Utility of Methadone:Metabolite Ratio as Marker of Methadone Metabolism During Methadone Initiation in Pregnancy.

Abstract

The methadone:metabolite ratio (MMR) is a laboratory value assessed pre-dose to discriminate between individuals who are rapid or slow metabolizers. It is a proposed alternative to peak:trough serum methadone ratios to assess the impact of individual genetics on methadone metabolism to guide dosing frequency of methadone in adults. Pregnancy represents a state of dynamic metabolism of many drugs, including methadone, but there is little study of the MMR in pregnancy. We aimed to (1) assess how well MMR assessed during methadone initiation in pregnancy correlates with the gold standard of assessing metabolism (peak:trough ratio which requires 2 blood draws), (2) describe MMR as assessed during initiation of methadone across gestation to see if it reflected altered metabolism in pregnancy, and (3) determine whether differences in MMR correlated with measures of therapeutic effect, which would suggest it is a potentially useful tool to guide dosing regimens of methadone in pregnancy. This is a prospective study of pregnant patients with singleton gestation admitted for methadone initiation starting with a dose of 30 mg and increasing by 10 mg every 4 hours as needed based on withdrawal symptoms, with an increase in the daily dose the next day. Plasma samples of methadone and the metabolite EDDP were obtained pre-morning dose and 4 hours post-dose. MMR was evaluated both as a continuous variable and categorical: MMR<5: ultra-rapid metabolizer, MMR 5-11: extensive metabolizer, MMR 12-16: intermediate metabolizer, MMR≥16 ultra-slow metabolizer. Additional endpoints of Clinical Opioid Withdrawal Scale (COWS) and pupil dilation were assessed. Multivariable generalized estimating equations used for analyses. From March 2023 to May 2024 31 patients with 107 samples available were included. MMRtrough increased with methadone dose the prior 24 hours [0.01 (0.01, 0.02), P<0.001] and decreased with advancing trimester of admission [-2.95 (-5.00, -0.90), P=0.005 for second vs. first trimester and -2.78 (-4.98, -0.58), P=0.01 for third vs. first trimester]. A greater proportion of results reflected an ultra-rapid metabolizing state in the second and third trimester compared with the first (77% and 71% vs. 23%, P<0.001). MMR was highly correlated with log-corrected methadone peak:trough throughout gestation, regardless of trimester [B coefficient -3.36 (-5.65 to -1.06), P=0.004]. Regarding clinical effects-pupil dilation was significantly associated with methadone dose, with an expected pupilar constriction associated with increasing methadone dose [-0.55 (-0.75, -0.34) P<0.001]. There was significantly reduced pupillary constriction (relative larger post-dose diameter) identified in the third trimester versus first [adjusted mean difference 0.67 (0.20, 1.13)]. There was no significant association between MMR and pupillary change. MMR was associated with time needed to achieve a stable dose, with those who were extensive metabolizers requiring greater time to stable dose compared with ultra-rapid metabolizers [mean difference 3.37 (0.61-6.13) d, P=0.02]. Although MMR has historically been used to reflect genetic variants impacting methadone metabolism, in pregnancy it reflects the increased metabolism with advancing gestation and is associated with clinical/therapeutic effect. MMR may be a useful marker to guide methadone dosing protocols in pregnancy to optimize therapeutic effect.