Risankizumab displayed linear pharmacokinetics across the doses evaluated in the phase I–III clinical trials in psoriasis, and a two-compartment model with first-order absorption and elimination best described its pharmacokinetics. |
Body weight, anti-drug antibody, and baseline levels of albumin, high-sensitivity C-reactive protein, and serum creatinine were identified to be statistically correlated with risankizumab clearance; however, none of these covariates had a clinically meaningful impact on risankizumab exposures with the proposed psoriasis clinical regimen. |
Risankizumab pharmacokinetics were similar between healthy subjects and patients with plaque psoriasis. |
1 Introduction
2 Methods
2.1 Study Population
Study |
n
a
| Description | Risankizumab dose(s)b | Sampling times |
---|---|---|---|---|
Study 1 M16-513 [23] | 67 | Phase I, single-dose study in healthy male Japanese, Chinese, and Caucasian subjects | Stage 1: 18, 90, or 300 mg SC in Chinese and Japanese subjects; 18 or 300 mg SC in Caucasian subjects Stage 2: 200, 600, or 1200 mg IV in Japanese subjects | PK Stage 1: 0 h (predose) and study days 2, 3, 4, 8, 15, 29, 57, 85, and 137 Stage 2: study day 1 at 0 h (predose) and 0.3, 1.5, 4, 8, and 12 h post-dose; study days 2, 3, 4, 8, 15, 29, 57, 85, and 137 ADAs and NAbs Stage 1 and Stage 2: study days 1, 8, 29, 85, and 137 |
Study 2 1311.1 [19] | 31 | Phase I, single-dose, placebo-controlled study in patients with moderate to severe plaque psoriasisc | Stage 1: 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg IV Stage 2: 0.25 or 1 mg/kg SC | PK Study day 1: − 0.5 h (predose) and 0.5, 1, 2, 4, 8, 16, and 24 h post-dose; study days 3, 4, 8, 15, 29, 57, 85, 113, 141, and 169 ADAs and NAbs Study days 1, 2, 8, 29, 85, and 169 |
Study 3 1311.2 [12] | 126 | Phase II, multiple-dose, active-controlled (ustekinumab) study in patients with moderate to severe plaque psoriasisc | 18 (single dose), 90 or 180 mg SC at weeks 0, 4, and 16 | PK Weeks 0, 4, and 16 at − 0.5 h (predose) and weeks 1, 2, 6, 8, 12, 20, 24, 28, 32, 40, and 48 ADAs and NAbs Weeks 0, 4, 16, 24, 32, 40, and 48 |
Study 4 | 401 | Phase III, multiple-dose, placebo- and active-controlled (ustekinumab) study in patients with moderate to severe plaque psoriasisc | 150 mg SC at weeks 0 and 4 and q12w thereafter; or 150 mg SC q12w | PK Weeks 0, 4, 12, 16, 28, 34, 40, and 52 ADAs and NAbs Weeks 0, 4, 16, 28, 40, and 52 |
