Upadacitinib is a novel Janus kinase 1 inhibitor being developed for the treatment of patients with moderate to severe rheumatoid arthritis (RA). A population pharmacokinetic model was developed for upadacitinib using data from phase I–III clinical trials in healthy volunteers and subjects with RA. |
A two-compartment model with first-order absorption with lag time for the immediate-release formulation, mixed zero- and first-order absorption with lag time for the extended-release formulation, and linear elimination well-described upadacitinib plasma concentration versus time data. |
Bodyweight and mild or moderate renal impairment had statistically significant but non-clinically relevant effects on upadacitinib exposures. |
Sex, race, concomitant use of pH-modifying agents, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib pharmacokinetics. |
1 Introduction
2 Methods
2.1 Study Design and Population
Study | Population |
N
a
| Study design; pharmacokinetic sampling | Upadacitinib doses | Formulation | References |
---|---|---|---|---|---|---|
Phase I | ||||||
Study 1, substudy 1 | Healthy subjects | 56 | Single-dose, randomized, placebo-controlled; 17 samples up to 72 h post-dose | 1, 3, 6, 12, 24, 36, 48 mg | IR | [10] |
Study 2 | Healthy subjects | 45 | Single-dose, randomized, placebo-controlled; 17 samples up to 72 h post-dose Multiple-dose, randomized, placebo-controlled; 11 samples up to 12 h post day 1 morning dose, and 18 samples up to 72 h post day 14 dose Single predose samples on days 5 6, 7, and 13 | 3, 6, 24 mg 18 mg bid for 14 days | IR IR | [10] |
Study 3, substudy 1 | Healthy subjects | 44 | Multiple-dose, randomized, placebo-controlled; 11 samples up to 12 h post day 1 morning dose and 18 samples up to 72 h post day 14 dose Single predose sample on days 5 6, 7, and 13 | 3, 6, 12, 24 mg bid for 14 days | IR | [10] |
Study 3, substudy 2 | Subjects with mild to moderate RA | 14 | Multiple-dose, randomized, placebo-controlled; 11 samples up to 12 h post day 3 and day 28 morning doses, and 17 samples up to 48 h post day 29 dose Single predose sample on days 8, 15, and 22 | 6, 12, 24 mg | IR | [10] |
Study 4, parts 1 and 2 | Healthy subjects | 23 | Single-dose, randomized; 16 samples up to 72 h post-dose | 12 and 24 mg 15 and 30 mg | IR ER | [12] |
Study 4, part 3 | Healthy subjects | 34 | Multiple-dose, randomized, placebo-controlled; 12 samples up to 24 h post day 1 dose, and 15 samples up to 72 h post day 7 dose Single predose sample on days 3, 4, 5, and 6 | 15 and 30 mg qd | ER | [12] |
Study 4, part 4 | Healthy subjects | 12 | Multiple-dose, randomized; 9 samples up to 12 h prior to evening dose, 8 samples up to 24 h post days 1 and 7 morning doses Single predose sample on days 3, 4, 5, and 6 | 6 and 12 mg bid | ER | [12] |
Study 4, part 5 | Healthy subjects | 12 | Multiple-dose, randomized; 12 samples up to 24 h post day 1 dose, and 15 samples up to 72 h post day 7 dose Single predose sample on days 3, 4, 5, and 6 | 15 and 30 mg qd | ER | [12] |
Phase II | ||||||
Study 5 | Subjects with moderate to severely active RA | 300 | Randomized, placebo-controlled dose-ranging Single predose trough sample at weeks 2, 4, 6, 8, and 12 Samples at 1, 2, 3 h after the morning dose on day 1 and week 8 in approximately 30% of subjects | 3, 6, 12, and 18 mg bid and 24 mg qd | IR | [11] |
Study 6 | Subjects with moderate to severely active RA | 276 | Randomized, placebo-controlled dose-ranging Single predose trough sample at week 2, 4, 6, 8, and 12 Samples at 1, 2, 3 h after the morning dose on day 1 and week 8 in approximately 30% | 3, 6, 12, and 18 mg bid | IR | [15] |
