Effect of Ritonavir/Saquinavir on Stereoselective Pharmacokinetics of Methadone: Results of AIDS Clinical Trials Group (ACTG) 401

Gerber, John G.; Rosenkranz, Susan L.; Segal, Yoninah; Aberg, Judith A.; D’Amico, Ronald; Mildvan, Donna; Gulick, Roy M.; Hughes, Valery; Flexner, Charles; Aweeka, Francesca; Hsu, Ann; Gál, J.

doi:10.1097/00042560-200106010-00010

Cited by 38 publications

(32 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Stein et al surveyed 42 HIV-infected patients on methadone maintenance and found that ongoing illicit drug use was associated with lower self-reported adherence but did not affect HIV-1 RNA suppression. 26 The interaction of methadone with highly active antiretroviral therapy may require higher doses of methadone [27][28][29][30] and make management more complex. One study of drug users in France found that the opioid-replacement drug buprenorphine had no effect on HIV-1 RNA suppression.…”

Section: Discussionmentioning

confidence: 99%

Alcohol Use and Incarceration Adversely Affect HIV-1 RNA Suppression Among Injection Drug Users Starting Antiretroviral Therapy

Palepu

Tyndall

et al. 2003

Journal of Urban Health: Bulletin of the New York Academy of Me

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Alcohol Use and Incarceration Adversely Affect HIV-1 RNA Suppression Among Injection Drug Users Starting Antiretroviral Therapy

Palepu

Tyndall

et al. 2003

Journal of Urban Health: Bulletin of the New York Academy of Me

View full text Add to dashboard Cite

show abstract

“…increases the oral clearance of methadone (Gerber et al, 2001), phenytoin (Lim et al, 2004), and ethinyl estradiol (Ouellet et al, 1998). Likewise, nelfinavir, also a PI, increases the oral clearance of ethinyl estradiol and zidovudine (Viracept package insert).…”

mentioning

confidence: 99%

Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

et al. 2007

View full text Add to dashboard Cite

ABSTRACT:Although many of the clinically significant drug interactions of the anti-human immunodeficiency virus (HIV) protease inhibitors (PIs) can be explained by their propensity to inactivate CYP3A enzymes, paradoxically these drugs cause (or lack) interactions with CYP3A substrates that cannot be explained by this mechanism (e.g., alprazolam). To better understand these paradoxical interactions (or lack thereof), we determined the cytochromes P450 and transporters induced by various concentrations (0-25 M) of two PIs, ritonavir and nelfinavir, and rifampin (positive control) in primary human hepatocytes. At 10 M, ritonavir and nelfinavir suppressed CYP3A4 activity but induced its transcripts and protein expression (19-and 12-and 12-and 6-fold, respectively; a >2-fold change over control was interpreted as induction). At 10 M, rifampin induced CYP3A4 transcripts, CYP3A protein, and activity by 23-, 12-, and 13-fold, respectively. The induction by rifampin of CYP3A activity was significantly correlated with its induction of CYP3A4 transcripts (r ‫؍‬ 0.96, p < 0.05) and CYP3A protein (r ‫؍‬ 0.89, p < 0.05). All three drugs (10 M) induced CYP2B6 activity by 2-to 4-fold, CYP2C8 and 2C9 activity by 2-to 4-fold and the transcripts of CYP2B6, 2C8, and 2C9 by >3-, 5-, and 3-fold, respectively. CYP2C19 and 1A2 activity and transcripts were modestly induced (2-fold), whereas, as expected, CYP2D6 was not induced by any of the drugs. Of the transporters studied, protease inhibitors moderately induced multidrug resistance 1 (ABCB1) and multidrug resistance-associated protein (ABCC1) transcripts but had no or minimal effect on the transcripts of breast cancer resistance protein (ABCG2), organic anion-transporting peptide (OATP) 1B1 (SLCO1B1), or OATP1B3 (SLCO1B3). On the basis of these data, we concluded that many of the paradoxical drug interactions (or lack thereof) with the PIs are metabolism-rather than transporter-based and are due to induction of CYP2B6 and 2C enzymes.

show abstract

“…Patients who took NFV or SQV-RTV with methadone also had greater decreases in the levels of the inactive isomer. Again, these patients did not experience opioid withdrawal (17,20). However, SQV-RTV elevated the fraction of unbound methadone by displacing it from protein binding.…”

Section: Discussionmentioning

confidence: 91%

“…Coadministration of indinavir did not lead to any change in methadone levels (8). Coadministration of NFV led to a decrease in methadone concentrations (20), and the AIDS Clinical Trials Group ACTG 401 trial found that there was a reduction in methadone levels when it was coadministered with saquinavir (SQV)-RTV (400/400 BID), the latter being a very strong inhibitor of CYP3A4 (17).…”

Section: Discussionmentioning

confidence: 99%

“…However, SQV-RTV elevated the fraction of unbound methadone by displacing it from protein binding. This effect, which may also occur with NFV-methadone coadministration, could be an alternative explanation for the absence of withdrawal symptoms (17). Two studies with patients taking methadone and lopinavir-RTV reported significant reductions in methadone AUCs (36% [10] and 26% [25]).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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,...

show abstract

Effect of Ritonavir/Saquinavir on Stereoselective Pharmacokinetics of Methadone: Results of AIDS Clinical Trials Group (ACTG) 401

Cited by 38 publications

References 22 publications

Alcohol Use and Incarceration Adversely Affect HIV-1 RNA Suppression Among Injection Drug Users Starting Antiretroviral Therapy

Alcohol Use and Incarceration Adversely Affect HIV-1 RNA Suppression Among Injection Drug Users Starting Antiretroviral Therapy

Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

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

Contact Info

Product

Resources

About