Table 2.
Population pharmacokinetic parameters of the base and final pharmacokinetic model for morphine and glucuronides in healthy volunteers and morbidly obese patients and results of the bootstrap analysis
| Parameter | Base model (RSE%) | Final model (RSE%) | Bootstrap (95% confidence interval) |
|---|---|---|---|
| Morphine a | |||
| CLF M3G (L/min) | 0.725 (4.0) | 0.748 (3.0) | 0.748 (0.706–0.797) |
| CLF M6G (L/min) | 0.128 (6.0) | ||
| CLF M6G = CLF M6G, 98.5 kg · (TBW/98.5)K | |||
| CLF M6G, 98.5 kg (L/min) | 0.129 (5.0) | 0.130 (0.119–0.140) | |
| K | −0.329 (36.0) | −0.310 (−0.534 to −0.125) | |
| V1M (L) | 3.96 (5.0) | 4.62 (9.0) | 4.66 (3.95–5.59) |
| V4M (L) | 5.76 (18.0) | 9.52 (33.0) | 9.91 (6.10–15.7) |
| V5M (L) | 101 (5.0) | ||
| V5M = V 98.5 kg · (TBW/98.5)L | |||
| V 98.5 kg (L) | 118 (9.0) | 117.5 (103.7–136.6) | |
| L | 0.483 (48.0) | 0.453 (0.112–0.859) | |
| Q2 (L/min) | 0.625 (7.0) | 0.814 (20.0) | 0.834 (0.598–1.16) |
| Q3 (L/min) | 1.27 (5.0) | 1.29 (5.0) | 1.28 (1.15–1.41) |
| Ktr (min−1) | 1.58 (9.0) | ||
| Ktr = Ktr98.5 kg · (TBW/98.5)M | |||
| Ktr98.5 kg (min-1) | 1.68 (9.0) | 1.71 (1.51–1.98) | |
| M | −0.701 (30.0) | −0.71 (−0.106 to 0.375) | |
| Ktr2 (min−1) | 0.151 (5.0) | 0.159 (7.0) | 0.158 (0.146–0.172) |
| Metabolites (M3G, M6G) | |||
| V M3G = V M6G (L) | 6.47 (7.0) | 5.29 (13.0) | 5.33 (4.28–6.52) |
| CLE M3G (L/min) | 0.131 (14.0) | ||
| CLE M3G = CLE M3G, 98.5 kg · (TBW/98.5)N | |||
| CLE M3G, 98.5 kg (L/min) | 0.134 (10.0) | 0.134 (0.110–0.155) | |
| N | –1.08 (22.0) | –1.06 (–1.53 to -0.60) | |
| CLE M6G (L/min) | 0.171 (15.0) | ||
| CLE M6G = CLE M6G, 98.5 kg · (TBW/98.5)O | |||
| CLE M6G, 98.5 kg (L/min) | 0.149 (10.0) | 0.154 (0.125–0.186) | |
| O | –1.03 (31.0) | –1.06 (–1.64 to –0.56) | |
| Inter-individual variability (%) | |||
| CLF M3G | 24.3 (12.0) | 20.8 (10.0) | 20.3 (16.8–23.4) |
| CLE M3G | 89.0 (19.0) | 65.9 (20.0) | 62.9 (41.9–86.1) |
| V M3G = V M6G | 32.3 (12.0) | 29.7 (12.0) | 29.2 (22.6–35.8) |
| Ktr2 | 37.7 (13.0) | 36.8 (13.0) | 35.9 (27.1–43.6) |
| Residual variability (%) | |||
| Healthy volunteers | |||
| Proportional error for morphine | 15.1 (16.0) | 14.0 (7.0) | 13.8 (12.0–15.7) |
| Proportional error for M3G | 18.0 (25.0) | 17.9 (12.0) | 18.0 (14.3–21.5) |
| Proportional error for M6G | 30.4 (19.0) | 29.5 (8.0) | 29.3 (24.2–32.8) |
| Morbidly obese patients | |||
| Proportional error for morphine | 37.3 (22.0) | 37.9 (11.0) | 37.1 (29.2–44.7) |
| Proportional error for M3G | 18.4 (17.0) | 17.1 (8.0) | 17.1 (14.9–19.1) |
| Proportional error for M6G | 32.8 (37.0) | 28.1 (9.0) | 26.5 (21.5–30.7) |
| OFV (−2LL) | 10,311.38 | 10,116.1 | 10,038.1 (9774.8–10,306.3) |
CL F formation clearance, CL E elimination clearance, Ktr transit rate constant, LL log likelihood, M3G morphine-3-glucuronide, M6G morphine-6-glucuronide, OFV objective function variable, Q inter-compartmental clearance from the central compartment of morphine to the peripheral compartments of morphine, RSE relative standard error, TBW total body weight, V volume of distribution (see also Fig. 1)
aFormation clearances are reported as absolute values, with CLF M3G and CLF M6G being 65% of total morphine clearance (see also Fig. 1)