Table S1. Human unbound PR-104 and PR-104A non-compartmental pharmacokinetic parameter estimates. Values are mean ± SEMa.

Dose / N / Human PR-104 non-compartmental estimates / Human PR-104A non-compartmental estimates
Cmax. / AUC0-∞ / CL / Vss / T1/2 / Cmax. / AUC0-∞ / T1/2
(mg/m2) / (µM) / (µM.h) / (L/h/kg) / (L/kg) / (h) / (µM) / (µM.h) / (h)
135 / 12 / 1.2 ± 0.2 / 0.7 ± 0.1 / 12.2 ± 3.2 / 3.9 ± 0.9 / 0.039 ± 0.003 / 1.8 ± 0.1 / 1.9 ± 0.1 / 0.66 ± 0.08
216 / 12 / 1.4 ± 0.3 / 0.9 ± 0.2 / 14.8 ± 2.0 / 4.5 ± 0.7 / 0.061 ± 0.008 / 2.7 ± 0.3 / 2.8 ± 0.3 / 0.71 ± 0.07
354 / 8 / 2.0 ± 0.2 / 1.3 ± 0.1 / 14.2 ± 1.9 / 4.7 ± 0.5 / 0.127 ± 0.021 / 4.6 ± 0.8 / 5.0 ± 0.6 / 0.84 ± 0.07
550 / 6 / 5.0 ± 1.1 / 2.8 ± 0.7 / 10.7 ± 2.9 / 3.6 ± 0.9 / 0.161 ± 0.014 / 8.6 ± 0.4 / 8.0 ± 1.0 / 0.72 ± 0.09
770 / 5 / 7.9 ± 3.9 / 5.4 ± 2.7 / 9.7 ± 2.5 / 3.1 ± 0.8 / 0.137 ± 0.022 / 11.5 ± 4.2 / 12.4 ± 5.0 / 0.73 ± 0.12
1100 / 6 / 8.8 ± 0.9 / 5.2 ± 0.3 / 9.2 ± 0.6 / 2.5 ± 0.4 / 0.136 ± 0.018 / 13.3 ± 1.2 / 16.9 ± 2.4 / 0.78 ± 0.03
1400 / 3 / 14.0 ± 7.1 / 8.9 ± 4.7 / 10.6 ± 3.8 / 3.1 ± 1.1 / 0.109 ± 0.012 / 22.8 ± 6.1 / 25.5 ± 6.0 / 0.75 ± 0.03

a Total drug non-compartmental PK parameters from study PR104-1001, have been previously reported in [17].

Table S2. Dog unbound PR-104 and PR-104A non-compartmental pharmacokinetic parameter estimates. Values are mean ± SEM.

