Pharmacokinetic Interactions of Nevirapine and Methadone and Guidelines for Use of Nevirapine to Treat Injection Drug Users

Clarke, Susan; Mulcahy, Fiona; Tjia, John; Reynolds, Helen; Gibbons, Sara; Barry, Michael; Back, David

doi:10.1086/322519

Cited by 98 publications

(43 citation statements)

References 11 publications

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“…Six subjects did not require any change in their methadone doses, despite significant reductions in methadone exposure. It has been suggested that a gradual detoxification from methadone occurs during NVP treatment (11). Our data strengthen this hypothesis because, after having increased their methadone doses, almost all of the patients still had lower methadone AUCs without any withdrawal symptoms.…”

Section: Discussionsupporting

confidence: 82%

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Nevirapine Significantly Reduces the Levels of Racemic Methadone and (R)-Methadone in Human Immunodeficiency Virus-Infected Patients

Stocker

Kruse

Kreckel

et al. 2004

Antimicrob Agents Chemother

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Methadone is metabolized by various isoforms of the cytochrome P450 family, which can be induced by many drugs, including nevirapine. The objective of the present study was to determine the effects of coadministration of nevirapine and methadone on the dose-adjusted areas under the concentration-time curves (AUCs) of racemic and (R)-methadone. Twenty-five human immunodeficiency virus-infected subjects taking stable single daily doses of racemic methadone or (R)-methadone were included in this prospective, single-crossover trial. At the baseline, nevirapine was either started as part of a new regimen containing two nucleoside reverse transcriptase inhibitors (NRTIs) or added to an ongoing NRTI regimen. Patients could increase their methadone doses if withdrawal symptoms developed. Twelve-hour pharmacokinetic profiles were obtained before and 28 days after the start of nevirapine treatment. The total concentrations of methadone and its inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in serum were determined by liquid chromatography-tandem mass spectrometry. Among the 20 evaluable patients, coadministration of nevirapine significantly decreased the mean dose-adjusted AUC of methadone by 41%. AUC reductions were similar for patients taking racemic methadone (37%; n ‫؍‬ 11) and (R)-methadone (44%; n ‫؍‬ 9). AUC changes ranged from mild increases in three patients to decreases of up to 70%. Fourteen of 20 patients required additional methadone due to withdrawal symptoms. However, the median dose increase was only 15%, which was less than that which would have been expected from the pharmacokinetic data. The AUC of EDDP increased significantly, by 35%. Methadone dose adjustments are justified when methadone is coadministered with nevirapine. Due to extensive variability, the adjustments must be tailored to the individual patient's needs.Human immunodeficiency virus (HIV)-infected patients who take methadone for the management of intravenous drug use frequently complain about symptoms of narcotic withdrawal after having started antiretroviral treatment containing nevirapine (NVP) (1,2,18,28,29). Symptoms rarely appear within the first few days, which suggests that the effect is caused by the induction of methadone metabolism by NVP (3, 11). One controlled trial involving eight patients has shown that concomitant NVP treatment substantially decreases the trough level and the area under the concentration-time curve (AUC) of methadone (11).Methadone is a racemic mixture of the pharmacodynamically inactive (S)-methadone and the active enantiomer (R)-methadone. It contains equal parts of both enantiomers. In some countries, methadone is frequently used in a formulation which contains only the active enantiomer, (R)-methadone. Both enantiomers are metabolized by members of the cytochrome P450 family. N-demethylation results in the formation of the inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) (4, 30).NVP, a nonnucleoside inhibitor of the HIV reverse transcriptase,...

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Section: Discussionsupporting

confidence: 82%

“…Symptoms rarely appear within the first few days, which suggests that the effect is caused by the induction of methadone metabolism by NVP (3,11). One controlled trial involving eight patients has shown that concomitant NVP treatment substantially decreases the trough level and the area under the concentration-time curve (AUC) of methadone (11).…”

mentioning

confidence: 99%

Nevirapine Significantly Reduces the Levels of Racemic Methadone and (R)-Methadone in Human Immunodeficiency Virus-Infected Patients

Stocker

Kruse

Kreckel

et al. 2004

Antimicrob Agents Chemother

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“…Efavirenz and nevirapine both were found to reduce the plasma concentrations of methadone, resulting in withdrawal symptoms [12][13][14], and, as a consequence, the methadone dose was increased when administered with efavirenz or nevirapine [12][13][14]. In contrast, saquinavir/ritonavir and lopinavir/ritonavir were also found to decrease methadone plasma concentrations of methadone with no significant withdrawal symptoms [15,16].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users

Hsyu¹,

Lillibridge²,

Daniels³

et al. 2006

Biopharm. Drug Dispos.

