Sonidegib

Sonidegib is an orally bioavailable inhibitor of the Hh signalling pathway. It binds to Smoothened (Smo), a G protein-coupled receptor-like molecule that positively regulates the Hh pathway and eventually activates and releases glioma-associated oncogene (GLI) transcription factors which induces the transcription of Hh target genes involved in proliferation, differentiation and survival. Aberrant Hh signalling has been linked to the pathogenesis of several types of cancer, including basal cell carcinoma (BCC). Sonidegib binding to Smo will inhibit Hh signalling and consequently block signal transduction.

Pharmacodynamic effects

The sonidegib plasma concentration-QTc analysis showed that the upper bound of one-sided 95% confidence interval for QTc increase was below 5 msec at steady-state C_max for 800 mg daily doses, which provide 2.3-fold plasma exposure compared with the recommended 200 mg dose. Therefore, therapeutic doses of sonidegib are not expected to cause clinically significant QTc prolongation. Further, sonidegib plasma concentrations above those achieved with the therapeutic doses were not associated with life-threatening arrhythmias or torsades de pointes.

Tumour response was independent of sonidegib dose or plasma concentration in the dose range of 200 mg to 800 mg.

Absorption

Following the administration of a single dose of sonidegib (100 mg to 3000 mg) without food in patients with cancer, the median time-to-peak concentration (T_max) was 2 to 4 hours. Sonidegib exhibited dose-proportional increases in AUC and C_max over the dose range from 100 mg to 400 mg, but less than dose-proportional increases above 400 mg. There was no evidence of clearance change with repeated dosing based on the population pharmacokinetic analysis and estimated accumulation at steady state was 19-fold irrespective of dose. Steady state was reached approximately 4 months after starting sonidegib. The average steady state C_trough for 200 mg was 830 ng/ml (range 200 to 2400 ng/ml) in cancer patients. Compared to the fasted state, the C_max and AUC of sonidegib 800 mg was increased 7.8- and 7.4-fold, respectively when the dose was given with a high-fat meal. Compared to the fasted state, the C_max and AUC of sonidegib 200 mg was increased 2.8- and 3.5-fold, respectively, when the dose was given with a light meal. Compared to the fasted state, the C_max and AUC of sonidegib 200 mg increased 1.8- and 1.6-fold, respectively, when a moderate meal was taken 2 hours before the administration. A moderate meal taken 1 hour after the administration of sonidegib 200 mg provided similar exposures compared to the fasted state.

Distribution

Based on a population pharmacokinetic analysis of 351 patients who received oral doses of sonidegib in the dose range of 100 mg to 3000 mg, the apparent steady-state volume of distribution (Vss/F) was 9170 litres. Steady-state level of sonidegib in the skin was 6-fold higher than in plasma.

Sonidegib was highly bound to human plasma proteins (human serum albumin and alpha-1 acid glycoprotein) in vitro (>97%), and binding was not concentration-dependent from 1 ng/ml to 2500 ng/ml.

Based on in vitro data, sonidegib is not a substrate of P-gp, BCRP or multi-resistance protein 2 (MRP2). Sonidegib did not inhibit apical efflux transporters, P-gp or MRP2, hepatic uptake transporters OATP1B1 or OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or the organic cation uptake transporters OCT1 or OCT2 at clinically relevant concentrations.

Biotransformation

Sonidegib is primarily metabolised by CYP3A4. Unchanged sonidegib represented 36% of circulating radioactivity and the major circulating metabolite (45% of parent exposure) identified in plasma is the hydrolysis product of sonidegib and is pharmacologically inactive. All the metabolites were deemed 4 to 90 times less potent than sonidegib.

Elimination

Sonidegib and its metabolites are eliminated primarily by the hepatic route with 93.4% of the administered dose recovered in the faeces and 1.95% recovered in urine. Unchanged sonidegib in faeces represented 88.7% of the administered dose and was not detectable in urine. The elimination half-life (t_1/2) of sonidegib estimated from population pharmacokinetic modeling was approximately 28 days.

Special populations

Patients with hepatic impairment

The pharmacokinetics of sonidegib were examined in subjects with mild (Child-Pugh class A; n=8), moderate (Child-Pugh class B; n=8) or severe (Child-Pugh class C; n=9) hepatic impairment and in 8 healthy subjects with normal hepatic function. C_max of sonidegib after a single oral 800 mg dose was 20%, 21% and 60% lower in mild, moderate and severe hepatic impairment, respectively, compared to normal hepatic function. AUC inf of sonidegib was 40%, 22% and 8% lower, respectively. AUC_last was 35% lower in mild hepatic impairment, 14% higher in moderate hepatic impairment and 23% lower in severe hepatic impairment. No dose adjustment is necessary in patients with hepatic impairment.

Patients with renal impairment

The effect of renal impairment on the systemic exposure of sonidegib has not been studied. Since sonidegib is not renally excreted, no change in systemic exposure is anticipated in patients with renal impairment. A population pharmacokinetic analysis did not find significant influence of renal function (creatinine clearance >27 ml/min) on the apparent clearance (CL/F) of sonidegib suggesting that dose adjustment is not necessary in patients with renal impairment.

Effect of age, weight and gender

Population pharmacokinetic analyses showed that there are no clinically relevant effects of age (range tested from 20-93 years, mean 61 years), body weight (range tested 42-181 kg, mean 77 kg), gender, or creatinine clearance (range tested 27.3-290 ml/min, mean 92.9 ml/min) on the systemic exposure of sonidegib.

Effect of ethnicity

The C_max and AUC_inf of sonidegib in Japanese healthy subjects were 1.56 and 1.68-fold higher, respectively, than those seen in Western healthy subjects for a single dose of 200 mg.

Sonidegib was evaluated in rats and dogs.

General toxicology

The majority of adverse effects of sonidegib can be attributed to its pharmacological mechanism of action on developmental pathways and effects in rats and dogs were similar. Most effects occurred close to the intended human exposures. These effects observed at clinically relevant exposures include closure of bone growth plates, effects on growing teeth, effects on the male and female reproductive tract, atrophy of the hair follicles with alopecia, gastrointestinal toxicity with body weight loss and effects on lymph nodes. At exposures well above the clinical exposure, an additional target organ was the kidney.

Carcinogenesis and mutagenesis

Carcinogenicity studies have not been performed with sonidegib, but sonidegib was not genotoxic in studies conducted in vitro and in vivo.

Reproductive and developmental toxicity

Sonidegib was shown to be foetotoxic in rabbits, as evidenced by abortion and/or complete resorption of foetuses and teratogenic resulting in severe malformations at very low exposure. Teratogenic effects included vertebral, distal limb and digit malformations, severe craniofacial malformations and other severe midline defects. Foetotoxicity in rabbits was also seen at very low maternal exposure. There was reduced fertility at low exposure in female rats. For sonidegib-treated male rats, exposure at approx. 2-fold the clinical exposure did not impact male fertility.