The pharmacokinetics of methadone and its metabolites in neonates, infants, and children

Abstract

Background: The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP).

Methods: Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics.

Results: A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) .

Conclusions: Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

Trial registration: ClinicalTrials.gov NCT00715988 NCT01094522.

Keywords: analgesia; modeling; opioid; pediatrics; pharmacodynamics; pharmacokinetics.

Conflict of interest statement

Disclosure

Conflict of Interest: Drs. Hammer and Anderson are Section Editors for the journal Pediatric Anesthesia. The other authors declare no conflict of interest

© 2014 John Wiley & Sons Ltd.

Figures

Figure 1

The racemate methadone 3-compartment PK model. V1 is the central compartment while V2 and V3 are peripheral compartments. Intercompartment clearances are expressed as Q2 and Q3. The EDDP metabolite is linked to the parent drug central compartment by a series of intermediate compartments (Rate MI). Formation clearance from the parent drug methadone to the EDDP metabolite was described using CL2M1 with subsequent formation clearance to EMDP by CL2M2. Formation clearance from parent to the EMDP metabolite was characterised by CLPM2. Clearance of EDDP and EMDP were described by parameters CLM1 and CLM2.

Figure 2

Neonatal enantiomer PK model. Dose has been split equally and enters central compartments for each enantiomer (V1R, V1S). The inter-compartment (QR, QS) clearances describe flow into peripheral compartments (V2R, V2S). EDDP metabolite formation clearances are CL2M1R, CL2M1S). FVM is a scale factor relating central volume to metabolite volume. Clearance of metabolites is described by CLM1R and CLM1S. The effect compartment is linked to the central compartment V1R by a rate constant Keo.

Figure 3

Visual predictive check for the methadone parent racemate model. All plots show median and 90% intervals (solid and dashed lines). Left hand plot shows all observed concentrations. Right hand plot shows prediction percentiles (10%, 50%, and 90%) for observations (lines with symbols) and predictions (lines) with 95% confidence intervals for prediction percentiles (gray shaded areas)

Figure 4

The upper panel shows individual predicted paracetamol clearances, standardised to a 70-kg person, from the NONMEM post hoc step, are plotted against postmenstrual age. No relationship between age and standardised clearance was found. Individual predicted paracetamol peripheral compartment volume of distribution (V2), standardised to a 70-kg person, from the NONMEM post hoc step, are plotted against postmenstrual age in the lower panel. The solid line represents the non-linear relation between V2 and age (p<0.005).

Figure 5

The upper panel shows a simulation for a 3.5 kg neonate given a methadone loading dose of 0.6 mg.kg−1 followed by a maintenance dose of 0.15 mg.kg−1 8 h. EDDP concentrations track parent drug concentrations. The methadone target concentration of 0.06 mg.L−1 is achieved rapidly when compared to the neonate given 0.2 mg.kg−1 8 hourly without a loading dose. A single dose of methadone 0.2 mg.kg−1 given for postoperative analgesia in a child is unlikely to achieve long duration of analgesia because concentrations are below 0.03 mg.kg−1 within 1.5 h (lower panel). Infusion may be a better option. A regimen comprising methadone bolus 0.15 mg.kg−1 followed by 0.15 mg.kg−1.h−1 for 1 h, 0.075 mg.kg−1.h−1 for 2 h and 0.025 mg.kg−1.h−1 for 6 h maintains a concentration of 0.06 mg.L−1. EDDP concentrations after this infusion regimen are also shown.