Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users

Hsyu, Poe‐Hirr; Lillibridge, Jim; Daniels, Elaine; Kerr, Bradley M.

doi:10.1002/bdd.482

Cited by 12 publications

(16 citation statements)

References 17 publications

(22 reference statements)

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“…Several mechanisms discussed by the authors included nelfinavir being highly bound to AGP, and an inducer or inhibitor of both the CYP P450 enzyme system and P-gp. Similar results were found by Hsyu et al 100 and Marco et al 101 in studies of 14 and seven patients, respectively. Both recommended that a routine reduction of methadone dose was not necessary when administered with nelfinavir.…”

Section: Nelfinavirsupporting

confidence: 92%

See 1 more Smart Citation

Methadone: a review of drug-drug and pathophysiological interactions

Kapur

Hutson²,

Chibber

et al. 2011

Critical Reviews in Clinical Laboratory Sciences

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Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α1-acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone's fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

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Section: Nelfinavirsupporting

confidence: 92%

“…Suggested mechanisms include nelfinavir binding to AGP and both induction and inhibition of P-gp and the CYP P450 system. (78,(99)(100)(101) Nevirapine Decrease Six independent studies and case reports found withdrawal symptoms after nevirapine and methadone treatments. Nevirapine is a potent inducer of CYP P450 enzymes.…”

Section: Naloxonementioning

confidence: 98%

Methadone: a review of drug-drug and pathophysiological interactions

Kapur

Hutson²,

Chibber

et al. 2011

Critical Reviews in Clinical Laboratory Sciences

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“…In the presence of ritonavir, which is a very potent inhibitor of CYP3A, any possible effects of methadone on CYP3 metabolism of atazanavir are most likely to be superimposed. Previous studies with, for example, nelfinavir have not shown any influence of methadone on the metabolism of HIV protease inhibitors [9].…”

Section: Resultsmentioning

confidence: 82%

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Haberl

Moesch

Nisius

et al. 2009

Eur J Clin Pharmacol

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Objective The human immundeficiency virus (HIV) protease inhibitor atazanavir is often used in once-daily observed therapy of methadone substituted former opiate drug users. We performed a matched-pairs analysis on 24 patients (12 men/women) taking atazanavir/ritonavir 300/100 mg daily plus reverse transcriptase inhibitors, with (n=12) or without (n=12) methadone co-administration. Methods Twenty-four-hour pharmacokinetic profiles of atazanavir/ritonavir were assessed at steady-state and measured by liquid chromatography-tandem mass spectrometry. The geometric mean (GM, t test) minimum and maximum plasma drug concentrations (C min , C max ), area under the concentration-time curve (AUC), and total clearance (CL total ) were compared between the groups of pairs, which were matched for age, sex, weight, and ethnicity. Results The GM [90% confidence interval (CI)] of the atazanavir C min , C max , and AUC of patients taking the methadone oral solution at doses of 20-175 mg/day simultaneously with antiretroviral therapy were impaired compared to patients not taking methadone oral solution: C min =315 (range 197-448) vs. 519 (279-793) ng/mL [GM ratio (GMR)=0.61, p=0.229]; C max =1714 (1238-2262) vs. 3190 (2412-4076) ng/mL (GMR=0.54, p=0.018); AUC=21,987 (15,870-29,327) vs. 35,572 (26,211-46,728) ng h/mL (GMR=0.62, p=0.074). Methadone dose, which is proportional to the amount of methadone oral solution (10 mg/mL), was significantly correlated to atazanavir C max (r 2 =0.40, p=0.001) and AUC (r 2 =0.32, p=0.006). Ritonavir pharmacokinetics was similar between the groups with C min , C max , and AUC GMR of 1.01, 0.80, and 0.96, respectively. Conclusion The partial decrease in atazanavir plasma concentrations in patients concomitantly taking racemic methadone oral solution in this daily observed therapy setting deserves further attention, and therapeutic drug monitoring should be considered.

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“…In patients on daily methadone, nelfinavir 1250 mg twice daily reduced the AUC of oral RS-methadone by 38% (McCance-Katz et al, 2004), and the AUC of oral R- and S-methadone by 43 and 51%, respectively (Hsyu et al, 2006). This is essentially identical to the 40 and 49% reduction of single-dose oral methadone enantiomers in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Methadone-antiretroviral drug interactions are common, and are typically attributed to CYP3A4, although the actual mechanism(s) remain largely unknown (Bruce et al, 2006; Maas et al, 2006; Robertson et al, 2007). The HIV protease inhibitor nelfinavir decreases plasma concentrations of both S- and R-methadone (the active enantiomer) in half, yet there are generally no withdrawal symptoms or need for dose adjustment in patients on daily methadone (Hsyu et al, 2006; McCance-Katz et al, 2004), with some exception (Brown et al, 2006). Nelfinavir is a well-known inhibitor of CYP3A activity, yet the apparent paradox of nelfinavir induction of methadone elimination, despite CYP3A inhibition, has never been addressed.…”

Section: Introductionmentioning

confidence: 99%

Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity

Kharasch

Walker

Whittington

et al. 2009

Drug and Alcohol Dependence

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Background Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. Methods Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). Results Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50% and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. Conclusions Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.

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Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users

Abstract: Although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. A routine reduction of methadone dose is not recommended when coadministered with nelfinavir.

Cited by 12 publications

References 17 publications

Methadone: a review of drug-drug and pathophysiological interactions

Methadone: a review of drug-drug and pathophysiological interactions

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity

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