Table 3.
Overview of the pharmacokinetic models, parameters and outcome measures in the included studies
| Study reference | Weight/BMI | Rivaroxaban dosing regimen | PK model | PK parameter | Outcomes |
|---|---|---|---|---|---|
| [69] |
Median weight: 132.5 kg BMI (IQR): 41 (37.6–47.6) kg/m2 |
Every patient received their medication as prescribed for their condition, which was generally ≥ 15 mg/day | Not reported | Median peak plasma concentration after > 15 mg rivaroxaban: 249 µg.L−1 | No obese subjects receiving rivaroxaban therapy had Cmax below the median trough; however, 28% of the obese subjects receiving rivaroxaban had a Cmax that was below the 5th percentile peak concentration |
| [30] |
Mean weight (±SD) for the whole sample: 88.0 (±23.4) kg BMI, kg/m2 (%) 16–18.49 (1) 18.5–24.9 (27) 25–29.9 (32) 30–34.9 (21) 35–39.9 (14) ≥40 (6) |
15 mg twice daily (57%) 20 mg once daily (38%) 10 mg once daily (4%) 15 mg once daily (1%) |
One-compartment model |
Value (%SD): CL: 8.59 (7%) L.h−1 Vd: 104 (13%) L Ka: 1.32 (24%) h−1 |
The findings suggest that rivaroxaban behaves differently from other traditional anticoagulants, in the extremes of weight population and that the dose does not need to be increased with weight The results suggest that the most important covariate impacting rivaroxaban PK is creatinine clearance, and weight has only a little effect The study showed that weight did not feature as a significant covariant in the study |
| [31] |
Mean BMI (±SD) kg/m2: 28.5 (±10.4) for the placebo group 19.3 (±1.1) for the intervention group who are ≤50 kg 24.3 (±2.3) for the intervention group who are 70–80 kg 43.5 (±4.2) for the intervention group who are > 120 kg |
10 mg/day or placebo in a 3:1 ratio, therefore 12 subjects in each weight group received rivaroxaban and 4 received placebo | Non-compartmental analysis |
Values expressed as means (coefficient of variation), except the tmax, which was expressed as median (range) after a 10 mg dose of rivaroxaban: For subjects > 120 kg: AUC∞: 1155 (15.60%) µg.h.L−1 AUC∞, norm: 15,230 (18.50%) g.h.L−1 Cmax: 149 (20.40%) µg.L−1 Cmax, norm: 1964 (23.10%) g.L−1 tmax: 4.00 (2.00-4.00) h t½: 7.30 (25.40%) h Vz/F: 0.69 (35.80%) L.kg−1 For subjects 70–80 kg: AUC∞: 1029 (20.10%) µg.h.L−1 AUC0, norm: 7611 (19.20%) g.h.L−1 Cmax: 143 (26.50%) µg.L−1 Cmax, norm: 1061 (25.90%) g.L−1 tmax: 3.50 (1.00–4.00) h t½: 7.20 (42.10%) h Vz/F: 1.36 (37.40%) L.kg−1 |
Rivaroxaban was well tolerated in subjects with extremes of body weight, as in subjects with normal body weight, and its PK and PD were not influenced by body weight to an extent considered likely to be clinically relevant |
| [70] |
Mean weight (±SD) for the whole sample: 82.48 (±16.87) kg BMI, kg/m2: <18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40 |
Ranged from 2.5 mg once daily to 30 mg twice daily | One-compartment model |
Value (% SE): Ka: 0.821 h−1 CL/F: 6.58 (2.33) L.h−1 V/F: 62.5 (2.04) L Population medians varied for AUC, Cmax, and Ctrough by 7.5%, 7.6%, and 44%, respectively, among the BMI categories compared with the reference groups |
The influence of body weight on rivaroxaban PK was minor, demonstrating that fixed doses of rivaroxaban can be prescribed in adult subjects without adjustment for body weight The study showed that the BMI had a minor influence on exposure of rivaroxaban |
| [71] |
Median weight (range): 76 (45–125) kg in the hip study 86 (50–173) kg in the knee study |
2.5, 5, 10, 20 or 30 mg every 12 ± 1 h (5, 10, 20, 40 or 60 mg total daily dose) | One-compartment model |
Values expressed as geometric means [except tmax, which was expressed as median (range)]: After a 10 mg dose of rivaroxaban: AUC12: 974 (63.0) µg.h.L−1 AUC12, norm: 7817 (57.4) g.h.L−1 Cmax: 180 (74.1) µg.L−1 Cmax, norm: 1423 (62.1) g.L−1 tmax: 1 (1–12) h CL/F: 9.80 (59.5) L.h−1 After a 20 mg dose of rivaroxaban: AUC12: 1764 (53.4) µg.h.L−1 AUC12, norm: 7267 (61.2) g.h.L−1 Cmax: 299 (45.6) µg.L−1 Cmax, norm: 1234 (49.8) g.L−1 tmax: 2 (1–4) h CL/F: 11.3 (53.4) L.h−1 |
Rivaroxaban has predictable PK and PD in subjects undergoing major orthopaedic surgery Body weight affected the volume of distribution of rivaroxaban in hip and knee studies; however, the effects of covariates on the PK of rivaroxaban were generally small |
