Voclosporin

Voclosporin is a calcineurin-inhibitor immunosuppressant that inhibits calcineurin in a dose-dependent manner up to a maximum dose of 1.0 mg/kg. Activation of lymphocytes involves an increase in intracellular calcium concentrations. Calcineurin is a calcium/calmodulin-dependent phosphatase whose activity is required for the induction of T-cell lymphokine production and proliferation. The immunosuppressant activity results in inhibition of lymphocyte proliferation, T-cell cytokine production, and expression of T-cell activation surface antigens.

Cardiac electrophysiology

In a randomised, placebo- and active-controlled (moxifloxacin 400 mg), single dose study with parallel study design, dose-dependent QT prolonging effect was detected with voclosporin in the dose range of 0.5 mg/kg to 4.5 mg/kg (up to 9-fold coverage of the therapeutic exposure). Dose-dependent QT prolongation effect was observed with a time to maximum QTc increase occurring at 4 hours to 6 hours post-dose across different dose levels. The maximum mean placebo-adjusted changes of QTcF from baseline after voclosporin 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg, and 4.5 mg/kg dose were 6.4 msec, 17.5 msec, 25.7 msec, and 34.6 msec, respectively.

In a separate, randomised, placebo-controlled, crossover study in 31 healthy subjects, an absence of large mean increases (i.e., >20 msec) was observed following 7 days of treatment with voclosporin at 0.3 mg/kg, 0.5 mg/kg and 1.5 mg/kg twice daily (approximately 6-fold coverage of the therapeutic exposure). The mechanism for the QT prolonging effect as observed in the single-dose and multipledose studies is unknown.

Based on data in LN patients receiving voclosporin 23.7 mg or 39.5 mg twice daily, a regression analysis of placebo corrected QTcF change from baseline showed a minimal negative slope (−0.065344 msec/ng/mL), not statistically different from a slope of 0 (p=0.1042).

Absorption

Following oral administration (voclosporin 23.7 mg twice daily) the median time to reach maximum whole blood concentrations (C_max) is 1.5 hours (range: 0.75 hour to 2 hours). With a twice daily dosing regimen, voclosporin steady state is achieved after 6 days and voclosporin accumulates approximately 2-fold relative to a single dose. At steady state, the whole blood mean C_max and pre-dose trough values for voclosporin were 120 ng/mL (32% CV) and 15.0 ng/mL (49% CV), respectively. In vitro data investigating if voclosporin is a substrate of the efflux transporters P-gp or BCRP are inconclusive, but clinically relevant effects of P-gp/BCRP inhibitors are not expected.

Co-administration of voclosporin with food decreased both the rate and extent of absorption. C_max and AUC of voclosporin were reduced by 53% and 25% when given with high-fat food and by 29% and 15% when given with low-fat food. These changes were not considered to be clinically relevant. Therefore, voclosporin can be taken with or without food.

Distribution

Voclosporin is 97% bound to plasma proteins. Voclosporin partitions extensively into red blood cells and distribution between whole blood and plasma is concentration- and temperature-dependent. A population pharmacokinetic analysis in patients resulted in an apparent volume of distribution (V_ss/F) of 2,154 L.

Biotransformation

Voclosporin is extensively metabolised, predominantly by CYP3A4 to form oxidative metabolites. Voclosporin is the major circulating component following a single dose of [¹⁴C]-voclosporin. One major metabolite was observed in human whole blood and represented 16.7% of total exposure. The major metabolite is not expected to contribute to the pharmacological activity of voclosporin since it was reported as about 8-fold less potent in a lymphocyte proliferation assay and has lower exposure than voclosporin.

Elimination

The mean apparent clearance at steady state (CL_ss/F) after voclosporin 23.7 mg twice daily is 63.6 L/h (37.5% CV). The mean terminal half-life (t_½) at steady state is approximately 30 hours (range: 24.9 hours to 36.5 hours).

Following single oral administration of 70 mg [¹⁴C]-voclosporin, 94.8% of the radioactivity was recovered by 168 hours post dose: 92.7% was recovered in faeces (including 5% as unchanged voclosporin), and 2.1% was recovered in urine (including 0.25% as unchanged voclosporin).

In-vitro data indicate that voclosporin is an inhibitor of OATP1B1 and OATP1B3.

Linearity/non-linearity

In healthy volunteers, a non-linearity between dose and exposure was observed at the lower end of the dose range studied (0.25 mg/kg to 1.5 mg/kg twice daily), which had a relatively minor effect on the pharmacokinetics. The dose-proportionality factor was always less than 1.5. This non-linearity has not been detected over the dose range studied in LN patients.

Pharmacokinetics in special populations

Renal impairment

In clinical studies, kidney function was monitored by eGFR and doses were adjusted based on a predefined dose adjustment protocol. Enrolled LN patients had a baseline eGFR > 45 mL/min/1.73 m².

