Chemical formula: C₁₉H₁₅F₃N₂O₃ Molecular mass: 376.335 g/mol PubChem compound: 16124688
Tecovirimat inhibits the activity of the orthopoxvirus VP37 protein, which is encoded by a highly conserved gene in all members of the orthopoxvirus genus. Tecovirimat blocks the interaction of VP37 with cellular Rab9 GTPase and TIP47, which prevents the formation of egress competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus.
In cell culture assays, the effective concentrations of tecovirimat resulting in a 50% reduction in virus induced cytopathic effect (EC50), were 0.016-0.067 μM, 0.014-0.039 µM, 0.015 µM and 0.009 µM, for smallpox, monkeypox, rabbitpox and vaccinia viruses, respectively.
There are no known instances of naturally occurring tecovirimat-resistant orthopoxviruses, although tecovirimat resistance may develop under drug selection. Tecovirimat has a relatively low resistance barrier, and certain amino acid substitutions in the target VP37 protein can confer large reductions in tecovirimat antiviral activity. The possibility of resistance to tecovirimat should be considered in patients either who fail to respond to therapy or who develop recrudescence of disease after an initial period of responsiveness.
Tecovirimat reaches maximum plasma concentrations 4 to 6 hours after oral administration with food.
The administration of tecovirimat with a meal of moderate fat and calories (~600 calories and ~25 grams of fat), as compared to tecovirimat taken in the fasted (unfed) state, increased the drug exposure (AUC) by 39%.
Tecovirimat is 77.3-82.2% bound to human plasma proteins. After a single 600 mg dose of [14C]-tecovirimat in healthy subjects, concentrations of total radioactivity were lower in whole blood compared to plasma at all time points, with ratios of whole blood to plasma ranging from 0.62-0.90 across all time points. Tecovirimat has a high volume of distribution (1356 L).
Based on human studies, tecovirimat is metabolized to form metabolites M4 (N-{3,5-dioxo-4-azatetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-en-4-yl}amine), M5 (3,5-dioxo-4-aminotetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-ene), and TFMBA (4 (trifluoromethyl) benzoic acid). None of the metabolites is pharmacologically active.
Tecovirimat is a substrate of UGT1A1 and UGT1A4. In urine, primary tecovirimat glucuronide conjugate and M4 glucuronide conjugate were the most abundant components accounting for means of 24.4% and 30.3% of dose, respectively. However, none of the glucuronide conjugates was found as a major metabolite in plasma.
After a single dose of [14C]-tecovirimat in healthy subjects, approximately 95% of the [14C]-radioactivity was recovered in urine and faeces over the 192-hour post-dose period, with approximately 73% of the [14C]-radioactivity administered being recovered in urine and 23% being recovered in faeces, indicating that the renal pathway is the major route of excretion. The renal excretion of parent compound was minimal, accounting for less than 0.02%. The majority of drug excreted by the renal system is in a glucuronidated form. In faeces, the excretion was mainly of unchanged tecovirimat. The terminal half-life of tecovirimat was 19.3 hr.
Tecovirimat exhibits linear pharmacokinetics over a dose range of 100-600 mg.
No clinically significant differences in the pharmacokinetics of tecovirimat were observed in healthy subjects based on age, gender or race.
In subjects with renal impairment (based on estimated GFR), no clinically significant differences in the pharmacokinetics of tecovirimat were observed.
In subjects with with mild, moderate or severe hepatic impairment (based on Child Pugh Scores A, B or C), no clinically significant differences in the pharmacokinetics of tecovirimat were observed. However, it is possible that patients with severe hepatic impairment may have higher unbound drug and metabolite levels.
The pharmacokinetics of tecovirimat has not been evaluated in paediatric patients. The recommended paediatric dosing regimen for subjects at least 13 kg body weight is expected to produce tecovirimat exposures that are comparable to those in adult subjects aged 18 to 50 years based on a population pharmacokinetic modeling and a simulation approach.
Effects in non-clinical studies were observed only at exposures considered in excess of the maximum human exposure indicating little relevance to clinical use.
The non-clinical safety was evaluated in 28-day and 3-month studies in mice and monkeys, respectively. Cmax exposures at the no observed adverse effect level in the toxicology studies compared to the human Cmax at the recommended human dose (RHD) have safety margins of 23 based on the mouse and 2.5 based on the monkey. The dog is a more sensitive species to tecovirimat and was tested after a single dose or repeated doses. Six hours after a single dose of 300 mg/kg, one dog experienced convulsions (tonic and clonic) with electroencephalography (EEG) consistent with seizure activity. This dose produce a Cmax in the dog that was approximately 4 times higher than the highest human Cmax at the RHD. In the dog, the no observe adverse effect level was determined to be 30 mg/kg with a Cmax safety margin at the RHD of 1.
Carcinogenicity studies have not been conducted with tecovirimat.
Tecovirimat was not genotoxic in in vitro or in vivo assays.
In a fertility and early embryonic development study in mice, no effects of tecovirimat on female fertility were observed at tecovirimat exposures (AUC) approximately 24 times higher than human exposure at the RHD. In a fertility and early embryonic development study in mice, no biologically meaningful effects of tecovirimat on male or female fertility were observed at tecovirimat exposures (AUC) approximately 24 times higher than human exposure at the RHD.
Reproductive toxicity studies have been performed in mice and rabbits. Based on pilot studies, the highest dose selected for the definitive study in rabbit was 100 mg/kg and in mice was 1,000 mg/kg. No embryo-foetal toxicities were observed in rabbit at doses up to 100 mg/kg/day (0.4 times the human exposure at the RHD) and no embryo-foetal toxicities were observed at doses up to 1,000 mg/kg/day in mice (approximately 23 times higher than human exposure at the RHD).
No embryo-foetal toxicities were observed at doses up to 100 mg/kg/day in rabbits (0.4 times the human exposure at the RHD). Maternal toxicity was detected in rabbits at 100 mg/kg/day, which included decreases in body weight and mortality.
Available toxicological/safety data in animals have shown excretion of tecovirimat in milk. In a lactation study at doses up to 1,000 mg/kg/day, mean tecovirimat milk to plasma ratios up to approximately 0.8 were observed at 6 and 24 hours post-dose when administered orally to mice on lactation Day 10 or 11.
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