Dose / Sex / Day / N / Dog PR-104 non-compartmental estimates / Dog PR-104A non-compartmental estimates
Cmax. / AUC0-∞ / CL / Vss / T1/2 / Cmax. / AUC0-∞ / T1/2
(mg/kg) / (µM) / (µM.h) / (L/h/kg) / (L/kg) / (h) / (µM) / (µM.h) / (h)
15 / F / 1 / 3 / 1.8 ± 0.3 / 0.27 ± 0.03 / 99.3 ± 13.4 / 13.5 ± 2.1 / 0.088 ± 0.004 / 5.7 ± 0.4 / 1.7 ± 0.1 / 0.18 ± 0.01
22 / 3 / 2.4 ± 0.2 / 0.35 ± 0.03 / 75.2 ± 5.3 / 9.7 ± 0.7 / 0.080 ± 0.002 / 6.2 ± 0.1 / 1.7 ± 0.2 / 0.21 ± 0.02
M / 1 / 3 / 2.2 ± 0.5 / 0.29 ± 0.05 / 93.0 ± 14.4 / 12.2 ± 2.5 / 0.094 ± 0.005 / 5.2 ± 0.8 / 1.6 ± 0.1 / 0.20 ± 0.01
22 / 3 / 2.6 ± 0.4 / 0.45 ± 0.03 / 58.6 ± 3.7 / 8.0 ± 0.7 / 0.078 ± 0.004 / 6.2 ± 0.5 / 1.8 ± 0.1 / 0.19 ± 0.03
50 / F / 1 / 3 / 8.3 ± 0.2 / 1.25 ± 0.02 / 69.4 ± 1.2 / 9.7 ± 0.7 / 0.159 ± 0.043 / 18.7 ± 1.1 / 5.8 ± 0.3 / 0.20 ± 0.01
22 / 3 / 10.5 ± 0.9 / 1.56 ± 0.15 / 56.3 ± 5.4 / 7.7 ± 0.6 / 0.105 ± 0.011 / 20.0 ± 1.9 / 6.4 ± 0.1 / 0.22 ± 0.01
M / 1 / 3 / 11.7 ± 1.5 / 1.71 ± 0.14 / 51.0 ± 4.1 / 7.0 ± 0.8 / 0.129 ± 0.006 / 21.7 ± 1.1 / 6.8 ± 0.3 / 0.21 ± 0.03
22 / 3 / 9.5 ± 0.5 / 1.51 ± 0.01 / 57.3 ± 0.3 / 8.1 ± 0.3 / 0.125 ± 0.006 / 21.8 ± 1.6 / 7.0 ± 0.4 / 0.23 ± 0.01
150 / F / 1 / 3 / 66.5 ± 14.3 / 10.4 ± 1.9 / 21.9 ± 5.5 / 3.1 ± 0.8 / 0.149 ± 0.014 / 66.6 ± 3.6 / 25.2 ± 0.9 / 0.22 ± 0.02
22 / 3 / 83.8 ± 9.1 / 13.3 ± 1.7 / 20.1 ± 2.3 / 2.8 ± 0.3 / 0.148 ± 0.002 / 87.5 ± 2.7 / 29.3 ± 0.7 / 0.21 ± 0.03
M / 1 / 3 / 52.9 ± 4.7 / 9.6 ± 0.6 / 27.2 ± 1.6 / 4.2 ± 0.3 / 0.156 ± 0.004 / 79.1 ± 5.5 / 25.0 ± 1.6 / 0.19 ± 0.01
22 / 3 / 75.1 ± 9.0 / 12.6 ± 1.6 / 21.2 ± 2.9 / 3.1 ± 0.4 / 0.155 ± 0.012 / 80.9 ± 5.7 / 28.5 ± 1.7 / 0.23 ± 0.02

Table S3. Rat unbound PR-104 and PR-104A non-compartmental pharmacokinetic parameter estimates. Values are mean ± SEM.