Dosing adjustments have to follow the recommendations outlined in table 1. A dedicated renal impairment study revealed that after single and multiple doses of voclosporin, C_max and AUC were similar in volunteers with mild (creatinine clearance (CL_Cr) 60 mL/min to 89 mL/min as estimated by Cockcroft Gault) and moderate (CL_Cr 30 mL/min to 59 mL/min) renal impairment compared to volunteers with normal renal function (CL_Cr ≥90 mL/min). After a single dose of voclosporin in volunteers with severe renal impairment (CL_Cr <30 mL/min), C_max and AUC increased 1.5-fold and 1.7-fold, respectively. The effect of end-stage renal disease (ESRD) with or without haemodialysis on the pharmacokinetics of voclosporin is unknown.

Hepatic impairment

A dedicated hepatic impairment study compared systemic exposure of voclosporin in patients with mild or moderate hepatic impairment (Child-Pugh A and B, respectively) vs. healthy controls with normal hepatic function. In patients with mild and moderate hepatic impairment, voclosporin C_max and AUC_0-48 increased by 1.5-fold and approximately 2-fold, respectively. Voclosporin has not been evaluated in patients with severe hepatic impairment (Child-Pugh C) and its use in these patients is not recommended.

Age, sex, race and body weight

A population pharmacokinetic analysis assessing the effects of age, sex, race and body weight did not suggest any clinically significant impact of these covariates on voclosporin exposures.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Repeated-dose animal studies have shown neuro-histological findings of gliosis and perivascular infiltrates in the brain and spinal cord in rats, but not in dogs or monkeys. These findings were not observed at doses approximately 0.3-times the maximum recommended human dose (MRHD) of 23.7 mg voclosporin twice a day on medicinal product exposure (AUC) basis.

In a 39-week oral toxicology study with cynomolgus monkeys, malignant lymphomas occurred at a dose of 150 mg/kg/day (approximately 4-times and 7-times above the MRHD based on medicinal product exposure (AUC), for male and female animals, respectively). At this dose, monkeys experienced high levels of immunosuppression as indicated by maximum calcineurin inhibition levels (Emax) of greater than 80 %. The no-observed-adverse-effect level (NOAEL) for this finding was 75 mg/kg/day (approximately 4-times the MRHD, on medicinal product exposure (AUC) basis, for male and female animals).

No mutagenic or genotoxic effects of voclosporin were observed in conventional genotoxicity studies.

In a 2-year mouse carcinogenicity study with oral voclosporin, an increased incidence of malignant lymphoma was observed at the highest dose tested (30 mg/kg/day; approximately 7.5-times the MRHD on a medicinal product exposure (AUC) basis). This result is considered secondary to voclosporin-related immune suppression. The NOAEL was 10 mg/kg/day (approximately 1-times the MRHD on medicinal product exposure (AUC) basis).

In a rat fertility study with a 50:50 mixture of voclosporin and its cis-isomer, decreases in male reproductive organ weights, including the cauda epididymis, epididymis, seminal vesicles, prostate, and testes were noted at a dose of 25 mg/kg/day. The NOAEL for these findings was 10 mg/kg/day (approximately 5-times the MRHD on medicinal product exposure (AUC) basis). Mating and fertility parameters, sperm motility, count and density, number of estrous stages per 14 days, and caesarean sectioning parameters were not affected. Decreases in prostate and testes weights were also observed in the 13-week and 26-week repeat-dose toxicity studies with oral 50:50 mixture of voclosporin and its cis-isomer at doses of 25 mg/kg/day and 10 mg/kg/day, or 18-times and 7-times the MRHD, on medicinal product exposure (AUC) basis. The NOAEL for these effects in the 26-week repeat-dose study was 2.5 mg/kg/day (approximately 1-times the MRHD on medicinal product exposure (AUC) basis).

Embryo-foetal development studies were conducted with the 50:50 mixture of voclosporin and its cisisomer in both rats and rabbits and with voclosporin in rabbits. Embryo-foetal toxicity was only observed at doses that were associated with maternal toxicity (at doses approximately 15-times and 1-times the MRHD, based upon medicinal product exposure (AUC), for rats and rabbits, respectively). The maternal effects included changes in body weight and/or swollen mammary glands while the foetal effects consisted of a slight reduction in body weight and related skeletal developmental variations. No malformative effects were noted in the studies. The NOAELs were 10 mg/kg/day in rats and 1 mg/kg/day in rabbits (approximately 7-times and 0.01-times the MRHD, based on medicinal product exposure (AUC), for rats and rabbits, respectively).

In a pre- and post-natal developmental study in rats, maternal toxicity at a dose of 25 mg/kg/day 50:50 mixture of voclosporin and its cis-isomer (approximately 17 times the MRHD on medicinal product exposure (AUC) basis) delayed parturition (dystocia) that resulted in reductions in the mean number of total pups delivered and surviving pups per litter. This dose was associated with maternal toxicity based on decreased body weight gain. No adverse effects on dams or their pups were observed at doses approximately 3-times the MRHD and lower (based on medicinal product exposure (AUC) with a maternal oral NOAEL dose of 10 mg/kg/day). There were no effects on behavioural and physical development, or the reproductive performance of male or female pups. The no effect dose for delivery and pup survival was 10 mg/kg/day.

Medicinal product-derived radioactivity was rapidly distributed to milk following the oral administration of [¹⁴C]-voclosporin to lactating rats. When a medicinal product is present in animal milk, it is likely that it will also be present in human milk.