, 0.82) |
| P-gp and moderate CYP3A inhibitor | ||
| Verapamil | 1.61 (1.21, 2.15) | 1.26 (0.96, 1.66) |
* at steady state, except for cyclosporine which was administered as a single dose
Avatrombopag does not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A, does not induce CYP1A, CYP2B6, CYP2C, and CYP3A, and weakly induces CYP2C8 and CYP2C9 in vitro.
Avatrombopag inhibits organic anion transporter (OAT) 1 and 3 and breast cancer resistance protein (BCRP) but not organic anion transporter polypeptide (OATP) 1B1 and 1B3, and organic cation transporter (OCT) 2 in vitro.
Avatrombopag is a substrate for P-glycoprotein (P-gp) mediated transport (see Table). Avatrombopag is not a substrate for OATP1B1, OATP1B3, OCT2, OAT1, and OAT3.
The predominant route of avatrombopag excretion is via faeces. Following administration of a single 20 mg 14C-avatrombopag dose to healthy male volunteers, 88% of the dose was recovered in faeces and 6% in urine. Of the 88% of drug-related material in the faeces, 77% was identified as parent (34%) and the 4-hydroxy metabolite (44%). No metabolites of avatrombopag were detected in plasma.
The mean plasma elimination half-life (CV) of avatrombopag is approximately 19 hours (19). The mean (CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29).
Avatrombopag demonstrated dose-proportional pharmacokinetics after single doses from 10 mg (0.5-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage).
Population pharmacokinetic analysis of avatrombopag plasma concentrations from clinical studies with healthy subjects and patients with thrombocytopenia due to chronic liver disease or healthy subjects and patients with ITP, that included 11% (84/787) and 4% (24/577) of the study population ≥65 years of age, respectively, suggested that avatrombopag exposures are not affected by age.
Population pharmacokinetic analysis of avatrombopag plasma concentrations from the clinical studies with healthy subjects, patients with thrombocytopenia due to chronic liver disease, and patients with ITP indicated that avatrombopag exposures were similar across the different races studied.
Human studies demonstrated that the renal route is not a major pathway for either unchanged avatrombopag or its metabolite’s elimination. Based on the known metabolic profile of avatrombopag and the fact that only 6% of the dose is excreted in urine, the likelihood of effects of renal impairment on pharmacokinetics of avatrombopag is considered to be very low. The population pharmacokinetic analysis of avatrombopag in healthy subjects and subjects with thrombocytopenia due to chronic liver disease indicated similar exposures between healthy subjects and subjects with mild and moderate renal impairment (CrCL ≥30 mL/min, Cockcroft-Gault).
Pharmacokinetics and pharmacodynamics of avatrombopag have not been investigated in patients with severe renal impairment (CrCL <30 mL/min, Cockcroft-Gault) including patients requiring haemodialysis.
A population pharmacokinetic analysis evaluated avatrombopag plasma exposures in patients with mild to moderate hepatic impairment based on Model for End-Stage Liver Disease (MELD) scores and Child-Turcotte-Pugh scores. No clinically important difference in avatrombopag exposures were observed between patients with Child-Turcotte-Pugh Scores (Range = 5 to 12) or MELD scores (Range = 4 to 23) and healthy subjects. Avatrombopag plasma exposure was comparable in patients with chronic liver disease secondary to viral hepatitis (n=242), non-alcoholic steatohepatitis (n=45) and alcoholic liver disease (n=49) in the pivotal Phase 3 studies, and also comparable to that in healthy subjects (n=391). Due to the limited information available, avatrombopag should only be used in Child-Pugh class C patients when the expected benefit outweighs the expected risks.
Avatrombopag does not stimulate platelet production in mice, rats, monkeys, or dogs because of the unique TPO receptor specificity. Therefore, data from these animal studies do not fully model potential adverse effects related to platelet count increases due to avatrombopag in humans.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. The primary toxicity of avatrombopag in pivotal repeated-dose studies was in the stomach at high doses with adequate safety margins when compared to the exposure at the maximum recommended human dose; these effects were reversible even in the chronic toxicity studies.
In two-year carcinogenicity studies in mice and rats, neuroendocrine cell (enterochromaffin-like cell, ECL cell) gastric tumours (carcinoids) occurred in the stomach at high doses. The gastric carcinoids were considered likely due to prolonged hypergastrinemia observed in toxicity studies. Hypergastrinemia-related gastric carcinoids in rodents are generally considered to be of low risk or relevance to humans.
Avatrombopag was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberrations assay or in an in vivo rat bone marrow micronucleus assay.
In 4-week or longer repeated-dose toxicity studies, treatment-related gastric lesions were observed in mice, rats, and cynomolgus monkeys. In these species, avatrombopag was associated with histopathologic changes in the fundic mucosa of the glandular stomach, characterised by degeneration of the glandular epithelium with a decrease in matured parietal cells. This effect was not associated with inflammatory response or any evidence of erosion or ulcer formation. The severity of gastric lesions was dependent on the dose and duration of avatrombopag administration and showed a clear trend towards reversibility during the recovery period. The exposures (AUC) at doses that showed no gastric lesions across the species were 3- to 33-fold higher than the exposures in humans at the maximum recommended human dose (MRHD).
Avatrombopag did not affect fertility or early embryonic development in male rats at exposures 22-times, or in female rats at exposures 114-times, the AUC observed in patients at the recommended dose of 60 mg once daily.
Avatrombopag was present in milk of lactating rats after oral administration of radioactive labeled avatrombopag. The pharmacokinetic parameters of avatrombopag in milk were similar to those in plasma with an exposure ratio of avatrombopag-related radioactivity (milk to plasma) of 0.94.
In a 10-week juvenile toxicology study in rats, avatrombopag was administered at doses ranging from 20 to 300 mg/kg/day. There were no test article-related mortality or clinical signs at doses up to 300 mg/kg/day. In the stomach, dose-dependent degeneration, regenerative hyperplasia, and atrophy of the glandular epithelium occurred at 100 and 300 mg/kg/day; exposures at 100 mg/kg/day in male rats were 14-times the AUC in patients at the maximum recommended dose of 60 mg once daily. Avatrombopag did not cause gastric changes in male juvenile rats at exposures 7 times the AUC observed in patients at the maximum recommended dose of 60 mg once daily. An increased incidence of background focal mineralization was also observed in the kidneys of females at 300 mg/kg/day (female rat exposure was 50-times the human exposure based on AUC at the 60 mg daily dose).
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