Table 2.
Population pharmacokinetic parameters of the base and final pharmacokinetic models for acetaminophen in 20 morbidly obese patients and 8 non-obese patients, and results from bootstrap analysis of the final model (996/1000 resamples successful)
| Parameter | Base model (RSE %) | Final model (RSE %) | Bootstrap (95 % confidence interval) |
|---|---|---|---|
| V acetaminophen [L] | 64.4 (5.3) | – | |
| V acetaminophen = V 65.2 kg × [LBW/65.2]S | |||
| V 65.2 kg | – | 67.2 (2.8) | 67.3 (64.1–70.9) |
| S | – | 0.90 (17.4) | 0.90 (0.59–1.22) |
| CLgluc [L/min] | 0.209 (7.5) | – | |
| CLgluc = CLgluc,65.2 kg × [LBW/65.2]T | |||
| CLgluc,65.2 kg | – | 0.224 (5) | 0.223 (0.202–0.246) |
| T | – | 1.33 (17) | 1.34 (0.85–1.75) |
| CLsulph [L/min] | 0.062 (7) | – | |
| CLsulph = CLsulph,65.2 kg × [LBW/65.2]U | |||
| CLsulph,65.2 kg | – | 0.065 (6) | 0.065 (0.057–0.073) |
| U | – | 0.92 (19.9) | 0.92 (0.55–1.34) |
| CLCYP2E1 [L/min] | 0.018 (14.8) | – | |
| CLCYP2E1 = CLCYP2E1,65.2 kg × [LBW/65.2]W | |||
| CLCYP2E1,65.2 kg | – | 0.021 (14.6) | 0.021 (0.015–0.026) |
| W | – | 0.67 (27.4) | 0.71 (0.21–1.38) |
| V glucuronide [L] | 29.7 (5.6) | – | |
| V glucuronide = V 130.9 kg × [TBW/130.9]X | |||
| V 130.9 kg | – | 32.3 (4.1) | 32.4 (29.7–34.9) |
| X | – | 0.55 (23.3) | 0.56 (0.27–0.83) |
| V sulphate,central = V sulphate,peripheral [L] | 5.66 FIX | 5.66 FIX | 5.66 FIX |
| Q [L/min] | 0.346 (14.2) | 0.339 (19.6) | 0.338 (0.245–0.511) |
| V cysteine and mercapturate [L] | 15.6 FIX | 15.6 FIX | 15.6 FIX |
| KtrCYP2E1 [min−1] | 0.0063 (11.7)a | – | |
| KtrCYP2E1 = Ktr65.2 kg × [LBW/65.2]Y | |||
| Ktr65.2 kg | – | 0.0057 (12.2)b | 0.0058 (0.0047–0.0079) |
| Y | – | 1.1 (33) | 1.12 (0.19–1.79) |
| Ktrgluc [min−1] | 0.094 (11) | 0.095 (11.5)c | 0.095 (0.076–0.121) |
| CLE gluc [L/min] | 0.211 (6.9) | – | |
| CLE gluc = CLE gluc,65.2 kg × [LBW/65.2]Z | |||
| CLE gluc,65.2 kg | – | 0.222 (6.3) | 0.221 (0.198–0.251) |
| Z | – | 0.89 (31) | 0.90 (0.26–1.50) |
| CLE sulph [L/min] | 0.097 (3.3) | 0.096 (3.4) | 0.096 (0.090–0.102) |
| CLE cys and mercap [L/min] | 0.294 (13.2) | 0.329 (14.5) | 0.324 (0.226–0.423) |
| Inter-individual variability [%] | |||
| V acetaminophen | 26.4 (39.4) | 14.4 (32.1) | 13.9 (9.6–17.5) |
| CLgluc | 36.6 (31.9) | 21.8 (32.5) | 21.0 (13.6–27.8) |
| CLsulph | 33.6 (30) | 24.3 (30.1) | 23.0 (16.1–30.7) |
| CLCYP2E1 | 58.6 (46.1) | 23.3 (37.4) | 21.4 (12.0–29.8) |
| V glucuronide | 28.2 (30) | 22.5 (29.5) | 21.1 (13.1–27.5) |
| CLE gluc | 35.4 (32) | 30.3 (23.9) | 28.3 (20.0–36.1) |
| CLE cys and mercap | 52 (34.1) | 34.9 (33.4) | 34.0 (21.8–49.2) |
| Residual variability [%] | |||
| Proportional error for acetaminophen | 17.2 (26.9) | 17.1 (27) | 16.7 (13.4–21.6) |
| Proportional error for glucuronide | 19.6 (27.5) | 19.7 (27.9) | 19.3 (14.7–25.0) |
| Proportional error for sulphate | 18.4 (20.3) | 18.5 (20.6) | 18.3 (15.1–22.0) |
| Proportional error for cys and mercap | 24.8 (9.2) | 25.0 (8.7) | 24.9 (22.7–27.0) |
| OFV [− 2LL] | −2937.3 | −3085.4 | −3147.2 (−3592.4 to −2759.2) |
CL gluc glucuronidation clearance, CL sulp sulphation clearance, CL CYP2E1 CYP2E1-mediated clearance, CL E gluc glucuronide elimination clearance, CL E sulph sulphate elimination clearance, CL E cys&mercap cysteine & mercapturate elimination clearance, Ktr CYP2E1 CYP2E1 transit compartment rate constant, Ktr gluc glucuronide transit compartment rate constant, LBW lean body weight, OFV objective function value, Q inter-compartmental clearance of acetaminophen sulphate between the central and peripheral compartment, TBW total body weight, V volume of distribution, -2LL -2 log likelihood (see also Fig. 1)
aThe mean transit time was 158.7 min
bThe mean transit time was 175.4 min
cThe mean transit time was 10.5 min