rifampin and Lopinavir Interactions

Interactions between rifampin and Lopinavir (lopinavir)

rifampin and lopinavir (Major Drug-Drug)

CONTRAINDICATED: Coadministration with rifampin may significantly decrease the plasma concentrations of lopinavir even in the presence of low-dose ritonavir as a pharmacokinetic booster. Rifampin is a potent inducer of CYP450 3A4 and may override some of the inhibiting effects of ritonavir, resulting in accelerated clearance of both lopinavir and ritonavir. In a study of 22 healthy, HIV-negative subjects, administration of lopinavir-ritonavir (400 mg-100 mg capsule twice a day for 20 days) in combination with rifampin (600 mg once a day for 10 days) decreased lopinavir peak plasma concentration (Cmin), systemic exposure (AUC) and trough plasma concentration (Cmin) by 55%, 75% and 99%, respectively, compared to administration of lopinavir-ritonavir alone. In another study, the same dosage of rifampin reduced the AUC and Cmin of lopinavir by 16% and 57%, respectively, in 10 healthy subjects when coadministered with lopinavir-ritonavir at a dosage of 800 mg-200 mg twice a day compared to lopinavir-ritonavir alone at 400 mg-100 mg twice a day. No significant changes in lopinavir pharmacokinetics were observed when lopinavir-ritonavir was administered at 400 mg-400 mg (400 mg-100 mg capsule + ritonavir 300 mg) twice a day with rifampin compared to lopinavir-ritonavir alone at 400 mg-100 mg twice a day. However, higher dosages of lopinavir-ritonavir coadministered with rifampin may be associated with an increased risk of liver and gastrointestinal toxicity. In the study, 28% of the subjects experienced a grade 2 or greater increase in ALT and AST, of which 21% prematurely discontinued study per protocol. It was not possible to determine whether the frequency or magnitude of the liver enzyme elevations observed is higher than what would be seen with rifampin alone.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, alternative antimycobacterial agents should be considered in patients already receiving effective antiretroviral therapy with lopinavir-ritonavir. For treatment of latent tuberculosis (TB) infection, a nine-month regimen of isoniazid may be considered if feasible. For treatment of HIV-related TB, a regimen that includes rifabutin is generally preferred, as rifabutin appears to be as effective as rifampin but is a much less potent inducer of CYP450 3A4. Nonrifamycin-containing regimens may be suboptimal (higher mortality rates; higher rates of treatment failure and relapse; increased adverse effects; longer treatment duration) and are usually not recommended for HIV-related TB except in patients who are intolerant of rifamycins or infected with a rifamycin-resistant isolate. In patients who have not begun antiretroviral therapy at the time TB treatment is initiated, clinicians may also consider using rifampin and postponing antiretroviral therapy. With early HIV disease, it may be reasonable to monitor CD4 cell count and postpone antiretroviral therapy until TB treatment is complete, since there is low risk of HIV disease progression or death during this period. However, the optimal time for starting antiretroviral therapy should be individualized based on initial response to TB treatment and occurrence of side effects. In patients with low CD4 cell counts, clinicians may consider delaying antiretroviral therapy until after the first one or two months of TB therapy, as side effects are common during this multi-drug phase of TB treatment and may overlap with those of antiretroviral medications. Moreover, delaying antiretroviral therapy may ameliorate adherence issues and decrease the frequency and severity of paradoxical reactions (i.e., immune restoration syndromes resembling exacerbation of TB that sometimes occur after initiation of antituberculosis treatment in patients receiving potent antiretroviral therapy). Rifabutin can be substituted approximately 2 weeks before the planned initiation of antiretroviral therapy to allow time for rifampin's enzyme induction effects to wane. In general, treatment of TB in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of HIV-related tuberculosis should be consulted, and TB and HIV care providers should work in close coordination throughout treatment.