TAGline - Volume 11 Issue 8 - October 2004

Yasmin Halima and Rob Camp attended the one-day Pharmacology Workshop held immediately after CROI in February 2004. Here is their report on some kooky, if not explosive, combinations. Thanks to all the presenters for reviewing their data.

Statins + HAART
Many HIV+ people are currently treated with statins to manage lipid elevations. Understanding the pharmacologic interactions between statins and HIV drugs is essential. Some statins have been implicated more than others in their potential for interactions with antiretroviral therapies.

Implementing lifestyle modifications like smoking cessation is extremely important. Dieting is also an efficient way to lower cholesterol levels and can lead to reductions of up to 10%. To reduce cholesterol levels even more significantly, the use of a statin to lower the LDL-C levels may be needed.

Hydrochlorothiazide(a diuretic and antihypertensive drug, trade name Hydrodiuril) and atorvastatin should control blood pressure and LDL cholesterol. But, myalgias and mild diffuse muscle weakness are not uncommon after a short time. Serum LFTs and CPK stats should be done to see if either is elevated; the statin could be responsible for muscle toxicity. Stopping statins in this case would be recommended. Switching to fenofibrate can reduce VLDL but is not as effective in reducing LDL-C elevations.

• Statins are not the same either in terms of efficacy or drug-drug interactions
• All statins have the capacity for severe toxicity that include rhabdomyolysis and hepatic dysfunction, which is dose- (concentration-) dependent
• Understanding the metabolism of statins will make predictions of drug-drug interactions possible

Structure of statins
Simvastatin and lovastatin are lactone pro-drugs that have to be converted into a hydroxy-acid form to be more lipophilic and active. Rosuvastatin (Crestor) is the newest in the class. Statins are metabolised by CYP450 into both active and inactive metabolites.

Relative potency and metabolism of statins

Statins can reduce LDL-C by as much as 50%. Table shows approximate levels needed to reduce LDL-C by 30%.

Impact of CYP450 inducers on statin metabolism
Simvastatin is metabolised to simvastatin-acid, although a significant portion of it is metabolised by the CYP3A isoform. The inhibition of CYP3A4 can lead to fairly significant increases in simvastatin-acid levels and toxicities. A study investigating the impact of RTV on the metabolism of statins showed remarkably high accumulation of simvastatin-acid levels, with increases of ∼3000%.

Pravastatin is metabolised differently and involves multiple oxidation pathways through the CYP450 system, but not CYP3A, so it is actually reduced by some 50% when coadministered with RTV.

Atorvastatin has two main active metabolites generated by CYP3A, and inhibition of CYP3A4 will again lead to increases in atorvastatin; the difference is that it actually has a decrease in the levels of the active metabolite, so the increase in total active atorvastatin activity is not that large (< 2-fold increase with RTV).

With NFV, similar results are seen—atorvastatin levels increased and simvastatin levels increased significantly. Data with lopinavir/r (Kaletra®) also shows increases in atorvastatin by up to 5-fold, although in this study only the unchanged atorvastatin levels were examined and not the total active levels of atorvastatin. Kaletra did not show any significant changes with pravastatin.

Other studies have shown that pravastatin exposure is reduced by 50% with use of RTV and SQV, by 40% with EFV and by 50% with NFV. EFV has been shown to be a potent inducer of simvastatin metabolism leading to reductions in exposure of 60% and of atorvastatin by 30%. Significant reductions in simvastatin, atorvastatin and pravastatin levels result in a slowing down of the LDL-C reduction in the presence of EFV.

A simple analysis of the data available on statins would suggest that pravastatin and fluvastatin are safe to use with CYP450 3A4 inhibitors, although there could be more data on fluvastaitin, and the efficacy of pravastatin may be "compromised" (its metabolism is induced). Atorvastatin should be used with caution, as it could get dangerously high with PIs and uselessly low with EFV. Simvastatin and lovastatin should not be co-administered (they interact severely with CYP3A4 inhibitors (all PIs, although not EFV).

