Methadone Disposition: Implementing Lessons Learned

Abstract

Keywordsclinical pharmacology (CPH), CYP2B6, drug abuse, drug-drug interactions, methadone, pharmacokinetics and drug metabolism Methadone is one of the most intensively studied and persistently misunderstood drugs in the contemporary therapeutic armamentarium. First synthesized in the 1930s, it was approved by the US Food and Drug Administration (FDA) in 1947 for analgesic and antitussive use. 1 Subsequently, in the mid-1960s, it was shown to be effective in treating opiate addiction and approved by the FDA in 1972 for this use. Methadone is effective in treating acute and chronic pain, is increasingly used in contemporary anesthesia practice owing to the long duration of effect, 2 is one of the two mainstays in treating opioid addiction, and is a major strategy for HIV/AIDS prevention. Methadone has the longest duration of effect of any approved opioid analgesic. It is used in infants, children, and adults and is administered by oral, intravenous, and other parenteral routes. Methadone is on the World Health Organization's List of Essential Medicines.Methadone was developed and approved long before the regulatory requirements for thorough pharmacokinetic characterizations and myriad in vitro and in vivo preclinical and clinical studies, which are required today for drug approvals. Hence, more than 2 decades ago, investigators began to fill in the missing information. There was reaction phenotyping of methadone metabolism to identify responsible cytochrome P450s (CYPs), and drug-drug interaction studies for both mechanistic discovery and practical clinical considerations. The ensuing evolution of data, concepts, and evidence regarding methadone disposition has been vast. Nevertheless, however, initial concepts and quickly adopted early "common knowledge," as well as practitioner guidelines and regulatory documents, which were later shown to be incorrect, have been remarkably resistant to change.This issue of the Journal of Clinical Pharmacology reports an important retrospective investigation, using the FDA database of drug-drug interaction studies, to provide information on the CYP isoform, which is responsible for methadone metabolism and exposure in humans. 3 The information is mechanistically important, clinically actionable, and relevant for new drug development. The investigators, from the FDA Office of Clinical Pharmacology in the Center for Drug Evaluation and Research, reviewed 29 drugdrug interaction studies between methadone and FDAapproved HIV/hepatitis C virus medications. Subjects in these studies were typically patients receiving daily methadone at steady state, and then the antiviral was introduced. Methadone plasma concentrations, before and after the antiviral, were then determined, either nonselectively or with enantioselective assays. In 16 of the 29 studies, the antivirals caused statistically significant changes in the methadone plasma concentrationtime area under the curve. Methadone exposure was reduced when coadministered with CYP2B6 inducers. In contrast, methadone exposure was either u...

Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients

“…The current simulations suggest that CYP2B6 may have a higher impact on methadone metabolism in neonates as tested in this study (age: median 2.6 days; n = 20), when compared to CYP3A. These findings correlate with an assessment made by Kharasch and Greenblatt . The data concluded that methadone is primarily metabolized by CYP2B6 and not CYP3A.…”

“…These findings correlate with an assessment made by Kharasch and Greenblatt. 41 The data concluded that methadone is primarily metabolized by CYP2B6 and not CYP3A. In addition, the observed improvement of PBPK model predictability with the revised data may reflect an age-independent expression of CYP2B6.…”

Toward precision prescribing for methadone: Determinants of methadone deposition

“…of opioid addiction by the United States Food and Drug Administration in 1972. Early in vitro studies concluded that methadone was mainly catalyzed by CYP3A4, although clinical data were lacking [47]. Indeed, CYP3A4 genetic polymorphisms were not predictive of methadone dose [48].…”

Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments

“… 53 Although CYP3A4 was long considered to be the major metabolizing enzyme of methadone, recent evidence has shown that CYP2B6, not CYP3A4, is predominantly responsible for methadone metabolism in humans. 54 Reported clearance ranges from 4 to 11 L/h, and correspondingly terminal half‐life ranges from 19 to 43 h. 52 Variability in the elimination half‐life among individuals can be attributed to variation in urinary pH and enzyme activity, and renal clearance of methadone only becomes quantitatively important when urine pH is less than 6. 55 On the other hand, one study reported the AUC ratio of methadone over EDDP in the first 24 h after oral dosing ranged from 5.9 to 44.6, indicating large interindividual variations due to different metabolic activity.…”