TABLE 4

Human DDI risk assessment for transport-proteins inhibition by risdiplam or M1

Compound / ProteinIC50
µM*
Total Cmax in Patients with SMA
ng/ml*
[I]
µM
[I]/IC50Threshold
Risdiplam / OCT28.7Median = 184 (0.2 mg/kg, <2 yr)
Max observed = 364
0.049
0.097
0.006
0.011
0.02
Risdiplam / MATE10.15Median = 184 (0.2 mg/kg, <2 yr)
Max observed = 364
0.049
0.097
0.33
0.65
Risdiplam / MATE2-K0.09Median = 184 (0.2 mg/kg, <2 yr)
Max observed = 364
0.049
0.097
0.54
1.08
M1 / MATE114.8Median = 61 (0.2 mg/kg, <2 yr)
Maximum = 122
0.011
0.022
0.0007
0.0015
M1 / BCRP2.3Median = 61 (0.2 mg/kg, <2 yr)
Maximum = 122
0.011
0.022
0.0047
0.0094
  • Embolden text indicate values above the [I]/IC50 threshold.

  • *Risdiplam and M1 plasma concentrations at steady state at pivotal doses [SUNFISH study (NCT02908685): 0.25 mg/kg (body weight < 20 kg) or 5 mg; FIREFISH study (NCT02913482): 0.2 mg/kg].

  • The assessment was based on the median and maximum observed Cmax values in the FIREFISH study; Cmax values were lower in older patients in the SUNFISH study. Median M1 percentage vs. parent of 33.4 = ∼30% was assumed for calculating M1 Cmax values.

  • [I] is the unbound plasma concentration (assuming free fraction in human plasma 10.7% for risdiplam and 7.4% for M1).

  • Most conservative [I]/IC50 threshold above which require further investigation of the DDI potential by conducting a clinical DDI study (European Medicines Agency, 2020; US Food and Drug Administration, 2020a).

  • BCRP, breast cancer resistance protein; Cmax, maximum plasma concentration; DDI, drug-drug interaction; MATE, multidrug and toxin extrusion protein; OCT2, organic cation transporter 2; SMA, spinal muscular atrophy.