Dose / Sex / Day / N / Rat PR-104 non-compartmental estimates / Rat PR-104A non-compartmental estimates
Cmax. / AUC0-∞ / CL / Vss / T1/2 / Cmax. / AUC0-∞ / T1/2
(mg/kg) / (µM) / (µM.h) / (L/h/kg) / (L/kg) / (h) / (µM) / (µM.h) / (h)
50 / F / 1 / 3 / 133 ± 29 / 6.4 ± 1.3 / 14.9 ± 3.5 / 0.4 ± 0.1 / 0.21 ± 0.12 / 21.6 ± 1.5 / 5.9 ± 0.4 / 0.46 ± 0.05
22 / 3 / 181 ± 16 / 8.6 ± 0.6 / 10.2 ± 0.8 / 0.2 ± 0.1 / 0.11 ± 0.02 / 19.1 ± 2.3 / 5.6 ± 0.2 / 0.35 ± 0.04
M / 1 / 3 / 128 ± 25 / 6.3 ± 1.4 / 15.2 ± 3.6 / 0.5 ± 0.2 / 0.16 ± 0.03 / 20.7 ± 1.5 / 6.0 ± 0.1 / 0.57 ± 0.07
22 / 3 / 148 ± 2 / 7.8 ± 0.2 / 11.0 ± 0.3 / 0.6 ± 0.3 / 0.11 ± 0.02 / 19.9 ± 0.6 / 5.9 ± 0.3 / 0.43 ± 0.02
225 / F / 1 / 3 / 566 ± 86 / 37.6 ± 4.6 / 10.7 ± 1.4 / 0.5 ± 0.1 / 0.09 ± 0.02 / 95.9 ± 2.8 / 33.9 ± 1.2 / 0.42 ± 0.04
22 / 3 / 500 ± 28 / 23.6 ± 5.5 / 18.6 ± 4.7 / 0.8 ± 0.5 / 0.15 ± 0.04 / 79.0 ± 3.4 / 24.8 ± 2.0 / 0.49 ± 0.02
M / 1 / 3 / 498 ± 27 / 32.8 ± 0.5 / 11.9 ± 0.2 / 0.6 ± 0.1 / 0.19 ± 0.06 / 85.5 ± 4.1 / 30.3 ± 0.4 / 0.40 ± 0.02
22 / 3 / 571 ± 22 / 29.6 ± 5.0 / 14.0 ± 2.8 / 0.4 ± 0.1 / 0.22 ± 0.05 / 72.4 ± 9.8 / 28.2 ± 0.5 / 0.45 ± 0.04
350 / F / 1 / 3 / 1017 ± 60 / 81.0 ± 2.5 / 7.5 ± 0.2 / 0.5 ± 0.2 / 0.17 ± 0.05 / 126 ± 3 / 60.5 ± 2.2 / 0.54 ± 0.07
22 / 1 / 1455 / 120.9 / 5.0 / 0.8 / 0.07 / 63.9 / 44.9 / 0.46
M / 1 / 3 / 1276 ± 318 / 87.1 ± 14.0 / 7.4 ± 1.4 / 0.4 ± 0.1 / 0.12 ± 0.05 / 114 ± 3 / 56.1 ± 2.5 / 0.47 ± 0.02
22 / 3 / 1299 ± 242 / 107.4 ± 13.5 / 5.7 ± 0.7 / 0.4 ± 0.2 / 0.17 ± 0.02 / 98.0 ± 9.0 / 36.7 ± 8.5 / 0.34 ± 0.03

Table S4. Mouse unbound PR-104 and PR-104A non-compartmental pharmacokinetic parameter estimates following dosing with PR-104. Values are mean ± SEM.

Dose / Sex / Route / N / Mouse PR-104 non-compartmental estimates / Mouse PR-104A non-compartmental estimates
Cmax. / AUC0-∞ / CL / Vss / T1/2 / Cmax. / AUC0-∞ / T1/2
(mg/kg) / (µM) / (µM.h) / (L/h/kg) / (L/kg) / (h) / (µM) / (µM.h) / (h)
32.6 / F / i.v. / 3 / 37.9 ± 2.0 / 1.8 ± 0.1 / 30.8 ± 1.3 / 0.9 ± 0.1 / 0.092 ± 0.011 / 15.1 ± 1.1 / 2.65 ± 0.15 / 0.19 ± 0.01
326 a / F / i.v. / 9 / 971 ± 103 / 51.3 ± 7.5 / 11.5 ± 1.7 / 0.4 ± 0.1 / 0.068 ± 0.009 / 163 ± 10 / 62.5 ± 2.7 / 0.24 ± 0.02
326 / F / i.p. / 3 / 45.8 ± 1.3 / 14.3 ± 0.9 / - / - / 0.203 ± 0.029 / 76.1 ± 0.6 / 50.7 ± 2.1 / 0.35 ± 0.03

a From ref 36.

Table S5. Mouse unbound PR-104A non-compartmental pharmacokinetic parameter estimates following dosing with PR-104A. Values are mean ± SEM.

Dose / Sex / Route / N / Mouse PR-104A non-compartmental estimates
Cmax. / AUC0-∞ / CL / Vss / T1/2
(mg/kg) / (µM) / (µM.h) / (L/h/kg) / (L/kg) / (h)
28.0 a / F / i.v. / 3 / 16.1 ± 1.5 / 4.44 ± 0.34 / 12.8 ± 0.9 / 2.6 ± 0.1 / 0.18 ± 0.02

a Molar dose equivalent to PR-104 at 32.6 mg/kg.

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