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Ten HIV-positive patients on stable methadonetherapy were started on the NNRTI nevirapine, a CYP3A4 inducer. After 7 days, the methadone AUC was reduced by 63%, resulting in opioid withdrawal symptoms in 9 of 10 patients, and requiring an average methadone dose increase of 20%. Increasing the nevirapine dose from 200 to 400 mg daily did not further decrease the methadone AUC
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Arroyo E, Valenzuela B, Portilla J, et al.: Pharmacokinetics of methadone in human-immunodeficiency-virus-infected patients receiving nevirapine once daily. Eur J Clin Pharmacol 2007, 63:669-675. Ten HIV-positive patients on stable methadonetherapy were started on the NNRTI nevirapine, a CYP3A4 inducer. After 7 days, the methadone AUC was reduced by 63%, resulting in opioid withdrawal symptoms in 9 of 10 patients, and requiring an average methadone dose increase of 20%. Increasing the nevirapine dose from 200 to 400 mg daily did not further decrease the methadone AUC.
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Sixteen HIV-negative methadone maintenance patients received etravirine, a CYP3A4 inducer and CYP2C19 inhibitor, for 14 days. Methadone AUC increased slightly without adverse events. Although no opioid withdrawal symptoms were observed during the 14-day study, they may occur later after CYP2C19 induction takes effect. This study was conducted by Tibotec, the pharmaceutical company that developed etravirine
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Scholler-Gyure M, van den Brink W, Kakuda TN, et al.: Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers. J Clin Pharmacol 2008, 48:322-329. Sixteen HIV-negative methadone maintenance patients received etravirine, a CYP3A4 inducer and CYP2C19 inhibitor, for 14 days. Methadone AUC increased slightly without adverse events. Although no opioid withdrawal symptoms were observed during the 14-day study, they may occur later after CYP2C19 induction takes effect. This study was conducted by Tibotec, the pharmaceutical company that developed etravirine.
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Withdrawal was documented in methadone-maintained participants receiving standard clinical doses of lopinavir/ritonavir
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This case report describes how after the methadone dose was increased to compensate for induction of methadone metabolism by lopinavir/ ritonavir, when the opinavir/ritonavir was stopped the patient had a cardiac arrhythmia due to excessive methadone levels
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This study showed that despite substantial and significant decreases in methadone plasma concentrations, withdrawal did not occur, underscoring the need to monitor patients individually for adverse drug-drug interactions even when a drug interaction might be expected
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McCance-Katz EF, Rainey PM, Smith P, et al.: Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and nelfinavir. Am J Addict 2004, 13:163-180. This study showed that despite substantial and significant decreases in methadone plasma concentrations, withdrawal did not occur, underscoring the need to monitor patients individually for adverse drug-drug interactions even when a drug interaction might be expected.
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healthy volunteers, the PI ritonavir immediately increased renal clearance of methadone 40% to 50%, resulting in decreased methadone plasma concentrations even though ritonavir also inhibited CYP3A4 by 70%
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Kharasch ED, Bedynek PS, Park S, et al.: Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics:I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther 2008, 84:497-505. In healthy volunteers, the PI ritonavir immediately increased renal clearance of methadone 40% to 50%, resulting in decreased methadone plasma concentrations even though ritonavir also inhibited CYP3A4 by 70%.
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February 10 (Epub ahead of print). This study showed that in addition to its known inhibition of CYP3A and 2D6, tipranavir/ritonavir induced CYP2C19 (which is known to metabolize methadone) and intestinal p-glycoprotein
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Dumond JB, Vourvahis M, Rezk NL, et al.: A phenotypegenotypeapproach to predicting CYP450 and p-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther 2010 February 10 (Epub ahead of print). This study showed that in addition to its known inhibition of CYP3A and 2D6, tipranavir/ritonavir induced CYP2C19 (which is known to metabolize methadone) and intestinal p-glycoprotein.
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Clin Pharmacol Ther
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Dumond, J.B.1
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Effect of saquinavir/ ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate dependent HIV-negative patients on stable methadone therapy
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Thirteen HIVnegative methadone maintenance patients received saquinavir/ ritonavir for 14 days. R-methadone AUC decreased only slightly (19%), and no opioid withdrawal or excess was observed
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Jamois C, Smith P, Morrison R, et al.: Effect of saquinavir/ ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate dependent HIV-negative patients on stable methadone therapy. Addict Biol 2009, 14:321-327. Thirteen HIVnegative methadone maintenance patients received saquinavir/ ritonavir for 14 days. R-methadone AUC decreased only slightly (19%), and no opioid withdrawal or excess was observed.
