ritonavir and Substance-Withdrawal-Syndrome

We aimed to assess the effect of coadministration and withdrawal of a potent cytochrome P450 3A (CYP3A) inhibitor (ritonavir) and a potent CYP3A inducer (St John's wort) on CYP3A enzyme activity in an open, fixed-sequence study design. We investigated the pharmacokinetics of midazolam: (i) at baseline, (ii) after a single dose of either St John's wort or ritonavir (each n = 6), (iii) after 14 days of coadministration of ritonavir (300 mg b.i.d.) and St John's wort (300 mg t.i.d.), and (iv) at 2 days after cessation of both St John's wort and ritonavir. Combined administration of inducer and inhibitor resulted in a predominance of enzyme inhibition: coadministration of St John's wort and ritonavir with intravenous administration of midazolam resulted in an increase in the area under the plasma concentration-time curve (AUC)(0-8 h) of midazolam to 180% of baseline value, whereas with orally administered midazolam, the AUC(0-6 h) increased to 412% of baseline value (P < 0.05 for each). After cessation of the coadministered drugs, the AUC(0-6 h) of orally administered midazolam decreased to 6% of the level observed during combined administration, and the AUC(0-8 h) of intravenously administered midazolam decreased to 33% of the values observed during combined administration (P < 0.001 for each). Induction may be unmasked after the withdrawal of a combination of a potent CYP3A inhibitor and a potent CYP3A inducer, leading to substantial drops in drug exposure of CYP3A substrates. This may require substantial dose adjustments, particularly of orally administered drugs.

Topics: Administration, Oral; Adult; Area Under Curve; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Female; HIV Protease Inhibitors; Humans; Hypericum; Infusions, Intravenous; Male; Midazolam; Plant Extracts; Ritonavir; Substance Withdrawal Syndrome; Young Adult

A study was designed to determine the interactions, both clinical and pharmacokinetic, between methadone and lopinavir-ritonavir. Results demonstrated a 36% reduction in the methadone area under the plasma concentration-time curve after the introduction of lopinavir-ritonavir, with no coincident symptoms of opioid withdrawal and no requirement for methadone dose adjustment.

Topics: Adult; Analgesics, Opioid; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Methadone; Opioid-Related Disorders; Pyrimidinones; Ritonavir; RNA, Viral; Substance Withdrawal Syndrome

Topics: Adolescent; AIDS Dementia Complex; Antipsychotic Agents; Brain; Citalopram; Cytochrome P-450 CYP2D6 Inhibitors; Delirium; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Risperidone; Ritonavir; Selective Serotonin Reuptake Inhibitors; Sertraline; Substance Withdrawal Syndrome

This study examines the pharmacokinetic/pharmacodynamic interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV disease, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone, an opiate frequently used in substance abuse pharmacotherapy for opioid (heroin)-dependent injection drug users, many of whom are infected with HIV. L/R was associated with significant reductions in the methadone area under the concentration-time curve (P<.001), maximum concentration (P<.001), and minimum concentration (P<.001), as well as increased methadone oral clearance (P<.001) and increased opiate withdrawal symptoms (P=.013), whereas ritonavir use alone modestly and nonsignificantly increased methadone concentrations. Lopinavir is a potent inducer of methadone metabolism, and treatment with L/R requires clinical monitoring and increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Methadone; Narcotics; Opioid-Related Disorders; Pyrimidinones; Ritonavir; Substance Withdrawal Syndrome

Topics: Anti-HIV Agents; Drug Interactions; Female; Humans; Indinavir; Male; Methadone; Narcotics; Nevirapine; Ritonavir; Stavudine; Substance Withdrawal Syndrome

Combination antiretroviral therapy including protease inhibitors such as ritonavir has added significant potency to therapy for human immunodeficiency viral (HIV) infection as well as substantial drug-drug interactions. Methadone metabolism is affected by cytochrome P450 (CYP) 3A4 inhibitors or inducers. Because ritonavir can induce CYP3A, it can decrease methadone plasma levels. An HIV-infected patient receiving methadone maintenance experienced withdrawal symptoms after ritonavir, saquinavir, and stavudine were added to his regimen; the most likely cause was ritonavir.

Topics: Analgesics, Opioid; Anti-HIV Agents; Diagnosis, Differential; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Male; Methadone; Middle Aged; Ritonavir; Saquinavir; Stavudine; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Adult; Analgesics, Opioid; HIV Protease Inhibitors; Humans; Male; Methadone; Ritonavir; Substance Withdrawal Syndrome