Chemical formula: C₂₆H₂₅N₅O₃ Molecular mass: 455.196 g/mol PubChem compound: 124111565
Tolebrutinib is primarily an inhibitor of Bruton's tyrosine kinase (BTK). Although the exact mechanism by which tolebrutinib exerts its therapeutic effect in MS is not fully understood, there is evidence to support it inhibits the activation of B cells, macrophages and microglia in the periphery and CNS.
The median steady state of BTK occupancy in peripheral blood mononuclear cells was maintained at greater than 90% over 24 hours in healthy subjects dosed with tolebrutinib 60 mg/day with a meal.
The effect of tolebrutinib and the active metabolite M2 on the QTc interval was evaluated using concentration–QTc effect modelling of data obtained during a Phase 1 study with high-quality ECG recording. There were no effects on QTc interval or other ECG parameters at single doses up to 300 mg of tolebrutinib.
The pharmacokinetics of tolebrutinib was studied in healthy subjects and patients with MS. Tolebrutinib mean maximum plasma concentration (Cmax) and AUC values increased higher than dose proportional with doses between 5 and 60 mg, but close to dose proportional for doses between 60 and 300 mg. At the recommended dose of 60 mg daily with a meal, the mean steady state (% coefficient of variation [CV]) and maximum plasma concentration (Cmax) for tolebrutinib were 29.6 (60%) ng•h/mL and 9.94 (62%) ng/mL, respectively, and for M2 metabolite were 84.6 (62%) ng•h/mL and 27.5 (59%) ng/mL, respectively. M2 metabolite circulates with an exposure ranging from 2.4 to 6.5-fold higher than the parent compound and exhibits similar covalent binding potency at nanomolar level on BTK to tolebrutinib.
Absolute oral bioavailability of tolebrutinib after a single oral 60 mg dose with a meal was 10.3%, increased by 2-fold compared to fasted state. Administration of a single oral 60 mg dose under a fed state led to an increase of tolebrutinib exposure by 1.77-fold with no increase in M2 metabolite exposure. The median time to reach Cmax of tolebrutinib and M2 were around 1.3 hours in all studied populations).
The steady state volume of distribution of tolebrutinib was approximately 255 L. The tolebrutinib and M2 in vitro unbound fraction ranged from 11.1 to 12.5% and from 8.65 to 38%, respectively. In healthy subjects, tolebrutinib and the M2 metabolite appear in the cerebrospinal fluid (CSF), with a mean CSF to plasma ratio up to 1.16 and 0.45, respectively.
Tolebrutinib is metabolised mainly by CYP2C8 and to a lesser extent by CYP3A4. The M2 metabolite is formed from tolebrutinib exclusively via CYP2C8 and is metabolised mainly by CYP3A4/5 and to a lesser extent by CYP2D6. M2 circulates with an exposure 2.4 to 6.5-fold higher than the parent compound and exhibits similar covalent binding potency at nanomolar level on BTK to tolebrutinib.
After single doses up to 300 mg and repeated doses up to 240 mg, the terminal half-lives for tolebrutinib and M2 were similar (4.4 to 7.8 hours) and did not vary according to dose after single and repeated once daily administration, with no measurable accumulation after repeated administration.
Following a single 60 mg radiolabelled tolebrutinib dose in healthy subjects, over 90% of the dose was recovered within 216 hours, with majority (85%) of radioactivity within 72 hours. 78% of the dose was recovered in the faeces and 14% of the dose was recovered in the urine. Unchanged tolebrutinib accounted for 3.8% of the radiolabelled excreted dose in faeces and none in urine.
Based on descriptive statistics on observed pharmacokinetic concentrations in patients, gender, age (over the range 18 to 76 years), body weight (over the range 37 to 143 kg), and race had no meaningful effect on tolebrutinib pharmacokinetics.
Following a single oral dose of 60 mg tolebrutinib under fed conditions in subjects with severe renal impairment (GFR less than 30 mL/min) not requiring dialysis, the total and unbound tolebrutinib Cmax and AUC in participants were slightly higher (≤1.6-fold) compared to subjects with normal renal function. The total and unbound M2 Cmax were similar, and the AUC were slightly higher (≤1.2-fold). There is very limited data in patients with severe renal impairment. Tolebrutinib has not been studied in patients requiring dialysis.
Following a single oral dose of 60 mg tolebrutinib under fed conditions in subjects with mild hepatic impairment, total and unbound tolebrutinib AUC and M2 AUC were similar (between 0.87-fold and 1.26-fold). No formal studies were conducted to examine the effects of moderate or severe hepatic impairment on the pharmacokinetics of tolebrutinib. Tolebrutinib is contraindicated in patients with moderate or severe hepatic impairment and in patients with baseline serum ALT or AST greater than 1.5 x ULN, alkaline phosphatase greater than 2 x ULN (unless explained by a stable chronic liver disorder) or total bilirubin greater than 1.5 x ULN (unless due to Gilbert syndrome or non-liver-related disorder).
In rats, dose-limiting toxicity was observed in the 6-month oral tolebrutinib toxicity study, consisting of immune system effects (decreased antigen response and increased susceptibility to rectal parasites), haemorrhage in various tissues and organs (including intraocular bleeding), and skin lesions. Microscopic findings in the pancreas (fibrosis, chronic inflammation and haemorrhages) correlated with species-specific pancreatic toxicity of BTK inhibitors in rats. In general, toxicities were observed at the lowest dose administered corresponding to 23- and 29-times the steady-state AUC at the maximum recommended human dose (MRHD), in male and female rats.
In a dedicated 6-month toxicity study with oral administration of the M2 metabolite to rats, similar toxicities to that of tolebrutinib were observed at the lowest dose administered, corresponding to 6- and 12-times the steady-state AUC of M2 at the MRHD of tolebrutinib in male and female rats.
In the 2-year tolebrutinib carcinogenicity study in rats, haemorrhages, skin lesions, immune system effects, and pancreatic findings occurred at the lowest dose administered corresponding to 1.2- and 4.4-times the steady-state AUC at the MRHD, in male and female rats. Increased mortality occurred in male rats at exposures 10-times steady-state AUC at the MRHD, notably as a result of premature euthanasia due to severe intraocular haemorrhages. Taken together, these findings indicate that prolonged tolebrutinib treatment appear to lower the exposure margin for toxicities to the clinically relevant area of concern.
In the 9-month tolebrutinib toxicity study in dogs, a non-adverse increased haemorrhagic tendency was seen in multiple organs from 15-times the steady-state AUC at the MRHD.
No genotoxic or carcinogenic potential was seen for tolebrutinib or the M2 metabolite based on conventional in vitro and in vivo studies.
No effects of tolebrutinib on reproductive, embryo-foetal and pre-/postnatal development were observed in rats and rabbits at exposures sufficiently in excess to human exposure (>100-times the steady-state AUC at the MRHD).
However, dose-dependent incomplete hyoid ossification was noted at clinically relevant exposure of the M2 metabolite in the embryo-foetal development study of tolebrutinib in rabbits (<1.3-times the steady-state AUC of M2 at the MRHD of tolebrutinib). The human relevance is unknown.
No biologically meaningful effects of the M2 metabolite were seen following direct oral administration in fertility or pre- and post-natal development studies in rats at clinically relevant exposures.
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