Summary: pharmacokinetic profile

Based on population PK modelling, tovorafenib at the labeled dose has a steady-state Cmax of 6.9 µg/mL and AUC of 508 µg·h/mL, reaches steady state in 12 days, and has a terminal half-life of approximately 56 hours with no clinically significant accumulation on once-weekly dosing. Median Tmax is 3 hours for tablets and oral suspension; a high-fat meal delays Tmax to 6.5 hours without clinically significant changes in Cmax or AUC. Plasma protein binding is 97.5%. Aldehyde oxidase and CYP2C8 are the primary metabolic enzymes (CYP2C8 fraction metabolized estimated at 49.23% in the PBPK model), and 65% to 66.1% of a radiolabeled dose is recovered in feces and 27% to 28.7% in urine, with less than 0.2% excreted unchanged in urine. In adults (phase 1, 600 mg once weekly), the mean terminal half-life was approximately 70 hours. No formal PK studies were conducted in the pediatric glioma population; exposure was estimated from sparse sampling, and the EMA considered predictions for participants younger than 2 years unreliable (three observations), requiring additional PK data by 30 April 2032. The popPK model estimated 21.5% higher apparent clearance in males than in females.

Pharmacokinetic parameters: US prescribing information

Parameter	Quoted value
Steady-state exposure	“Tovorafenib steady state maximum concentration (C max ) is 6.9 µg/mL (23%) and the area under the concentration-time curve (AUC) is 508 µg*h/mL (31%).”
Time to steady state and accumulation	“Time to reach steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in a dose-proportional manner. No clinically significant tovorafenib accumulation occurs.”
Absorption	“is 3 hours (1.5, 4 hours), following a single dose with tablets or oral suspension.”
Effect of food	“No clinically significant differences in tovorafenib C max and AUC were observed following administration of tablets with a high-fat meal (approximately 859 total calories, 54% fat) compared to fasted conditions, but the T max was delayed to 6.5 hours.”
Distribution	“Tovorafenib apparent volume of distribution is 60 L/m 2 (23%). Tovorafenib is 97.5% bound to human plasma proteins in vitro.”
Elimination	“Tovorafenib terminal half-life is approximately 56 hours (33%) and the apparent clearance is 0.7 L/h/m 2 (31%).”
Metabolism	“Tovorafenib is primarily metabolized by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9, and CYP2C19 metabolize tovorafenib to a minor extent.”
Excretion	“Following a single oral dose of radiolabeled tovorafenib, 65% of the total radiolabeled dose was recovered in the feces (8.6% unchanged) and 27% of the dose was recovered in the urine (0.2% unchanged).”

Plasma protein binding and mass balance: EU product information

“Tovorafenib is highly protein-bound to albumin (≈ 95%) and moderately bound to alpha-1 acid glycoprotein (AAG) (≈42%).” (opens the source at this quote in a new tab)
“Based on clinical study in healthy volunteers, following a single oral dose of radiolabelled tovorafenib, 66.1% of the total radiolabelled dose was recovered in the faeces (8.6% unchanged) and 28.7% of the dose was recovered in the urine (0.2% unchanged).” (opens the source at this quote in a new tab)

Population PK model structure and data sources

“According to the applicant, tovorafenib concentration-time course was described by a one-compartment model with three-transit compartments absorption model (designated as Ka [Tablet]) for” (opens the source at this quote in a new tab)
“No formal studies were conducted in paediatric and young adult patients with glioma. In this target group of patients only sparse samples were collected and analysed according to a PPK approach.” (opens the source at this quote in a new tab)
“The PBPK model was refined by adjusting the CYP2C8 fractional metabolism value to 49.23%, based on available enzyme kinetic and clinical mass balance data.” (opens the source at this quote in a new tab)

Covariates: sex, renal function, and hepatic function in the popPK analysis

“Based on this analysis CL /F was associated with sex, where males were estimated to have a 21.5% higher CL/F than females.” (opens the source at this quote in a new tab)
“In this PPK analysis 21 patients with moderate and 107 patients with mild RI were part of the analysed dataset.” (opens the source at this quote in a new tab)
“Moderate and mild hepatic impairment was not identified as a significant covariate of clearance in population PK analysis by the applicant.” (opens the source at this quote in a new tab)

Pediatric exposure and uncertainty below 2 years of age

“Cmax and AUC in paediatric patients aged 11 months to 17 years were within the range of values observed in adults given the same dose per body surface area.” (opens the source at this quote in a new tab)

“No reliable estimation could be made in patients under two-years of age even with the model incorporating maturation functions.” (opens the source at this quote in a new tab)
“The reliability of the predictions of the systemic exposure in paediatric patients below 2 years could not be confirmed as very few data are available in this sub-group of patients (three observations).” (opens the source at this quote in a new tab)

Brain distribution: nonclinical

“The brain:plasma AUC ratio of tovorafenib-derived radioactivity was 0.57 (cerebellum), 0.54 (cerebrum) and 0.67 (medulla) indicating the passage of the blood-brain barrier.” (opens the source at this quote in a new tab)

Adults with advanced solid tumors: once-weekly pharmacokinetics

“The mean plasma terminal half-life ( t 1/2 ) of tovorafenib was approximately 70 h (range 31–119 h) as defined in 20 evaluable patients receiving 600 mg QW.” (opens the source at this quote in a new tab)
“For QW dosing regimens, minimum drug accumulation was observed and the geometric mean R auc (accumulation ratio based on AUC 0-last ) was in the range of 1.03–1.09.” (opens the source at this quote in a new tab)

Children with relapsed or recurrent MAPK-altered tumors: PNOC014 phase 1

“Administration of tovorafenib once every week to children resulted in dose-proportional increases in Cmax and AUC like that described in the adult study” (opens the source at this quote in a new tab)
“Much of the PK sampling for this phase was disrupted due to COVID-19 restrictions on travel.” (opens the source at this quote in a new tab)

Tovorafenib (DAY101)

Pharmacokinetics