Pharmacokinetic Interactions Between Protease Inhibitors and
Pharmacokinetic Interactions Between Protease Inhibitors and
Objective: Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug drug interactions ( Table 1 ).
Design: Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA.
Methods: Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1-4 and 15-18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4-18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1-14 with pravastatin 40 mg daily added from days 15-18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry.
Results: Fifty-six subjects completed both pharmacokinetic study days. In arms 1-3, the median estimated area under the curves (AUC)0-24 for the statins were: pravastatin (arm 1, n = 13), 151 and 75 nguu.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P = 0.005); simvastatin (arm 2, n = 14), 17 and 548 nguu.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P <0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 nguu.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P <0.001). In arm 4, the median estimated AUC0-8 for NFV (24,319 versus 26,760 nguu.h/ml; P = 0.58) and its active M8 metabolite (15,565 versus 14,571 nguu.h/m; P = 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin).
Conclusions: Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.
The major findings of this study were the significant drug-drug interactions between statins and HIV protease inhibitor that inhibits cytochrome P450 3A4. Much of the focus was on the potential for elevated levels of simvastatin, lovastatin and atorvastatin because of the risk of muscle injury. An under-appreciated finding in this study was the induction of pravastatin metabolism by ritonavir and saquinavir ( Table 2 ). The 50% reduction in area under the curve (AUC) was unexpected. We have confirmed this observation in more recent work. Gerber and colleagues have recently demonstrated a similar reduction in pravastatin AUC with nelfinavir and efavirenz (Proceedings of the Second International AIDS Society Meeting. Paris, Month 2003 [abstract 870]). This may explain, in part, why pravastatin therapy has not been very effective in reducing lipids in persons with dyslipidemia and HIV infection. The metabolism of pravastatin is complex involving glucuronidation, non-CYP3A4 oxidation and isomerization. Some of the protease inhibitors are known to induce glucuronidation, although the mechanism of the interaction between some antiretroviral drugs and pravastatin is not known. It may be useful to conduct some dose ranging studies of pravastatin (with appropriate consideration for potential safety issues) in HIV-infected patients with dyslipidemia who are taking ritonavir, nelfinavir, efavirenz or other antiretrovirals that may induce pravastatin's metabolism.
-- Carl J. Fichtenbaum, Judith Aberg and John Gerber on behalf on the ACTG A5047 team
Access to and availability of effective antiretroviral therapy has increased dramatically in the last few years. In this current era of highly active antiretroviral therapy, it has become possible to consider HIV infection a chronic manageable disease, and the recognition and management of concomitant complications of HIV infection and/or its therapy have become increasingly important. There would be little advantage to long-term, effective suppression of the virus and restitution of immune function if the cost included uncontrolled diabetes, atherogenic lipid profiles and increased vascular or cardiovascular disease. As recognition of these metabolic complications of HIV infection and its therapy has increased, attempts to devise preventive strategies and therapeutic interventions have stumbled with the lack of understanding of the pathogenesis of the complications. Patient response to these concerns is often to consider discontinuation of the therapies that they believe are the cause of the complications, although such discontinuation of therapy is obviously counterproductive to viral control. An equipoise must be found between antiretroviral therapy, the virus, and the accompanying confounders. The need to conduct studies to clarify the aetiologies and best means to intervene in these syndromes are made more complex by the interaction of virus, chronic inflammation, coinfection with hepatitis C, hepatotoxicity of antiretroviral drugs and the requirement for combinations of antiretroviral agents. Interventions or therapies that appear on the surface to be beneficial may ultimately complicate further the syndromes they are used to control.
This paper by Fichtenbaum and colleagues used the AIDS Clinical Trial Groups as a mechanism to delineate the proper role of HMG-CoA reductase inhibitors in the control of atherogenic lipid profiles induced in some HIV infected patients by some protease inhibitors. As with the best of other HIV clinical research, this is a multidisciplinary study, which factors out the role of the virus by studying the pharmacology of the lipid-lowering agents and individual agents or combinations of antiretroviral agents in HIV negative individuals. The study is well designed, well controlled and carefully done, with appropriate documentation of adverse events caused by the agents in the HIV negative study participants and of the potential for bidirectional drug interactions. The authors are rigorous in their interpretation of their data, placing it appropriately in context with practical strategies for adjusting doses of the most appropriate lipid lowering agents.
The management of HIV infection is in constant flux, frustrating the attempts of clinical research such as this, as the combination of ritonavir/saquinavir soft gel capsule - which was chosen for this study - was often replaced by the low dose use of ritonavir as a pharmacologic boosting agent before the study was published. In the clinical update the authors provided for this issue, they note they have continued these studies by looking at the pharmacologic interactions of pravastatin, nelfinavir and efavirenz. The continual evolution of the need for more data to effectively manage HIV and its complications needs to be tempered the ability to do the proper studies properly. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047 not only provides useful and practical data for clinical practice, it provides a model for the rigor with which this type of study needs to be conducted.