Phase IIb/III | ||||||
Study 7 | Japanese subjects with moderate to severe RA | 192 | Randomized, double-blind, parallel-group, placebo-controlled Single sample at weeks 1, 2, 4, 8 and 12/PD, and serial PK samples during one visit in approximately 32 subjects prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 and 24 h after dose | 7.5, 15, 30 mg qd | ER | [20] |
Phase III | ||||||
Study 8 | Subjects with moderate to severe RA | 499 | Randomized, double-blind, parallel-group, placebo-controlled Single sample at weeks 1, 2, 4, 8, 12, 16, 20, and 24/PD | 15, 30 mg qd | ER | [13] |
Study 9 | Subjects with moderate to severe RA | 661 | Randomized, double-blind, parallel-group, placebo-controlled; Single sample at weeks 1, 2, 4, 8, and 12/PD | 15, 30 mg qd | ER | [16] |
Study 10 | Subjects with moderate to severe RA | 600 | Randomized, double-blind, parallel-group, controlled Single sample at weeks 2, 4, 8, and 14/PD | 15, 30 mg qd | ER | [19] |
Study 11 | Subjects with moderate to severe RA | 1500 | Randomized, double-blind, parallel-group, placebo-controlled and active comparator-controlled Single sample at weeks 2, 4, 8, 12, 14, 18, 22, 26, 30, 36, 42, and 48/PD | 15 mg qd | ER | [17] |
Study 12 | MTX-naïve subjects with moderate to severe RA | 975 | Randomized, double-blind, parallel-group, active comparator-controlled Single sample at weeks 2, 4, 12, 16, 20, 24, 32, 36, 40, and 48/PD | 7.5, 15, 30 mg qd | ER | [18] |
2.2 Pharmacokinetic Analysis
2.2.1 Model Development
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For apparent clearance (CL/F): baseline serum bilirubin concentration, baseline creatinine clearance (CrCl), baseline total bodyweight, age, baseline aspartate aminotransaminase (AST), baseline alanine aminotransferase (ALT), baseline Disease Activity Score (DAS) 28–C-reactive protein (CRP), baseline high-sensitivity CRP (hsCRP), sex, race (White, Black, Hispanic, Asian), country (Taiwan, Japan, China, Korea), concomitant use of methotrexate, concomitant use of any pH-modifying medications, concomitant use of antacids, concomitant use of H2 blockers, concomitant use of proton-pump inhibitors, concomitant use of moderate or strong CYP3A inhibitors, and concomitant use of strong CYP3A inducers.
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For apparent volume of distribution of the central compartment (Vc/F): sex, race (White, Black, Hispanic, Asian), baseline total bodyweight, and country (Taiwan, Japan, China, Korea).
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For relative bioavailability of the ER formulation: upadacitinib dose, concomitant use of antacids, concomitant use of H2 blockers, concomitant use of proton pump inhibitors, concomitant use of any pH-modifying agents, concomitant use of moderate or strong CYP3A inhibitors, and concomitant use of strong CYP3A inducers.
2.2.2 Final Model Evaluation
2.2.2.1 Bootstrap
2.2.2.2 Visual Predictive Checks
2.2.3 Evaluation of the Impact of Statistically Significant Covariates on Upadacitinib Exposures
3 Results
3.1 Dataset and Demographic Summary
Characteristics | Phase I [N = 188] | Phase II [N = 456] | Phase IIb/III [N = 147] | Phase III [N = 3379] | All subjects [N = 4170] | |
---|---|---|---|---|---|---|
Age, years | Mean (SD) | 36.0 (11.50) | 56.0 (12.33) | 55.5 (11.90) | 54.5 (12.13) | 53.9 (12.73) |
Range | 19.0–70.0 | 19.0–85.0 | 19.0–78.0 | 18.0–87.0 | 18.0–87.0 | |
Bodyweight, kg | Mean (SD) | 75.4 (11.09) | 76.4 (15.98) | 58.3 (11.31) | 77.2 (19.98) | 76.4 (19.33) |
Range | 52.0–101.0 | 42.0–134.0 | 40.0–93.0 | 36.0–196.0 | 36.0–196.0 | |
BMI, kg/m2 | Mean (SD) | 25.3 (3.07) | 28.4 (5.30) | 23.1 (3.85) | 28.9 (6.84) | 28.5 (6.60) |