| [72] |
Mean weight (±SD): 140.9 (±16.9) kg, with range 120–181 kg |
20 mg daily | Not reported |
Cmax (IQR): 222 (186–313) µg.L−1 |
There was no significant correlation between body weight and peak plasma concentration of rivaroxaban The peak rivaroxaban concentrations are largely unaffected in subjects weighing ≥120 kg |
| [73] |
Weight, kg (%): < 50 (3.3) 50–100 (73.2) 100–120 (14.1) > 120 (9.4) BMI, kg/m2 (%): < 18.5 (2.1) 18.5–25 (25.3) 25–30 (30.9) 30–35 (20.3) 35–40 (13.4) > 40 (8.1) |
Ranged from 10 to 30 mg once daily | One-compartment model |
After a 20 mg dose of rivaroxaban in patients with weight 125 kg:a AUC24: 2800 µg.h.L−1 Cmax: 305 µg.L−1 After a 20 mg dose of rivaroxaban in patients with normal weight:a AUC24: 3200 µg.h.L−1 Cmax: 360 µg.L−1 |
Creatinine clearance was the single best predictor of rivaroxaban exposure Weight alone was not the most significant factor influencing rivaroxaban PK To conclusively answer the question of whether rivaroxaban is as well tolerated and effective as warfarin at extremes of bodyweight, a large randomized controlled trial would be required; however, conducting a prospective analysis of patients weighing <50 kg or > 120 kg, or with a BMI > 40 kg/m2, would be challenging |
| [74] |
Median weight (range): 100 (73–178) kg BMI, kg/m2 [n (%)] 30–34.9 [79 (54)] 35–39.9 [38 (26)] ≥40 [29 (20)] |
20 mg once daily | Not reported | The median (min–max) of rivaroxaban concentration reported at a median time of 7 h after dose intake: 108 (20–453) µg.L−1 | DOAC use in obese patients treated for VTE at fixed doses led to concentrations similar to those of the general population in a high proportion of patients, without a noticed BMI effect |
| [75] |
Mean weight (±SD): 134.9 (±16.7) kg for the apixaban group 133.2 (±21.9) kg for the rivaroxaban group Mean BMI (±SD): 44.5 (±5.1) kg/m2 for the apixaban group 42.3 (±5.9) kg/m2 for the rivaroxaban group |
20 mg once daily | Not reported |
For subjects with weight from 120 to 130 kg:a Peak range of anti-Xa level: 200–380 µg.L−1 For subjects with weight > 130 to 150 kg:a Peak range of anti-Xa level: 320–350 µg.L−1 |
Plasma anti-Xa level measurements were predominantly within the therapeutic range in morbidly obese patients. In patients using rivaroxaban, no statistically significant relation between plasma anti-Xa levels and body weight was found |
| [76] |
BMI, kg/m2 [n (%)] 30–34.99 [3 (3.2)] 35–39.99 [12 (12.7)] ≥40 [54 (57.5)] ≥50 [16 (17)] ≥60 [9 (9.6)] |
20 mg once daily | Not reported |
In the AF cohort, values expressed as mean (5th–95th): Cmax: 214 (61–672) Ctrough: 59 (14–148) In the VTE cohort, values expressed as mean (5th–95th): Cmax: 220 (99–474) Ctrough: 98 (20–299) |
Subjects with high body weight or morbid obesity receiving factor Xa inhibitors for AF or VTE were unlikely to be underexposed to anticoagulant therapy when administered in standard doses |
| [77] |
Mean BMI (±SD) for the whole sample: 44.43 (±3.54) kg/m2 |
20 mg once daily | One-compartment model |
Values expressed as median (IQR): AUC24: 1204 (861–1390) µg.h.L−1 CL/F: 16.8 (14.4–23.3) L.h−1 Vd: 73.4 (63.5–97.9) L |
Subjects with extreme obesity receiving DOAC therapy for AF had a DOAC plasma concentration in the expected range. The inappropriate DOAC underdosing seems to be the only independent factor associated with the drugs’ plasma concentration out of the expected range |
BMI body mass index, PK pharmacokinetics, PD pharmacodynamics, IQR interquartile range, Cmax maximum plasma concentration, SD standard deviation, CL clearance, Vd volume of distribution, Ka absorption rate constant, AUC∞ area under the plasma concentration-time curve from time zero to infinity, tmax time needed to reach Cmax, t½ elimination half-life, Vz/F apparent volume of distribution during the terminal phase, SE standard error, CL/F apparent clearance, V/F apparent volume of distribution, Ctrough trough concentration, AUCx area under the plasma concentration time curve from time zero to x h, min minimum, max maximum, DOAC direct oral anticoagulant
aValues were visually extracted from study graphs