Rosuvastatin data is unknown right now and should be avoided right now with HAART. There are concerns about rhabdomyolysis. The package insert states that cyclosporine increases rosuvastatin levels by 12-fold. Direct interactions studies are currently underway.

There are currently no interaction data between statins and NVP, but until there are, the effects should be suspected to be similar to EFV.

Smoking cessation drugs and their interactions with HIV therapies have not been looked at definitively, but there may be an induction effect.

Bupropion (probably metabolised through CYP2B6) is contraindicated with RTV (probably an inducer, not an inhibitor, of CYP2B6) and the use of 150mg QD may achieve therapeutic levels with patients on boosted PIs.

Tenofovir and other NRTIs
An important factor for all nucleoside and nucleotide reverse transcriptase inhibitors is that they need to be phosphorylated intracellularly into the DP (diphosphate) and TP (triphosphate) forms.

Tenofovir (TDF) has a complex metabolic process leading to the possibility of inter-patient variability and response.

TDF has been shown to increase the plasma concentrations of ddI although the mechanism of this interaction is as yet unclear. The active forms of nucleosides like ddI and nucleotides such as TDF are phosphorylated derivatives produced inside the host cell. These "anabolites" remain inside the cell and are de-phosphorylated there. The rate of de-phosphorylation may be different from the rate of disappearance (half-life or t_1/2) of the nucleoside in plasma.

Depending on weight, ddI should be dosed at 250mg or 200mg with full-dose (300mg) TDF. The ddI taken 2 hours before the TDF produces approximately the same peak plasma concentration (Cmax) and area-under-the-curve (AUC) of ddI seen in the absence of TDF.

The tenofovir t_1/2 is approximately 17 hours, while its DP half-life can be as long as 50 hours, which explains why TDF is administered as a single daily dose that achieves adequate drug levels to maintain intracellular levels and viral suppression. Intracellular phosphorylation (of either TDF or ddI) is difficult to measure. If DP is the important measure, might we be overdosing at QD? Has this been looked at?

With a serum creatinine of 3.2 mg/dL, which equals a creatinine clearance of approximately 30 mL/min, the TDF package insert recommends 300mg dosed every other day, allowing for sufficient serum concentration levels over the dosing period.

Prolonged treatment with TDF is contraindicated in patients with pre-existing renal insufficiency. Toxicities due to too high concentration levels may result. The dose recommended in the package insert is based on a model of single dose HIV-subjects and as such, HIV+ people need to be cautious. Dosing on alternate days may not be an easy adherence scheme, although treatment on Monday, Wednesday and Friday with the weekend off might work. Drug levels of TDF (according to the chart below), may be sufficient to allow dosing in this way.

In patients with normal renal function, 20% of TDF is excreted renally.

Dosage adjustment for tenofovir for people with altered creatinine clearance

Drug Dosing and Renal Function

Could an increased level of nausea and GI side-effects be related to drug levels when LPV/r is used with TDF? There is some data showing this combination as having an impact on renal function, as well as renal failure in a few patients.

Nelfinavir TDM during pregnancy
The use of antiretroviral drugs in pregnancy is complicated by factors like hormonal and metabolic changes as well as the need for maternal and fetal safety. Use of therapeutic drug monitoring (TDM) can provide guidance for clinicians in the management of patients who have either suboptimal or toxic (super-optimal?) drug levels.

Example: a pregnant woman initially showed a good response to HAART despite low nelfinavir plasma levels, but one fine day her viral load shot up above detectable. The levels of NFV are probably relevant—so the frequency of VL monitoring should be increased. Increasing the dose might help to increase the blood levels of NFV. Doing both (repeating the VL and increasing the dose) would be most appropriate.

Nelfinavir plasma levels may be low during pregnancy. It is unknown whether these low levels are associated with suboptimal antiviral response. With NLF, a TID regimen would maybe give better drug levels, although one retrospective ACTG study said no. Would prospective PK studies on the use of nelfinavir in pregnant women be helpful?

