Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Review of Published PPK Models
2.2. Independent External Validation Data Set
2.3. External Predictive Performance Evaluation of Apixaban and Rivaroxaban PPK Models
2.4. Prediction-Based Diagnostics
2.5. Simulation-Based Diagnostics
3. Results
3.1. Review of Published PPK Studies
3.1.1. Apixaban
3.1.2. Rivaroxaban
3.2. External Validation Dataset Cohort
3.3. External Predictability Evaluation
3.3.1. Prediction-Based Diagnostics
Apixaban
Rivaroxaban
3.3.2. Simulation-Based Diagnostics
Apixaban
Rivaroxaban
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Model Reference | PK Study Reference | N Patients | Age | Weight | Daily Dose (mg) | Dosing Frequency | N PK Samples | Sampling Regimen | Assay | Intended Application of the PPK Model |
---|---|---|---|---|---|---|---|---|---|---|
EVD apixaban | Ballerie 2021 [16] | 69 | 55 (20–86) | 99 (79–150) | 2.5, 5 | BID | 116 | Sparse | Anti-Xa chromogenic assay LLOQ 20 ng/mL | No PPK model |
A1 | Byon 2017 [22] | 970 | (18–89) | 167 patients > 100 kg | 2.5–50 | single dose, QD, BID | 8323 | Intensive + sparse | LC-MS/MS LLOQ 1 ng/mL | PKPD EER analysis in patients with VTE |
A2 | Cirincione 2018 [23] | 4385 | 68 (18–94) | 81.4 (32–198.2) | 2.5–50 | single dose, QD, BID | 11,968 | Intensive + sparse | LC-MS/MS LLOQ 1 ng/mL | Explain PK heterogeneity in patients with NVAF |
A3 | Goto 2020 [24] | 140 | 79.1 * ± 5.8 (2.5 mg BID) 70.9 * ± 7.5 (5 mg BID) | 55.7 * ± 10.6 (2.5 mg BID) 62.8 * ± 11.7 (5 mg BID) | 2.5, 5 | BID | 183 | Sparse | Anti-Xa chromogenic assay LLOQ 20 ng/mL | Compare anti-Xa DOAC PK |
A4 | Leil 2014 [25] | 1284 | NA | NA | 2.5–50 | single dose, QD, BID | 11,252 | Intensive + sparse | LC-MS/MS LLOQ 1 ng/mL | PKPD EER analysis in patients undergoing orthopedic surgery |
A5 | Ueshima 2018 [26] | 81 | 68 (40–85) | 65 (41–92) | 5–20 | BID | 276 | Sparse | LC-MS/MS LLOQ 2.5 ng/mL | Explain PK heterogeneity in patients with NVAF |
EVD rivaroxaban | Ballerie 2021 [16] | 81 | 64.5 (20–85) | 102 (73.0–178) | 20 | QD | 121 | Sparse | Anti-Xa chromogenic assay LLOQ 20 ng/mL | No PPK model |
R1 | Barsam 2017 [27] | 101 | 52 * (20–86) | 88 * ± 23.4 | 10–30 | QD, BID | 193 | Sparse | Anti-Xa chromogenic assay LLOQ 20 ng/mL | Study the impact of weight on rivaroxaban PK |
R2 | Girgis 2014 [28] | 161 | NA | NA | 15–20 | QD | 801 | Sparse | LC-MS/MS LLOQ 0.5 ng/mL | Confirm dose selection in patients with NVAF |
