Within- and between- subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects.
OBJECTIVE
To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state.


METHODS
Six non-holder subjects were studied on three occasions at 7-16 day intervals; doses (20-170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10-12 times over a 24-h inter-dosing interval. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value.


RESULTS
Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2-12.8 for pharmacodynamic measures, and 1.3-7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged < or = 2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging < or = 2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance.


CONCLUSIONS
Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1-2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population.
Hanna
Julia
J
Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, Australia.
Foster
David J R
DJ
Salter
Amy
A
Somogyi
Andrew A
AA
White
Jason M
JM
Bochner
Felix
F
D000328:Adult; D019540:Area Under Curve; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008691:Methadone / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009294:Narcotics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009293:Opioid-Related Disorders / Q000534:rehabilitation*; D011680:Pupil / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D011795:Surveys and Questionnaires
D009294:Narcotics; D008691:Methadone