Study 5 | 394 | Phase III, multiple-dose, placebo- and active- controlled (ustekinumab) study in patients with moderate to severe plaque psoriasisc | 150 mg SC at weeks 0 and 4 and q12w thereafter; or 150 mg SC q12w | PK Weeks 0, 4, 12, 16, 28, 34, 40, and 52 ADAs and NAbs Weeks 0, 4, 16, 28, 40, and 52 |
Study 6 IMMvent [26] | 392 | Phase III, multiple-dose, active-controlled (adalimumab) study in patients with moderate to severe plaque psoriasisc | 150 mg SC at weeks 0 and 4 and q12w thereafter; or 150 mg SC q12w | PK Weeks 0, 4, 12, 16, 28, 36, and 44 ADAs and NAbs Weeks 0, 4, 16, 28, and 44 |
Study 7 IMMhance [27] | 500 | Phase III, multiple-dose, placebo-controlled study in patients with moderate to severe plaque psoriasisc | 150 mg SC at weeks 0 and 4 and q12w thereafter; or 150 mg SC q12w | PK Weeks 0, 4, 12, 16, 28, 32, 40, 52, 58, 64, 70, 76, 88, and 104 ADAs and NAbs Weeks 0, 4, 16, 28, 40, 52, 64, 76, 88, and 104 |
2.2 Bioanalyses
2.3 Population Pharmacokinetic Analyses
2.3.1 Software
2.3.2 Model Development
2.3.3 Model Evaluation
2.3.4 Simulation Analyses for Evaluating the Impact of Covariates
3 Results
3.1 Data
Characteristic | Study | All subjects | ||||||
---|---|---|---|---|---|---|---|---|
M16-513 | 1311.1 | 1311.2 | UltIMMa-1 | UltIMMa-2 | IMMvent | IMMhance | ||
n
| 67 | 31 | 126 | 401 | 394 | 392 | 500 | 1911a |
Country [n (%)] | ||||||||
USA (USA, Canada) | 20 (65) | 81 (64) | 239 (60) | 291 (74) | 202 (52) | 354 (71) | 1187 (62) | |
Taiwan | 37 (9) | 37 (2) | ||||||
Korea | 12 (18) | 43 (11) | 51 (10) | 106 (6) | ||||
Japan | 36 (54) | 39 (10) | 13 (3) | 88 (5) | ||||
Europe | 11 (35) | 45 (36) | 52 (13) | 86 (22) | 144 (37) | 52 (10) | 390 (20) | |
China | 19 (28)b | 19 (1) | ||||||
Rest of world | 28 (7) | 17 (4) | 9 (2) | 30 (6) | 84 (4) | |||
Age (years) | ||||||||
Mean (SD) | 28.5 (6.47) | 42.4 (10.5) | 46.0 (13.9) | 48.4 (13.4) | 46.4 (13.6) | 46.1 (13.8) | 49.2 (13.3) | 46.8 (13.8) |
Median | 27 | 45 | 47 | 48 | 47 | 47 | 51 | 47 |
Min–max | 21–45 | 24–61 | 20–72 | 21–85 | 19–76 | 18–78 | 19–79 | 18–85 |
Body weight (kg) | ||||||||
Mean (SD) | 65.8 (10.1) | 88.7 (18.9) | 89.8 (19.0) | 88.1 (22.3) | 92.2 (21.2) | 90.2 (24.3) | 91.8 (22.9) | 89.7 (22.6) |
Median | 64.2 | 89.0 | 89.0 | 84.0 | 90.3 | 86.8 | 89.4 | 87.0 |
Min–max | 50.6–94.4 | 47.0–121 | 49.2–138 | 45.0–161 | 46.0–170 | 42.6–190 | 47.0–193 | 42.6–193 |
Body mass index (kg/m2) | ||||||||
Mean (SD) | 21.9 (2.37) | 29.6 (5.79) | 30.3 (5.61) | 29.8 (6.81) | 31.1 (6.75) | 30.5 (8.04) | 31.2 (7.11) | 30.3 (7.16) |
Median | 21.4 | 29.1 | 29.9 | 28.6 | 30.4 | 29.3 | 30.1 | 29.4 |