R3 | Goto 2020 [24] | 119 | 73.1 * ± 10.0 (10 mg QD) 66.7 * ± 10.0 (15 mg QD) | 60.3 * ± 15.5 (10 mg QD) 67.3 * ± 13.8 (15 mg QD) | 10, 15 | QD | 162 | Sparse | Anti-Xa chromogenic assay LLOQ 20 ng/mL | Compare anti-Xa DOAC PK |
R4 | Kaneko 2013 [29] | 597 | 72 (34–89) | 63.9 (35–104) | 10, 15 | QD | 1834 | Sparse | LC-MS/MS LLOQ 0.5 ng/mL | Confirm dose selection in Japanese patients with NVAF |
R5 | Mueck 2007 [30] | 43 | 33 * (20–45) | NA | 5–60 | QD, BID | 1809 | Intensive | LC-MS/MS LLOQ 0.5 ng/mL | Describe rivaroxaban PK in healthy subjects |
R6 | Mueck 2008 CPK [31] | 1009 | 65 (26–87) (hip study) 67 (39–92) (knee study) | 76 (45–125) (hip study) 86 (50–173) (knee study) | 5–60 | QD, BID | 7568 | Intensive + sparse | LC-MS/MS LLOQ 2.5 ng/mL | Describe rivaroxaban PK in patients undergoing major orthopaedic surgery |
R7 | Mueck 2008 TH [32] | 758 | 66 (26–93) | 75 (45–120) | 5–20 | QD, BID | 5743 | Sparse | LC-MS/MS LLOQ 2.5 ng/mL | Compare the PKPD of QD and BID rivaroxaban in patients undergoing total hip replacement |
R8 | Mueck 2011 [33] | 870 | 61 (18–94) | 85 * ± 17 (male) 73 * ± 16 (female) | 10–60 | QD, BID | 4634 | Sparse | LC-MS/MS LLOQ 2.5 ng/mL | Describe rivaroxaban PK in patients treated for acute DVT and simulate exposure in patients with NVAF |
R9 | Ollier 2016 [34] | 12 | 26 (20–30) | 71 (62–88) | 40 | Single dose | 192 | Intensive | LC-MS/MS LLOQ 5 ng/mL | Study the effect of activated charcoal on rivaroxaban absorption |
R10 | Speed 2020 [35] | 913 | 67.0 * ± 15.0 | 85.8 * ± 23.1 | 15–30 | QD, BID | 1108 | Sparse | Anti-Xa chromogenic assay LLOQ 20 ng/mL | Understand the influence of WT on rivaroxaban PK |
R11 | Suzuki 2018 [36] | 96 | 68.0 * ± 9.5 | 69.1 ± 11.4 | 10–15 | QD | 192 | Sparse | LC-MS/MS LLOQ 1 ng/mL | Describe rivaroxaban PK in Japanese patients with NVAF |
R12 | Tanigawa 2013 [37] | 182 | 65.6 (30–92) | 67.2 (45–103) | 5–40 | QD, BID | 842 | Sparse | LC-MS/MS LLOQ 0.5 ng/mL | Select dose for Japanese patients with NVAF |
R13 | Willman 2018 [8] | 4918 | 60.5 * ± 11.8 | 82.5 * ± 16.9 | 5–60 | QD, BID | 22,843 | Sparse | LC-MS/MS LLOQ 0.5 ng/mL | Describe rivaroxaban PK across multiple patient populations |
R14 | Xu 2012 [38] | 2290 | 57 (24–87) | 84 (36–181) | 5–20 | QD, BID | 6644 ** | Sparse | LC-MS/MS LLOQ 0.5 ng/mL | Describe rivaroxaban PKPD in patients with ACS |