Berger would recommend increasing the frequency of VL monitoring and perform TDM as soon as possible. At 2 weeks after starting treatment, TDM should be undertaken and the interpretation of that result plus the virologic response should be used to adjust the treatment and drug levels.

Resistance and PK
The care of patients with prior experience of multiple antiretroviral agents and a limited number of options for switching presents challenges. The understanding of significant mutations that confer drug resistance and the impact of cumulative changes in the viral mutations can help guide therapeutic choices.

In the presence of many NAMs (nucleoside analogue mutations) plus the M184V, it is unlikely that any NRTI change will have much effect. With 4 or more TAMs (thymidine analogue mutations), there is little impact of new NRTIs, based on both expert opinion and the recent GSK 30009 debacle (TDF + ABC + 3TC is a nix).

The co-administration of TDF and ddI shows an increase in plasma ddI concentrations, and TDF + LPV/r increases TDF levels (see above).

The ability of PIs to inhibit viruses with accumulating resistance mutations is a relative phenomenon. Viruses may not be fully susceptible but may still retain some activity. We need to understand the impact of resistance and to combine what may be partially active drugs in a regimen that confers the greatest cumulative activity. By integrating pharmacologic and virologic interventions we can enhance PI activity and improve therapeutic outcomes.

Pharmacologic principles are based on risk-benefit ratios. ACTG study addresses the question of whether increasing LPV or /r levels has an impact on viral suppression. Balancing the potency of the regimen needs to looked at with any increase in toxicity—will patient adherence be compromised? A small pilot study compared adding 200mg /r + 3 Kaletra tabs to 4 tablets of Kaletra#151;and showed greater toxicity in the extra /r arm both on GI-related toxicities and lipid elevations.

In another recent study involving patients with multiple accumulations of resistance mutations in whom the dosing regimen was increased to 4 Kaletra pills (533mg LPV and 133mg /r), there was an improved response in reaching target concentrations of 5,500ng/ml, which is predictive of a longer-term anti-viral response.

There have been fairly definitive studies that have seen the non-favorable interaction of LPV/r + APV (or 908) to where blood levels of both drugs are lowered to a dangerously ineffective level. This scenario is complicated with many variables. Significant interactions are likely between APV and LPV/r, with reductions in levels of LPV and APV of up to 50%. Although avoiding this combo is the most straightforward strategy, TDM might be worthwhile to guide the dosing strategy, in the case of there not being another choice. 908/r (vs APV/r) has further complicated this issue and we have little data on the possible interactions between 908/r and LPV/r. Although these two drugs are not exactly bioequivalent, they are chemically close enough to each other to raise the warning flag—interactions-wise, there has been little difference between the two.

We should also be mindful of the fact that much of the 908 data is based on un-boosted levels, which is probably not a real-life scenario.

Given the complex interactions, if this combination must be used, TDM is probably a good idea to correct for any imbalances of the already adjusted dosing. TDM should provide an effective therapeutic range, although the side effects are not known and could very well be severe.

C Flexner, Johns Hopkins University, USA, T Gulick, Cornell, USA and J Schapiro, Stanford University, USA, T Blaschke, Stanford University, C Boucher, University of Utrecht, The Netherlands, D Burger, University of Nijmegen Medical Center, The Netherlands, C Fletcher, University of Colorado, USA, J Gerber, University of Colorado, Denver, USA, 11TH Conference on Retroviruses and Opportunistic Infections, Post-Conference Workshop, 12 Feb 2004, San Francisco, USA.
Wit et al, IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. 129.
Fichtenbaum et al, AIDS. 2002 Mar 8;16(4):569-77,
Hsyu et al, AAC 2001, 45:3445-50,
Carr et al, abstract 1644, 40th ICAAC, 2000,
Gerber et al., IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. 870
Gerber et al, Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th: Abstract No. 603.

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