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“…Metadon tedavisi alan bir hastada kullanılmaları yoksunluk sendromları yaşanmasına neden olabilir. Nevirapin ile birlikte kullanımda metadona maruz kalmada %51 kadar azalma olduğu gösterilmiştir [47] . Nelfinavir ile birlikte kullanımda metadon klirensinde 1,7-1,8 kat artış olduğu görülmüştür [48] .…”

Section: Opiatlarunclassified

Recreational Drugs and Antiretrovirals: Is It Worth the World or Trivial?

Kara¹,

İnkaya²,

Demirkan³

et al. 2018

mjima

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According to the World Health Organization, 1 out of 200 people in the world was living with Human immunodeficiency virus (HIV)/Acquired immune deficiency syndrome (AIDS) in 2015 and four new HIV infections occurred each minute. A relationship between HIV infection and recreational drug use was evident from the very beginning of the HIV epidemic. Recreational drug use is more common in patients living with HIV/AIDS compared to others. Needle-sharing activities, psychological and cognitive consequences of the abused substances facilitate new infections. It is assumed that 1.650.000 individuals were infected with HIV out of 12.190.000 intravenous drug users in 158 countries in 2013. Cytochrome isoenzymes (i.e. CYP3A4, CYP2D6) are responsible from metabolism of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and chemokine receptor 5 inhibitors as well as recreational drugs. Recreational and antiretroviral drugs (ARV) may share the same metabolic pathways resulting in drug interactions. Drug interactions may occur because of pharmacodynamic and pharmacokinetic properties of the drugs. Induction of CYP3A4 (due to cocaine, tobacco, chronic alcohol use, etc.) may lead to decreased antiretroviral treatment (ART) effectiveness and increased risk of metabolites-related toxicity, however, inhibition of CYP3A4 (due to marijuana, acute alcohol use, etc.) may lead to increased side effects and drug toxicity. The feeling of moving away from reality and reduction of social pressure associated with recreational drugs mean all the world to the user. However, drug interaction risk makes it challenging for the physicians, when it is time for the selection of ARV. Therefore, physicians' awareness on Abstract Özİnsan immün yetmezlik virüsü ["Human immunodeficiency virus" (HIV)]/Edinsel immün yetmezlik sendromu ["Acquired immune deficiency syndrome" (AIDS)] ile yaşayan insan sayısı, 2015 yılı Dünya Sağlık Örgütü verilerine göre, dünya üzerinde yaşayan tüm insanların yaklaşık 1/200'ini oluşturmaktadır ve her dakika yaklaşık dört kişi HIV ile enfekte olmaktadır. İnsan immün yetmezlik virüsü/Edinsel immün yetmezlik sendromu salgını ilk ortaya çıktığı zamandan itibaren keyif verici madde kullanıcıları ile salgın arasında bir ilişki olduğu fark edilmiştir. Keyif verici maddelerin kullanımı HIV/AIDS ile yaşayan bireylerde genel nüfusa oranla daha fazla görülmektedir. Bu ilişkide enjektörlerin paylaşılması, kullanılan maddelerin neden olduğu psikolojik ve bilişsel durumun etkisi gibi faktörler rol oynamakta ve bulaşı kolaylaştırmaktadır. Tahminlere göre 2013 yılında 158 ülkede 12 milyon 190 bin damar içi madde kullanıcısı bulunmaktadır ve bu kişilerin yaklaşık 1.650.000'i HIV ile enfektedir. Sitokrom izoenzimleri (örneğin; CYP3A4, CYP2D6) antiretroviral tedavide (ART) kullanılan ilaçlardan non-nükleozit revers transkriptaz inhibitörleri, proteaz inhibitörleri, integraz inhibitörleri ve kemokin reseptör tip 5 inhibitörlerinin ve aynı zamanda keyif verici maddelerin metabolizasyonundan...

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Pharmacokinetic Interactions of Nevirapine and Methadone and Guidelines for Use of Nevirapine to Treat Injection Drug Users

Abstract: Administration of nevirapine to HIV-infected injection drug users who also receive methadone results in a significant reduction in methadone exposure after 7-10 days of therapy. Many patients require an increase in methadone dose to counteract this effect.

Cited by 98 publications

References 11 publications

Nevirapine Significantly Reduces the Levels of Racemic Methadone and (R)-Methadone in Human Immunodeficiency Virus-Infected Patients

Nevirapine Significantly Reduces the Levels of Racemic Methadone and (R)-Methadone in Human Immunodeficiency Virus-Infected Patients

Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users

Recreational Drugs and Antiretrovirals: Is It Worth the World or Trivial?

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