R15 | Zdovc 2019 [39] | 17 | 64 (49–82) | 84 (54–125) | 10 | QD | 82 | Sparse | Anti-Xa chromogenic assay LLOQ 1 ng/mL | Investigate the influence of ABCB1 polymorphism on rivaroxaban PKPD |
R16 | Zhang 2017 [40] | 285 | 59 (31–83) (DVT study) 65 (51–81) (NVAF study) | 54.1 (40.1–72.7) (DVT study) 56.6 (42.5–73.6) (NVAF study) | 20–40 | QD | NA | Sparse | LC-MS/MS LLOQ 0.5 ng/mL | Evaluate the effect of food on rivaroxaban PK |
Model Reference | Modeling Software | Structural Model | Relative Bioavailability | Parameter Values | Covariates | Interpatient Variability | Residual Error |
---|---|---|---|---|---|---|---|
A1 | NONMEM 7.2 | 2 CMT | NA | Ka (1/h) = 0.440 CL (L/h) = 4.35 Vc (L) = 32.1 Q (L/h) = 1.62 Vp (L) = 19.8 | Ka: evening dosing CL: Sex, WT, CrCL *, Race, INH Vc: WT | ωKa = 0.474 ωCL = 0.322 ωVc = 0.232 | Additive |
A2 | NONMEM 7.1 | 2 CMT | I50 = −0.322 Gamma = 0.857 | Ka (1/h) = 0.473 CL (L/h) = 3.59 Vc (L) = 30.0 Q (L/h) = 1.91 Vp (L) = 27.0 | Ka: AMPM CL: CrCL *, Age, Sex, Race, INH, SUB Vc: WT, SUB | ωKa = 0.513 ωK = 0.309 ωk12 = 1.245 ωk21 = 0.490 ωVc = 0.172 | Proportional = 0.31 |
A3 | Phoenix NLME 8.1 | 1 CMT | NA | Ka (1/h) = 0.42 CL (L/h) = 4.74 Vc (L) = 30 | CL: CrCL | ωCL = 0.266 ωVc = 0.566 | Proportional = 0.34 |
A4 | NONMEM 6.1.1 | 2 CMT | ED50 = 32.5 Imax = 0.705 Gamma = 2.21 | Ka (1/h) = 0.188 CL (L/h) = 4.75 ** Vc (L) = 22.9 Q (L/h) = 2.60 Vp (L) = 22.2 | Ka: SUB CL: Age, Sex, Dose ***, CrCL, Vc: WT, HCT | ωKa = 0.532 ωCL = 0.375 ωVc = 0.252 ωQ = 0.491 ωVp = 0.735 correlation ωVc ωCL = 0.915 | Proportional = 0.34 Additive = 3.38 |
A5 | NONMEM 7.3.0 | 1 CMT | NA | Ka (1/h) = 0.42 CL (L/h) = 1.53 Vc (L) = 24.7 | CL: CrCL, PGx | ωCL = 0.266 ωVc = 0.566 | Proportional = 0.34 |
R1 | NONMEM 7.2.13 | 1 CMT | NA | Ka (1/h) = 1.21 CL (L/h) = 8.86 Vc (L) = 101 | CL: CrCL | ωCL = 0.480 ωVc = 0.600 | Proportional = 0.31 |
R2 | NONMEM 7.10 | 1 CMT | NA | Ka (1/h) = 1.16 CL (L/h) = 6.10 Vc (L) = 79.7 | CL: Age, SCre Vc: LBM, Age | ωCL = 0.342 ωVc = 0.175 | Proportional = 0.479 |
R3 | Phoenix NLME 8.1 | 1 CMT | F1 = 1 | Ka (1/h) = 0.617 CL (L/h) = 5.59 Vc (L) = 50.9 | CL: CrCL | ωKa = 0.540 ωCL = 0.394 ωVc = 0.583 ωF1 = 0.365 | Proportional = 0.131 |
R4 | NONMEM 6.2.0 | 1 CMT | F1 = 1 | Ka (1/h) = 0.617 CL (L/h) = 4.73 Vc (L) = 43.8 | CL: CrCL, HCT | ωKa = 0.582 ωCL = 0.410 ωVc = 0.636 ωF1 = 0.377 correlation ωVc ωCL = 0.729 | Proportional = 0.131 |