-- Christine Wanke, Editor
Objective: Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug drug interactions ( Table 1 ).
Design: Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA.
Methods: Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1-4 and 15-18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4-18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1-14 with pravastatin 40 mg daily added from days 15-18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry.
Results: Fifty-six subjects completed both pharmacokinetic study days. In arms 1-3, the median estimated area under the curves (AUC)0-24 for the statins were: pravastatin (arm 1, n = 13), 151 and 75 nguu.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P = 0.005); simvastatin (arm 2, n = 14), 17 and 548 nguu.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P <0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 nguu.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P <0.001). In arm 4, the median estimated AUC0-8 for NFV (24,319 versus 26,760 nguu.h/ml; P = 0.58) and its active M8 metabolite (15,565 versus 14,571 nguu.h/m; P = 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin).
Conclusions: Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.
The major findings of this study were the significant drug-drug interactions between statins and HIV protease inhibitor that inhibits cytochrome P450 3A4. Much of the focus was on the potential for elevated levels of simvastatin, lovastatin and atorvastatin because of the risk of muscle injury. An under-appreciated finding in this study was the induction of pravastatin metabolism by ritonavir and saquinavir ( Table 2 ). The 50% reduction in area under the curve (AUC) was unexpected. We have confirmed this observation in more recent work. Gerber and colleagues have recently demonstrated a similar reduction in pravastatin AUC with nelfinavir and efavirenz (Proceedings of the Second International AIDS Society Meeting. Paris, Month 2003 [abstract 870]). This may explain, in part, why pravastatin therapy has not been very effective in reducing lipids in persons with dyslipidemia and HIV infection. The metabolism of pravastatin is complex involving glucuronidation, non-CYP3A4 oxidation and isomerization. Some of the protease inhibitors are known to induce glucuronidation, although the mechanism of the interaction between some antiretroviral drugs and pravastatin is not known. It may be useful to conduct some dose ranging studies of pravastatin (with appropriate consideration for potential safety issues) in HIV-infected patients with dyslipidemia who are taking ritonavir, nelfinavir, efavirenz or other antiretrovirals that may induce pravastatin's metabolism.
-- Carl J. Fichtenbaum, Judith Aberg and John Gerber on behalf on the ACTG A5047 team
Access to and availability of effective antiretroviral therapy has increased dramatically in the last few years. In this current era of highly active antiretroviral therapy, it has become possible to consider HIV infection a chronic manageable disease, and the recognition and management of concomitant complications of HIV infection and/or its therapy have become increasingly important. There would be little advantage to long-term, effective suppression of the virus and restitution of immune function if the cost included uncontrolled diabetes, atherogenic lipid profiles and increased vascular or cardiovascular disease. As recognition of these metabolic complications of HIV infection and its therapy has increased, attempts to devise preventive strategies and therapeutic interventions have stumbled with the lack of understanding of the pathogenesis of the complications. Patient response to these concerns is often to consider discontinuation of the therapies that they believe are the cause of the complications, although such discontinuation of therapy is obviously counterproductive to viral control. An equipoise must be found between antiretroviral therapy, the virus, and the accompanying confounders. The need to conduct studies to clarify the aetiologies and best means to intervene in these syndromes are made more complex by the interaction of virus, chronic inflammation, coinfection with hepatitis C, hepatotoxicity of antiretroviral drugs and the requirement for combinations of antiretroviral agents. Interventions or therapies that appear on the surface to be beneficial may ultimately complicate further the syndromes they are used to control.
This paper by Fichtenbaum and colleagues used the AIDS Clinical Trial Groups as a mechanism to delineate the proper role of HMG-CoA reductase inhibitors in the control of atherogenic lipid profiles induced in some HIV infected patients by some protease inhibitors. As with the best of other HIV clinical research, this is a multidisciplinary study, which factors out the role of the virus by studying the pharmacology of the lipid-lowering agents and individual agents or combinations of antiretroviral agents in HIV negative individuals. The study is well designed, well controlled and carefully done, with appropriate documentation of adverse events caused by the agents in the HIV negative study participants and of the potential for bidirectional drug interactions. The authors are rigorous in their interpretation of their data, placing it appropriately in context with practical strategies for adjusting doses of the most appropriate lipid lowering agents.
The management of HIV infection is in constant flux, frustrating the attempts of clinical research such as this, as the combination of ritonavir/saquinavir soft gel capsule - which was chosen for this study - was often replaced by the low dose use of ritonavir as a pharmacologic boosting agent before the study was published. In the clinical update the authors provided for this issue, they note they have continued these studies by looking at the pharmacologic interactions of pravastatin, nelfinavir and efavirenz. The continual evolution of the need for more data to effectively manage HIV and its complications needs to be tempered the ability to do the proper studies properly. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047 not only provides useful and practical data for clinical practice, it provides a model for the rigor with which this type of study needs to be conducted.
-- Christine Wanke, Editor