Min–max | 18.5–29.1 | 20.9–39.6 | 18.5–39.9 | 16.6–59.8 | 15.0–57.4 | 16.4–92.7 | 17.3–67.0 | 15.0–92.7 |
Sex [n (%)] | ||||||||
Male | 67 (100) | 25 (81) | 82 (65) | 286 (71) | 270 (69) | 271 (69) | 349 (70) | 1350 (71) |
Female | 6 (19) | 44 (35) | 115 (29) | 124 (31) | 121 (31) | 151 (30) | 561 (29) | |
Race [n (%)] | ||||||||
White and others (including all categories except Asians) | 12 (18) | 31 (100) | 124 (98) | 289 (72) | 362 (92) | 338 (86) | 422 (84) | 1578 (83) |
Asian | 55 (82) | 2 (2) | 112 (28) | 32 (8) | 54 (14) | 78 (16) | 333 (17) | |
hs-CRP (mg/L) | ||||||||
Mean (SD) | 0.5 (0.5) | 4.8 (6.6) | 4.4 (4.8) | 6.0 (9.7) | 5.7 (7.7) | 6.7 (12.2) | 6.5 (11.6) | 5.9 (10.0) |
Median | 0.4 | 3.3 | 2.6 | 2.9 | 3.1 | 2.7 | 3.3 | 2.8 |
Min–max | 0.1–2.3 | 0.3–34.4 | 0.2–30.0 | 0.2–78.8 | 0.2–79.7 | 0.2–103 | 0.2–131 | 0.1–131 |
Baseline PASI score | ||||||||
Mean (SD) | 18.5 (7.4) | 18.7 (7.4) | 20.6 (7.4) | 20.0 (7.6) | 20.0 (7.7) | 20.0 (7.9) | 20.0 (7.6)c | |
Median | 16.3 | 16.2 | 18.4 | 17.8 | 17.7 | 17.4 | 17.8c | |
Min–max | 10.5–43.4 | 11.9–61.0 | 12.0–54.7 | 12.0–60.3 | 12.0–50.4 | 12.0–63.4 | 10.5–63.4c | |
Total bilirubin (µmol/L) | ||||||||
Mean (SD) | 15.0 (5.0) | 9.0 (6.0) | 8.6 (4.7) | 9.6 (5.5) | 8.6 (5.2) | 8.9 (4.6) | 9.0 (5.3) | 9.2 (5.2) |
Median | 13.7 | 7.0 | 6.8 | 8.6 | 7.0 | 8.0 | 8.0 | 8.0 |
Min–max | 6.8–25.7 | 3.4–27.4 | 3.4–29.1 | 3.4–45.0 | 3.0–57.0 | 3.4–39.0 | 3.0–55.0 | 3.0–57.0 |
Serum albumin (g/L) | ||||||||
Mean (SD) | 45.7 (2.38) | NA | 42.2 (3.32) | 44.6 (2.94) | 44.0 (2.92) | 44.7 (2.96) | 44.2 (2.76) | 44.3 (2.97)d |
Median | 46.0 | NA | 42.0 | 45.0 | 44.0 | 45.0 | 44.0 | 44.0d |
Min–max | 40.0–51.0 | NA | 34.0–51.0 | 34.0–58.0 | 35.0–52.0 | 35.0–53.0 | 34.0–51.0 | 34.0–58.0d |
Serum creatinine (µmol/L) | ||||||||
Mean (SD) | 79.5 (11.4) | 79.3 (14.9) | 78.5 (14.8) | 76.6 (16.3) | 77.7 (17.0) | 75.1 (15.2) | 76.4 (17.1) | 76.8 (16.2) |
Median | 79.6 | 79.6 | 79.6 | 76.0 | 79.6 | 74.0 | 73.5 | 76.0 |
Min–max | 55.7–105 | 53.1–106 | 53.1–124 | 35.4–133 | 35.4–159 | 35.4–128 | 35.4–203 | 35.4–203 |
Creatinine clearancee (mL/min) | ||||||||
Mean (SD) | 115 (18.3) | 134 (40.3) | 129 (39.2) | 129 (47.6) | 135 (45.4) | 137 (52.7) | 133 (47.0) | 132 (46.9) |
Median | 114 | 132 | 129 | 118 | 127 | 127 | 125 | 124 |
Min–max | 76.0–163 | 57.3–227 | 44.5–327 | 33.5–388 | 49.2–389 | 33.1–404 | 37.2–360 | 33.1–404 |
Aspartate aminotransferase (U/L) | ||||||||
Mean (SD) | 20.8 (5.5) | 26.7 (12.4) | 25.8 (12.8) | 25.8 (12.7) | 24.2 (12.4) | 25.8 (20.8) | 24.6 (11.9) | 25.0 (14.4) |
