Pharmacokinetics and Safety of Tenofovir Disoproxil Fumarate
Pharmacokinetics and Safety of Tenofovir Disoproxil Fumarate
Objective: Lopinavir/ritonavir (LPV/r) and tenofovir disoproxil fumarate (TDF) are frequently used antiretrovirals. A pharmacokinetic study in healthy volunteers was conducted to assess the potential for a drug interaction between these agents.
Methods: This was a 36-day, multiple-dose, drug-drug interaction study of TDF and lopinavir/ritonavir (LPV/r). Subjects received TDF alone for 7 days, followed by 14 days each of TDF plus LPV/r and LPV/r alone in a randomized manner. Pharmacokinetic assessments were performed over 24 hours on days 7, 21, and 35. LPV/r and tenofovir plasma/serum concentrations were measured by high-performance liquid chromatography/mass spectometry (MS)/MS. Geometric mean ratios and 90% confidence intervals of pharmacokinetic parameters for tenofovir, LPV, and ritonavir (RTV) were estimated using analysis of variance and compared with the no-effect criterion for pharmacokinetic equivalence.
Results: Tenofovir measurements with an area under the concentration-time curve over the dosing interval, maximum concentration, and concentration at the end of the dosing interval (Cτ) were 32%, 15%, and 51% higher, respectively, when TDF was coadministered with LPV/r (n = 24). LPV and RTV pharmacokinetics, including Cτ, were unaffected by TDF (n = 24). Clinical estimates of renal function were unaffected by administration of TDF alone or with LPV/r.
Discussion: Coadministration of TDF with LPV/r resulted in increased tenofovir exposures at steady state, possibly through increased absorption. This increase is not believed to be clinically relevant based on the safety and efficacy of TDF plus LPV/r-containing regimens in HIV-infected patients in long-term controlled clinical trials.
Highly active antiretroviral therapy (HAART) regimens are defined as those containing at least 3 antiretroviral agents and combine a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). Results from studies in treatment-naive patients have confirmed that NNRTI- and PI-based regimens can provide sustained virologic response; however, in drug-experienced patients, regimens that include PIs are necessary for complete viral suppression because of their high genetic barrier to resistance and the diversity of available agents within the class.
In PI-based regimens, lopinavir/ritonavir (LPV/r) is a preferred agent because of demonstrated durable treatment responses among those who can tolerate adverse events related to ritonavir (RTV); virologic failure associated with the emergence of resistance is rare. In this combined-dose form, LPV is coformulated with a low dose of RTV, wherein the latter acts as a pharmacokinetic booster of LPV, increasing its bioavailability and increasing drug exposure. This and other RTV-boosted PI regimens generally allow for simpler dosing schedules with lower pill burden and less frequent administration, factors that are known to improve adherence, and thus outcomes of anti-HIV therapy. Moreover, boosting with RTV allows for high LPV trough concentrations, which have been shown to result in better treatment responses, even in patients whose HIV strains exhibit some degree of reduced susceptibility.
Several options for NRTIs are available, including a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine, which is a recommended preferred backbone in treatment-naive and treatment-experienced patients. This NRTI combination offers the potential for the highest level of regimen simplicity-once-daily dosing-because of long plasma and intracellular half-lives for tenofovir diphosphate and emtricitabine triphosphate.
Given the demonstrated tolerability, efficacy, and resistance profile of TDF, it is frequently included in LPV/r PI-based regimens. This necessitates attention to potential pharmacokinetic drug interactions on the coadministration of these drugs. Therefore, we conducted a drug-drug interaction pharmacokinetic study in healthy volunteers to assess the potential for interaction and provide, if necessary, a dosing recommendation for concomitant administration of these compounds. We examined the steady-state pharmacokinetics of LPV/r and tenofovir during multiple-dose administration of these agents relative to administration of LPV/r and TDF alone. As a secondary objective, we evaluated the safety of concomitant administration of these 2 agents.
Abstract and Introduction
Abstract
Objective: Lopinavir/ritonavir (LPV/r) and tenofovir disoproxil fumarate (TDF) are frequently used antiretrovirals. A pharmacokinetic study in healthy volunteers was conducted to assess the potential for a drug interaction between these agents.
Methods: This was a 36-day, multiple-dose, drug-drug interaction study of TDF and lopinavir/ritonavir (LPV/r). Subjects received TDF alone for 7 days, followed by 14 days each of TDF plus LPV/r and LPV/r alone in a randomized manner. Pharmacokinetic assessments were performed over 24 hours on days 7, 21, and 35. LPV/r and tenofovir plasma/serum concentrations were measured by high-performance liquid chromatography/mass spectometry (MS)/MS. Geometric mean ratios and 90% confidence intervals of pharmacokinetic parameters for tenofovir, LPV, and ritonavir (RTV) were estimated using analysis of variance and compared with the no-effect criterion for pharmacokinetic equivalence.
Results: Tenofovir measurements with an area under the concentration-time curve over the dosing interval, maximum concentration, and concentration at the end of the dosing interval (Cτ) were 32%, 15%, and 51% higher, respectively, when TDF was coadministered with LPV/r (n = 24). LPV and RTV pharmacokinetics, including Cτ, were unaffected by TDF (n = 24). Clinical estimates of renal function were unaffected by administration of TDF alone or with LPV/r.
Discussion: Coadministration of TDF with LPV/r resulted in increased tenofovir exposures at steady state, possibly through increased absorption. This increase is not believed to be clinically relevant based on the safety and efficacy of TDF plus LPV/r-containing regimens in HIV-infected patients in long-term controlled clinical trials.
Introduction
Highly active antiretroviral therapy (HAART) regimens are defined as those containing at least 3 antiretroviral agents and combine a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). Results from studies in treatment-naive patients have confirmed that NNRTI- and PI-based regimens can provide sustained virologic response; however, in drug-experienced patients, regimens that include PIs are necessary for complete viral suppression because of their high genetic barrier to resistance and the diversity of available agents within the class.
In PI-based regimens, lopinavir/ritonavir (LPV/r) is a preferred agent because of demonstrated durable treatment responses among those who can tolerate adverse events related to ritonavir (RTV); virologic failure associated with the emergence of resistance is rare. In this combined-dose form, LPV is coformulated with a low dose of RTV, wherein the latter acts as a pharmacokinetic booster of LPV, increasing its bioavailability and increasing drug exposure. This and other RTV-boosted PI regimens generally allow for simpler dosing schedules with lower pill burden and less frequent administration, factors that are known to improve adherence, and thus outcomes of anti-HIV therapy. Moreover, boosting with RTV allows for high LPV trough concentrations, which have been shown to result in better treatment responses, even in patients whose HIV strains exhibit some degree of reduced susceptibility.
Several options for NRTIs are available, including a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine, which is a recommended preferred backbone in treatment-naive and treatment-experienced patients. This NRTI combination offers the potential for the highest level of regimen simplicity-once-daily dosing-because of long plasma and intracellular half-lives for tenofovir diphosphate and emtricitabine triphosphate.
Given the demonstrated tolerability, efficacy, and resistance profile of TDF, it is frequently included in LPV/r PI-based regimens. This necessitates attention to potential pharmacokinetic drug interactions on the coadministration of these drugs. Therefore, we conducted a drug-drug interaction pharmacokinetic study in healthy volunteers to assess the potential for interaction and provide, if necessary, a dosing recommendation for concomitant administration of these compounds. We examined the steady-state pharmacokinetics of LPV/r and tenofovir during multiple-dose administration of these agents relative to administration of LPV/r and TDF alone. As a secondary objective, we evaluated the safety of concomitant administration of these 2 agents.
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