R5 | NONMEM 5.1.1 | 2 CMT | NA | Tlag (h) = 0.25 Ka (1/h) = 0.97 CL (L/h) = 9.17 Vc (L) = 55.3 Q (L/h) = 1.35 Vp (L) = 12.6 | Vc: Dose Vp: Dose | IOV Tlag = 0.847 ωKa = 0.497 IOV Ka = 0.794 ωCL = 0.173 ωVc = 0.300 ωVp = 0.373 | Proportional = 0.254 |
R6 | NONMEM 5.1.1 | 1 CMT | F1 = 1 | Ka (1/h) = 1.81 CL (L/h) = 7.3 Vc (L) = 49.1 | F1: Dose | ωCL = 0.373 | Proportional = 0.371 |
R7 | NONMEM 5.1.1 | 1 CMT | F1 = 1 | Ka (1/h) = 1.49 CL (L/h) = 7.51 Vc (L) = 58.2 | F1: Dose | ωCL = 0.369 ωVc = 0.316 | Proportional = 0.526 |
R8 | NONMEM 5.1.1 | 1 CMT | F1 = 1 | Ka (1/h) = 1.23 CL (L/h) = 5.67 Vc (L) = 54.4 | F1: Dose CL: Age, SCr Vc: LBM, Age | ωCL = 0.384 ωVc = 0.282 | Proportional = 0.407 |
R9 | Monolix 4.3.2 | 1 CMT | F = 0.569 | f1 = 0.748 f2 = 0.348 Tmax1 (h) = 0.274 dTmax2 (h) = 1.94 dTmax3 (h) = 11.5 CV1 = 0.495 CV2 = 0.167 CV3 = 0.651 CL (L/h)= 7.4 Vc (L) = 28.4 | Activated charcoal effect on input rate | ωF = 0.253 IOV F = 0.728 IOV f1 = 0.997 IOV correlation ωF ωf1 = −0.717 ωCV1 = 0.570 ωVc = 0.085 | Proportional = 0.194 |
R10 | NONMEM 7.4.2 | 1 CMT | NA | Ka (1/h) = 0.707 CL (L/h) = 5.57 Vc (L) = 59.4 Lambda = −1.83 | CL: CrCl ***** Vc: LBM ****** | ωCL = 0.227 ******* | Proportional = 0.4637 |
R11 | Phoenix NLME 1.4 | 1 CMT | NA | Ka (1/h) = 1.37 CL (L/h) = 4.40 Vc (L) = 38.2 | CL: CrCL, ALT, INH | ωKa = 0.426 ωCL = 0.204 ωVc = 0.583 | Proportional = 0.418 |
R12 | NONMEM 5.1.1 | 1 CMT | F1 = 1 | Ka (1/h) = 0.60 CL (L/h) = 4.72 Vc (L) = 42.9 | CL: BUN | ωF1 = 0.244 ωKa = 0.680 ωCL = 0.213 | Proportional = 0.402 |
R13 | NONMEM 7.3 | 1 CMT | Fmin = 0.590 Fmax = 1.25 D50 = 14.4 | Ka (1/h) = 0.821 CL (L/h) = 6.58 Vc (L) = 62.5 | CL: CrCL, WT, INH, SUB Vc: WT, Age, Sex | ωKa = 0.792 ωCL = 0.409 ωVc = 0.198 correlation ωCL ωVc = 0.834 | Proportional = 0.451 |
R14 | NONMEM 6.1.1 | 1 CMT | F1 = 1 | Ka (1/h) = 1.24 CL (L/h) = 6.48 Vc (L) = 57.9 | F: Dose CL: Age, SCr **** Vc: LBM, Age | ωKa = 1.037 ωCL = 0.306 IOV CL = 0.316 ωVc = 0.010 | Additive = 0.352 |
R15 | NONMEM 7.3 | 1 CMT | NA | Ka (1/h) = 0.147 CL (L/h) = 6.12 Vc (L) = 96.8 | CL: PGx | ωKa = 2.004 ωCL = 0.709 | Proportional = 0.595 |
R16 | NONMEM 7.2 | 1 CMT | F1 = 1 | Ka (1/h) = 0.982 CL (L/h) = 6.31 Vc (L) = 70.3 | F1: SUB CL: Age, SCr **** Vc: LBM, Age | ωCL = 0.336 ωVc = 0.154 | Proportional = 0.475 |
MDPE (%) | MDAE (%) | F20 (%) | F30 (%) | |
---|---|---|---|---|
A1 (Byon 2017 [22]) | −7.8 | 25.0 | 42.2 | 56.0 |