Median | 20.0 | 23.0 | 23.0 | 22.0 | 21.0 | 22.0 | 22.0 | 22.0 |
Min–max | 12.0–37.0 | 14.0–65.0 | 11.0–88.0 | 10.0–121 | 9.0–135 | 10.0–236 | 8.0–155 | 8.0–236 |
Alanine transaminase (U/L) | ||||||||
Mean (SD) | 20.6 (11.6) | 30.2 (17.0) | 29.2 (20.0) | 29.3 (20.0) | 27.8 (20.3) | 30.3 (25.2) | 27.5 (15.6) | 28.4 (20.0) |
Median | 16.0 | 28.0 | 24.0 | 23.0 | 23.0 | 23.5 | 24.0 | 23.0 |
Min–max | 7.0–59.0 | 10.0–72.0 | 6.0–115 | 6.0–128 | 7.0–239 | 6.0–229 | 7.0–112 | 6.0–239 |
Treatment-emergent ADA status (yes) [n (%)] | 4 (6) | 3 (10) | 18 (14) | 90 (22) | 75 (19) | 99 (25) | 138 (27) | 427 (22) |
ADA titer ≥ 128 (nf) | – | 3 | 5 | 2 | 8 | 10 | 4 | 32 |
NAb treatment-emergent status (yes) [n (%)] | NA | NA | 4 (3) | 52 (13) | 41 (10) | 56 (14) | 85 (17) | 238 (12) |
3.2 Population Pharmacokinetic Model
Parameter | Population estimate | %RSEa | Bootstrap median (95% CI)b |
---|---|---|---|
Pharmacokinetic parameters | |||
CL (L/day) | 0.243 | 1.8 | 0.239 (0.217–0.263) |
Vc (L) | 4.86 | 3.8 | 4.70 (3.95–5.53) |
ka (day−1) | 0.229 | 4.8 | 0.223 (0.179–0.296) |
Q (L/day) | 0.656 | 3.7 | 0.656 (0.540–0.783) |
Vp (L) | 4.25 | 2.0 | 4.24 (3.85–4.65) |
Absolute SC bioavailability of formulation used in phase I and II studiesc | 0.710 | 11.1 | 0.698 (0.624–0.781) |
Absolute SC bioavailability of formulation used in phase III studiesd | 0.890 | 7.2 | 0.877 (0.791–0.960) |
Exponent for the effect of body weight on risankizumab CL | 0.933 | 3.3 | 0.931 (0.862–0.995) |
Exponent for the effect of body weight on risankizumab Vc | 1.17 | 7.2 | 1.17 (0.979–1.35) |
Exponent for the effect of serum albumin on risankizumab CL | − 0.715 | 10.6 | − 0.713 (− 0.886 to –0.516) |
Exponent for the effect of serum creatinine on risankizumab CL | − 0.253 | 10.2 | − 0.255 (− 0.308 to –0.203) |
Exponent for the effect of C-reactive protein on risankizumab CL | 0.044 | 10.5 | 0.043 (0.034–0.054) |
Exponent for the effect of body weight on risankizumab Vp | 0.377 | 12.0 | 0.382 (0.245–0.520) |
Proportional increase in CL for an ADA titer ≥ 128 | 0.428 | 5.1 | 0.432 (0.287–0.766) |
Inter-individual correlation and residual variability | |||
IIV for CL (%CV)e | 24 | 3.6 | 0.053 (0.038–0.067) |
IIV for Vc (%CV)e | 34 | 6.6 | 0.109 (0.052–0.158) |
IIV for ka (%CV)e | 63 | 5.5 | 0.315 (0.129–0.578) |
Variance of IIV for Ff; (additive error model in logit domain) | 0.492 | 16.9 | 0.454 (0.269–0.795) |
Covariance between IIV CL and IIV Vc (% correlation) | 39 | 8.1 | 0.028 (− 0.003 to 0.051) |
Proportional residual error (%CV) | 19 | 0.68 | 0.036 (0.033–0.039) |