Table 2.
Comparison of (R)- and (S)-methadone pharmacokinetic parameters obtained from maximum a posteriori probability Bayesian predictions using the Full Basic population pharmacokinetics model in 59 methadone maintenance patients
| Parameter* | Rac-methadone | (R)-methadone | (S)-methadone | Significance (P-value)‡ |
|---|---|---|---|---|
| CL/F (l h−1) | 8.5 (7.6, 9.5) | 8.7 (7.9, 9.6) | 8.3 (7.3, 9.5) | 0.19 |
| Vc/F (l) | 112 (107, 118) | 145 (138, 152) | 94 (89, 99) | <0.0001 |
| k12 (h−1) | 0.57 (0.52, 0.61) | 0.54 (0.50, 0.58) | 0.55 (0.51, 0.59) | 0.16 |
| k21 (h−1) | 0.20 (0.19, 0.21) | 0.18 (0.16, 0.19) | 0.21 (0.20, 0.23) | <0.0001 |
| ka (h−1) | 0.59 (0.54, 0.63) | 0.55 (0.51, 0.60) | 0.62 (0.57, 0.67) | <0.0001 |
| tlag (h) | 0.45 (0.40, 0.49) | 0.53 (0.49, 0.58) | 0.39 (0.35, 0.43) | <0.0001 |
| t1/2α (h) | 0.83 (0.78, 0.88) | 0.90 (0.85, 0.95) | 0.82 (0.78, 0.87) | <0.0001 |
| t1/2β (h) | 39 (35, 43) | 51 (45, 57) | 31 (28, 35) | <0.0001 |
| Vdss/F (l) | 440 (398, 487) | 597 (538, 663) | 345 (312, 382) | <0.0001 |
| Vp/F (l) | 321 (283, 364) | 444 (390, 504) | 246 (217, 279) | <0.0001 |
| Vdβ/F (l) | 474 (428, 525) | 637 (573, 707) | 376 (339, 417) | <0.0001 |
| AUCτ (µg.hr. ml−1)† | 8.27 (7.39, 9.26) | 4.02 (3.64, 4.44) | 4.20 (3.69, 4.79) | 0.026 |
| MRT (h) | 52 (46, 58) | 69 (61, 77) | 41 (37, 47) | <0.0001 |
| Cmax (ng.ml−1)† | 494 (448, 544) | 225 (206, 246) | 268 (241, 298) | <0.0001 |
| Clast (ng.ml−1)† | 269 (236, 308) | 139 (124, 156) | 128 (109, 150) | 0.24 |
| Tmax (h) | 2.3 (2.2, 2.5) | 2.5 (2.3, 2.7) | 2.2 (2.1, 2.4) | <0.0001 |
Apparent oral clearance (CL/F), apparent volume of distribution of the central compartment (Vc/F), rate contrant for the transfer to (k12) and from (k21) the peripheral compartment, absorption rate constant (ka), absorption lag time (tlag), distribution (t1/2α) and terminal half-life (t1/2β), apparent volume of distribution at steady state (Vdss/F), and apparent volume of the peripheral compartment (Vp/F), apparent volume of distribution during the elimination phase (Vdβ/F), area under the plasma concentration–time curve during a steady-state interdosing interval (AUCô), mean residence time (MRT), time (Tmax) to reach maximum plasma concentration (Cmax).
AUCτ, Cmax and measured trough (end of study, Clast) plasma methadone concentrations were corrected to a 70 mg dose of rac-methadone and 35 mg for each enantiomer. Values are reported as geometric mean (95% confidence intervals) of the MAP Bayesian estimates of individual subject parameters assuming a log-normal parameter distribution.
Wilcoxon-matched pairs test for the comparison of (R)-methadone versus (S)-methadone.