TPOXX Capsule Ref.[10236] Active ingredients: Tecovirimat

Cardiac Electrophysiology

TPOXX does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.

At the approved recommended dosage, the mean steady-state values of TPOXX AUC_0-24hr, C_max, and C_min are 28791 hr·ng/mL (CV: 35%), 2106 ng/mL (CV: 33%), and 587 ng/mL (CV: 38%), respectively. Tecovirimat steady-state AUC is achieved by Day 6. Refer to Table 4 for pharmacokinetic parameters of tecovirimat.

Table 4. Pharmacokinetic Properties of Tecovirimat:

^a Value reflects administration of drug with food.
^b Value refers to mean systemic exposure (AUC_24hr). Meal: ~600 kcal, ~25 g fat.
^c Tecovirimat is metabolized by hydrolysis of the amide bond and glucuronidation. The following inactive
metabolites were detected in plasma: 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)
^d Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) enzymes
^e t_1/2 value refers to mean terminal plasma half-life.
^f Single dose administration of [¹⁴C]-tecovirimat in mass balance study.

Comparison of Animal and Human PK Data to Support Effective Human Dose Selection

Because the effectiveness of TPOXX cannot be tested in humans, a comparison of tecovirimat exposures achieved in healthy human subjects to those observed in animal models of orthopoxvirus infection (nonhuman primates and rabbits infected with monkeypox virus and rabbitpox virus, respectively) in therapeutic efficacy studies was necessary to support the dosage regimen of 600 mg twice daily for treatment of smallpox disease in humans. Humans achieve greater systemic exposure (AUC, C_max, and C_min) of tecovirimat following a twice daily dose of 600 mg when compared to the therapeutic exposures in these animal models.

Specific Populations

No clinically significant differences in the pharmacokinetics of tecovirimat were observed based on age, sex, ethnicity, renal impairment (based on estimated GFR), or hepatic impairment (Child Pugh Scores A, B or C).

Pediatric Patients

TPOXX pharmacokinetics has not been evaluated in pediatric patients. The recommended pediatric dosing regimen is expected to produce tecovirimat exposures that are comparable to those in adult subjects based on a population pharmacokinetic modeling and simulation approach [see Dosage and Administration (2.2) and Use in Specific Populations (8.4)].

Drug Interaction Studies

The effect of tecovirimat on the exposure of co-administered drugs are shown in Table 5.

Table 5. Drug Interactions – Changes in Pharmacokinetic Parameters for Co-Administered Drug in the Presence of TPOXX^a:

^a All interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily.
^b Comparison based on exposures when administered as flurbiprofen + omeprazole + midazolam.

No pharmacokinetic changes were observed for the following drug when co-administered with tecovirimat: flurbiprofen.

Cytochrome P450 (CYP) Enzymes: Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19, and a weak inducer of CYP3A4. Tecovirimat is not an inhibitor or an inducer of CYP2B6 or CYP2C9.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

CYP Enzymes: Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an inducer of CYP1A2. Tecovirimat is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.

UGT Enzymes: Tecovirimat is a substrate of UGT1A1 and UGT1A4.

Transporter Systems: Tecovirimat inhibited Breast Cancer Resistance Protein (BCRP) in vitro.

Tecovirimat is not an inhibitor of P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporter 1 (OAT1), OAT3, and organic cation transporter 2 (OCT2). Tecovirimat is not a substrate for P-gp, BCRP, OATP1B1, and OATP1B3.

Mechanism of Action

Tecovirimat targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction 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.

Activity in Cell Culture

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 variola, monkeypox, rabbitpox, and vaccinia viruses, respectively. Ranges given for variola and monkeypox viruses are reflective of results from multiple strains assayed.

Resistance

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 who either fail to respond to therapy or who develop recrudescence of disease after an initial period of responsiveness.

Cross Resistance: There are no other antiviral drugs approved for the treatment of variola (smallpox) virus infection.

Carcinogenicity studies have not been conducted with tecovirimat.

Tecovirimat was not genotoxic in in vitro or in vivo assays, including a bacterial reverse mutation assay, a mammalian mutagenicity assay in mouse lymphoma L5178Y/TK^± cells, and in an in vivo mouse micronucleus study.

Impairment of Fertility

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 male mice, decreased male fertility associated with testicular toxicity (increased percent abnormal sperm and decreased sperm motility) was observed at 1,000 mg/kg/day (approximately 24 times the human exposure at the RHD).

In a repeat-dose toxicology study in dogs, convulsions (tonic and clonic) were observed in one animal within 6 hours of a single dose of 300 mg/kg (approximately 4 times higher than the highest observed human exposure at the RHD based on C_max). Electroencephalography (EEG) findings in this animal were consistent with seizure activity during the observed convulsions. Tremors, which were considered non-adverse, were observed at 100 mg/kg/dose (similar to the highest observed human exposure at the RHD based on C_max), although no convulsions or EEG findings were observed at this dose.

Overview

The effectiveness of TPOXX for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical. Therefore, the effectiveness of TPOXX for treatment of smallpox disease was established based on results of adequate and well-controlled animal efficacy studies of non-human primates and rabbits infected with non-variola orthopoxviruses. Survival rates observed in the animal studies may not be predictive of survival rates in clinical practice.

Study Design

Efficacy studies were conducted in cynomolgus macaques infected with monkeypox virus, and New Zealand white (NZW) rabbits infected with rabbitpox virus. The primary efficacy endpoint for these studies was survival. In non-human primate studies, cynomolgus macaques were lethally challenged intravenously with 5 × 10⁷ plaque-forming units of monkeypox virus; tecovirimat was administered orally once daily at a dose level of 10 mg/kg for 14 days, starting at Day 4, 5 or 6 post-challenge. In rabbit studies, NZW rabbits were lethally challenged intradermally with 1,000 plaque-forming units of rabbitpox virus; tecovirimat was administered orally once daily for 14 days at a dose level of 40 mg/kg, starting at Day 4 post-challenge. The timing of tecovirimat dosing in these studies was intended to assess efficacy when treatment is initiated after animals have developed clinical signs of disease, specifically dermal pox lesions in cynomolgus macaques, and fever in rabbits. Clinical signs of disease were evident in some animals at Day 2-3 post-challenge but were evident in all animals by Day 4 post-challenge. Survival was monitored for 3-6 times the mean time to death for untreated animals in each model.

Study Results

Treatment with tecovirimat for 14 days resulted in statistically significant improvement in survival relative to placebo, except when given to cynomolgus macaques starting at Day 6 post-challenge (Table 6).

Table 6. Survival Rates in Tecovirimat Treatment Studies in Cynomolgus Macaques and NZW Rabbits Exhibiting Clinical Signs of Orthopoxvirus Disease:

^b p-value is from 1-sided Boschloo Test (with Berger-Boos modification of gamma = 0.000001) compared to placebo
^c Survival percentage in tecovirimat treated animals minus survival percentage in placebo treated animals
^d Exact 95% confidence interval based on the score statistic of difference in survival rates
^e A placebo control group was not included in this study.
KEY: NA = Not Applicable