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Twenty-six HIV-negative methadone maintenance patients received fosamprenavir-ritonavir for 14 days. This reduced R-methadone AUC only slightly (18%), and no opioid withdrawal or excess was observed
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Cao YJ, Smith PF, Wire MB, et al.: Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with fosamprenavir-ritonavir in opioid-dependent subjects. Pharmacotherapy 2008, 28:863-874. Twenty-six HIV-negative methadone maintenance patients received fosamprenavir-ritonavir for 14 days. This reduced R-methadone AUC only slightly (18%), and no opioid withdrawal or excess was observed.
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Twenty HIV-negative patients on buprenorphine maintenance received delavirdine for 7 days or efavirenz for 15 days. Delavirdine increased and efavirenz decreased buprenorphine AUC, but no opioid withdrawal or adverse symptoms were observed. Buprenorphine did not alter antiretroviral pharmacokinetics
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McCance-Katz EF, Moody DE, Morse G, et al.: Interactions between buprenorphine and antiretrovirals I: Non-nucleoside reverse transcriptase inhibitors I: efavirenz and delavirdine. Clin Infect Dis 2006, 43(Suppl 4):S224-S234. Twenty HIV-negative patients on buprenorphine maintenance received delavirdine for 7 days or efavirenz for 15 days. Delavirdine increased and efavirenz decreased buprenorphine AUC, but no opioid withdrawal or adverse symptoms were observed. Buprenorphine did not alter antiretroviral pharmacokinetics.
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Clin Infect Dis
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McCance-Katz, E.F.1
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Lack of clinically significant drug interactions between nevirapine and buprenorphine
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Seven HIV-negative patients on buprenorphine maintenance received nevirapine for 15 days. Buprenorphine AUC decreased only slightly, and no opioid withdrawal symptoms or excess were observed. Nevirapine levels were also not significantly lower than among HIV-positive control subjects receiving nevirapine and not buprenorphine
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McCance-Katz EF, Moody DE, Morse E, et al.: Lack of clinically significant drug interactions between nevirapine and buprenorphine. Am J Addict 2010, 19:30-37. Seven HIV-negative patients on buprenorphine maintenance received nevirapine for 15 days. Buprenorphine AUC decreased only slightly, and no opioid withdrawal symptoms or excess were observed. Nevirapine levels were also not significantly lower than among HIV-positive control subjects receiving nevirapine and not buprenorphine.
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Am J Addict
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McCance-Katz, E.F.1
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Interactions between buprenorphine and antiretrovirals II: Protease inhibitors, nelfinavir, lopinavir/ritonavir, or ritonavir
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Unlike for methadone, buprenorphine is not associated with opiate withdrawal when coadministered with standard clinical doses of these PIs
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McCance-Katz EF, Moody DE, Morse G, et al.: Interactions between buprenorphine and antiretrovirals II: Protease inhibitors, nelfinavir, lopinavir/ritonavir, or ritonavir. Clin Infect Dis 2006, 43(Suppl 4):S235-S246. Unlike for methadone, buprenorphine is not associated with opiate withdrawal when coadministered with standard clinical doses of these PIs.
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Clin Infect Dis
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Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ ritonavir in HIV-negative subjects chronically receiving buprenorphine/ naloxone
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Ten HIV-negative patients on buprenorphine maintenance received tipranavir/naloxone for 7 days or more (until steady state was achieved). Buprenorphine AUC did not changesignificantly. However, tipranavir AUC decreased 19% compared to historical control subjects receiving tipranavir/ritonavir alone
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Bruce RD, Altice FL, Moody DE, et al.: Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ ritonavir in HIV-negative subjects chronically receiving buprenorphine/ naloxone. Drug Alcohol Depend 2009, 105:234-239.Ten HIV-negative patients on buprenorphine maintenance received tipranavir/naloxone for 7 days or more (until steady state was achieved). Buprenorphine AUC did not changesignificantly. However, tipranavir AUC decreased 19% compared to historical control subjects receiving tipranavir/ritonavir alone.
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Interaction between buprenorphine and atazanavir or atazanavir/ritonavir
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