Range | 18.5–33.4 | 18.8–44.3 | 16.2–41.5 | 13.3–71.9 | 13.3–71.9 | |
Sex | Male | 164 (87) | 95 (21) | 35 (24) | 697 (21) | 991 (24) |
Female | 24 (13) | 361 (79) | 112 (76) | 2682 (79) | 3179 (76) | |
Race | White | 83 (44) | 426 (93) | – | 2827 (84) | 3336 (80) |
Black | 52 (28) | 21 (5) | – | 183 (5) | 256 (6) | |
Asian | 34 (18) | 3 (1) | 147 (100) | 290 (9) | 474 (11) | |
Multiple races | 18 (10) | 5 (1) | – | – | 23 (1) | |
Other | 1 (1) | 1 (0) | – | 79 (2) | 81 (2) | |
Subject population | Healthy subjects | 178 (95) | – | – | – | 178 (4) |
Subjects with RA | 10 (5) | 456 (100) | 147 (100) | 3379 (100) | 3992 (96) | |
High-sensivity C-reactive protein, mg/La | Mean (SD) | 2.5 (4.21) | 13.6 (18.11) | 13.9 (15.09) | 17.9 (21.88) | 17.1 (21.25) |
Range | 0.1–28.0 | 0.1–135.3 | 0.8–84.6 | 0.2–207.0 | 0.1–207.0 | |
DAS28 C-reactive proteinb | Mean (SD) | Not collected | 5.7 (0.95) | 5.1 (0.91) | 5.8 (0.97) | 5.7 (0.97) |
Range | Not collected | 3.0–8.0 | 3.4–7.8 | 1.8–8.4 | 1.8–8.4 | |
Methotrexate use | No | 178 (95) | – | 24 (16) | 1270 (38) | 1472 (35) |
Yes | 10 (5) | 456 (100) | 123 (84) | 2109 (62) | 2698 (65) | |
Creatinine clearance, mL/min | Mean (SD) | 111.7 (21.86) | 109.6 (36.25) | 96.3 (28.14) | 115.1 (38.98) | 113.7 (37.92) |
Range | 64.1–184.7 | 41.2–241.1 | 38.3–173.1 | 30.2–390.9 | 30.2–390.9 | |
CYP3A inhibitors | None/weak | 188 (100) | 436 (96) | 144 (98) | 3248 (96) | 4016 (96) |
Moderate | – | 16 (4) | 2 (1) | 118 (3) | 136 (3) | |
Strong | – | 4 (1) | 1 (1) | 13 (0.4) | 18 (0.4) | |
CYP3A inducers | None/weak/moderate | 188 (100 | 453 (99) | 147 (100) | 3371 (99.8) | 4159 (99.7) |
Strong | – | 3 (1) | – | 8 (0.2) | 11 (0.3) | |
pH-modifying drugs | No | 188 (100) | 278 (61) | 70 (48) | 1946 (58) | 2482 (60) |
Yes | – | 178 (39) | 77 (52) | 1433 (42) | 1688 (40) |
3.2 Population Pharmacokinetic Model
Parameter | Population analysis | Bootstrap analysisa | |
---|---|---|---|
Estimate (%RSE) | Median | 95% CI | |
CL/F (L/h) | 40.9 (1.6) | 41.3 | 39.6–42.5 |
Vc/F (L) | 156 (1.7) | 156 | 150–161 |
Q/F (L/h) | 3.22 (5.8) | 3.22 | 2.86–3.63 |
Vp/F (L) | 68.0 (7.2) | 67.4 | 59.7–78.3 |
Extended-release Ka (1/h) | 0.0523 (6.0) | 0.0523 | 0.0460–0.0590 |
Extended-release absorption lag time (h) | 0.154 (7.7) | 0.155 | 0.110–0.186 |
Fraction of extended-release dose absorbed through zero-order process (%) | 74.5 (1.7) | 74.3 | 71.3–77.0 |
Zero-order infusion duration (h) | 3.29 (1.7) | 3.29 | 2.77–3.63 |
Immediate-release Ka (1/h) | 2.77 (7.4) | 2.77 | 2.35–3.25 |
Immediate-release absorption lag time (h) | 0.200 (3.9) | 0.202 | 0.176–0.225 |
Bioavailability of the extended-release formulation relative to the immediate-release formulation (%) | 76.2 (1.4) | 76.3 | 73.0–79.7 |
CL/F ratio of RA patients compared with healthy subjects | 0.754 (1.7) | 0.754 | 0.727–0.777 |
Covariate exponent of creatinine clearance on CL/F | 0.256 (10.0) | 0.256 | 0.205–0.305 |
Covariate exponent of weight on Vc/F | 0.804 (8.0) | 0.789 | 0.656–0.921 |
Covariate exponent of weight on CL/F | 0.132 (28.7) | 0.127 | 0.0595–0.206 |
ISV on CL/F in phase I (%) | 20.5 (30.6) | 20.3 | 18.3–22.3 |
ISV on CL/F in phase II/III (%) | 36.5 (23.2) | 36.9 | 35.1–38.9 |
ISV on Vc/F in phase I (%) | 24.4 (37.6) | 24.1 | 20.9–27.7 |
ISV on Vc/F in phase II/III (%) | 53.0 (36.6) | 53.2 | 45.1–61.5 |
ISV on extended-release Ka (%) | 66.8 (34.9) | 66.2 | 58.1–74.8 |
Proportional error SD in phase I | 0.344 (23.9) | 0.344 | 0.324–0.370 |
Additive error SD (ng/mL) | 0.0858 (54.5) | 0.0858 | 0.0467–0.109 |
Proportional error SD in phase II/III | 0.543 (14.0) | 0.543 | 0.533–0.555 |