A2 (Cirincione 2018 SUB = ACS [23]) | 17.0 | 29.0 | 37.1 | 51.7 |
A2 (Cirincione 2018 SUB = NVAF [23]) | 5.5 | 24.8 | 41.4 | 55.2 |
A3 (Goto 2020 [24]) | −38.0 | 39.7 | 16.4 | 31.9 |
A4 (Leil 2014 SUB = patients [25]) | 1.7 | 27.3 | 37.1 | 52.6 |
A4 (Leil 2014 SUB = non patients [25]) | 7.6 | 27.2 | 39.7 | 56.0 |
A5 (Ueshima 2018 [26]) | 7.2 | 25.8 | 40.5 | 54.3 |
R1 (Barsam 2017 [27]) | −31.5 | 39.6 | 21.5 | 34.7 |
R2 (Girgis 2014 [28]) | 9.7 | 29.9 | 33.9 | 50.4 |
R3 (Goto 2020 [24]) | 11.6 | 34.0 | 36.4 | 45.4 |
R4 (Kaneko 2013 [29]) | −12.2 | 45.8 | 26.4 | 33.9 |
R5 (Mueck 2007 [30]) | −22.2 | 41.2 | 24.0 | 39.7 |
R6 (Mueck 2008 CPK [31]) | −3.4 | 41.7 | 25.6 | 38.8 |
R7 (Mueck 2008 TH [32]) | −7.3 | 36.0 | 25.6 | 42.1 |
R8 (Mueck 2011 [33]) | 24.8 | 35.4 | 34.7 | 43.8 |
R9 (Ollier 2016 [34]) | −53.4 | 53.9 | 14.9. | 20.7 |
R10 (Speed 2020 [35]) | 17.3 | 32.2 | 32.2 | 47.9 |
R11 (Suzuki 2018 [36]) | 36.2 | 46.4 | 19.8 | 33.1 |
R12 (Tanigawa 2013 [37]) | 49.0 | 49.4 | 25.6 | 35.5 |
R13 (Willman 2018 SUB = VTE [8]) | −30.4 | 42.7 | 23.1 | 33.1 |
R13 (Willman 2018 SUB = NVAF [8]) | 6.6 | 28.5 | 32.2 | 51.2 |
R14 (Xu 2012 [38]) | 10.9 | 37.5 | 30.6 | 46.2 |
R15 (Zdovc 2019 [39]) | 18.6 | 51.8 | 19.0 | 24.8 |
R16 (Zhang 2017 SUB = DVT [40]) | 7.6 | 30.1 | 25.6 | 48.8 |
R16 (Zhang 2017 SUB = NVAF [40]) | 8.5 | 31.0 | 25.6 | 48.8 |
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Leven, C.; Ménard, P.; Gouin-Thibault, I.; Ballerie, A.; Lacut, K.; Ollier, E.; Théreaux, J. Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations. Pharmaceutics 2023, 15, 665. https://doi.org/10.3390/pharmaceutics15020665
Leven C, Ménard P, Gouin-Thibault I, Ballerie A, Lacut K, Ollier E, Théreaux J. Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations. Pharmaceutics. 2023; 15(2):665. https://doi.org/10.3390/pharmaceutics15020665
Chicago/Turabian StyleLeven, Cyril, Pauline Ménard, Isabelle Gouin-Thibault, Alice Ballerie, Karine Lacut, Edouard Ollier, and Jérémie Théreaux. 2023. "Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations" Pharmaceutics 15, no. 2: 665. https://doi.org/10.3390/pharmaceutics15020665
APA StyleLeven, C., Ménard, P., Gouin-Thibault, I., Ballerie, A., Lacut, K., Ollier, E., & Théreaux, J. (2023). Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations. Pharmaceutics, 15(2), 665. https://doi.org/10.3390/pharmaceutics15020665