Important note: Information in this article was accurate in March 2001. The state of the art may have changed since the publication date.
P-glycoprotein (P-gp) for HIV Clinicians
P-gp is an ATP-dependent transporter involved in cellular detoxification, pumping out substances that could be potentially deleterious to the body. This transporter plays a very important role in resistance to cancer chemotherapy, by extruding anti-cancer drugs from the intracellular to the extracellular space, thus interfering with the pharmacological effects of these agents. P-gp has attracted a lot of attention in the HIV field because several antiretroviral agents have been identified as P-gp substrates. Some of the PIs, such as nelfinavir, saquinavir, and ritonavir, are not only substrates but are also P-gp inhibitors, making this transporter a potential site for drug interactions. P-gp is found in several tissues, including the liver and intestine, and contributes to the CNS blood brain barrier. Cytochrome P450, an important hepatic enzyme involved in the metabolism of several antiretroviral agents, is often coexpressed in the same tissues as P-gp and shares a common range of substrates. An entire symposium at the 8th CROI was dedicated to this important efflux pump.
In the CNS, P-gp expression has been associated with poor PI penetration and the concern that this organ may become a sanctuary for HIV replication, allowing virologic escape and development of resistance in patients on HAART. A recent study showed that P-gp knockout mice (mice that do not express P-gp) had profoundly higher CSF concentrations of PIs than controls. Current research in this field is focused on identifying pharmacological probes that could inhibit P-gp activity and enhance antiretroviral tissue penetration. Though several approved drugs, such as verapamil and cyclosporine, are known to be P-gp inhibitors, they lack specificity and potency. In fact, some of the currently available P-gp inhibitors also block CYP3A4 activity. This could result in decreased metabolism and accumulation of the parent drug, leading to toxicity.
Richard Kim from Vanderbilt University reviewed the most recent developments in the field of P-gp inhibitors [Abstract S1]. Kim presented results of a study using LY335970, a P-gp inhibitor developed by Lilly. In that study, mice treated with LY335970 experienced a substantial increase in nelfinavir concentrations, more pronounced in the CNS than in the plasma, when compared to controls. In addition, LY335970's inhibitory effect seemed only to target P-gp function, with minimal effect on CYP3A4 activity. This compound also proved to be the most potent P-gp inhibitor when compared to other P-gp inhibitors such as cyclosporin and PIs. A number of other compounds are currently under investigation as potential P-gp inhibitors including oral ketoconazole, and preliminary studies revealed encouraging PK results [Back, Abstract S3].
The same investigator reported on the possible role of P-gp polymorphism in antiretroviral pharmacology. P-gp is encoded by the mdr-1 gene in humans. Duodenal cells from healthy volunteers treated with rifampin (a P-gp inducer) and digoxin (a P-gp substrate) had their mdr-1 gene sequenced. Patients homozygous for the TT allele had much lower P-gp activity and consequently higher digoxin concentrations, while patients with the CC allele experienced higher P-gp expression and much lower digoxin concentrations. This is interesting in light of the fact that these are silent mutations, i.e. they encode proteins with the same amino acid sequence. Like digoxin, PIs are P-gp substrates, and one can postulate that the interpatient variability observed in the pharmacokinetics of these agents could be the result not only of adherence and pharmacokinetics, but also P-gp activity.
The most intriguing new revelations about P-gp took place during a talk by Flexner on the role of P-gp in HIVpathogenesis [Abstract S4]. There is now evidence that cells expressing high levels of P-gp may be resistant to HIV-infection. Mechanistically, P-gp seems to interfere with HIV entry and egress. A recent clinical study seems to confirm some of these observations. David Back summarized the findings of a study that showed much higher levels of P-gp expression in the PBMCs of treated patients with complete HIV suppression, when compared to their treated, unsuppressed counterparts [Back, Abstract S3]. In addition, naïve patients with viremia had P-gp levels similar to their unsuppressed treated counterparts. It seems that the effect of P-gp on intracellular drug levels is only part of the story. We also need to pay attention to the effects of P-gp on the virus. Though cells with high P-gp expression would have lower antiretroviral concentrations, P-gp expression makes the same cells less susceptible to HIV infection, and causes infected cells to produce much less virus [Abstract S4].
More on Drug Interaction Between Herbal Medications and Protease Inhibitors
Garlic supplements join Saint Johns' wort on the list of herbal medications that should be avoided with PIs. Piscitelli and colleagues [Abstract 743] evaluated the effects of garlic on saquinavir pharmacokinetics. In this study, ten healthy volunteers went through 4 treatment phases:
Period 1 - saquinavir 1200 mg TID for 3 days;
Period 2 - garlic capsules 1 BID for 19 days;
Period 3 - saquinavir + garlic for 3 days followed by a 10-day wash out period;
Period 4 - saquinavir 1200 mg TID for 3 days.
In the presence of garlic supplements, the mean saquinavir AUC, Cmax, and trough values decreased by 51%, 49%, and 54% respectively. Even after a 10-day washout period, saquinavir PK parameters returned to only 60-70% of the baseline values. The magnitude of decrease in the PK parameters suggest that garlic affects saquinavir bioavailability rather than systemic clearance, though the specific mechanism is unclear. At this point, it is unknown whether double PI combinations using small doses of ritonavir would prevent the low concentrations observed with a single PI agent plus garlic. Patients taking garlic supplements should be cautioned against using garlic when taking PIs.
To TDM or not To TDM - The Debate Goes On
Clevenbergh and colleagues presented the results of a prospective multicenter randomized controlled trial investigating the usefulness of therapeutic drug monitoring (TDM) in patients receiving PI-containing regimens [Abstract 206B]. A total of 256 HIV-infected patients failing therapy (VL >2000 c/mL) were randomized to two arms: treatment modification by genotype resistance test (control) or treatment modification by genotype resistance test + PI plasma trough levels measured at week 4. Although suboptimal PI trough levels were found at week 4 in some patients in both groups, treatment modifications did not take place until week 8. The results revealed similar virologic outcomes in both arms. Several major design flaws make these findings difficult to interpret. By waiting 4 weeks to make treatment modifications in patients on failing regimens, it is possible that the development of viral resistance may have already occurred, making treatment modifications futile. Also, target trough concentrations of PIs may have been too low. Unfortunately this study does not put to rest the debate about whether TDM will improve outcome of patients on HAART.
A group of investigators from the Netherlands reviewed the intra- and interlaboratory variability of antiretroviral drug assays in 19 laboratories from several countries to determine the accuracy of their analytical methods [Abstract 734]. Both PI and NNRTI plasma concentrations were analyzed. Data were available for 17 laboratories and showed a huge variability in results. These findings are concerning, since a lack of standardization in reporting measurements of antiretroviral drugs concentrations could have a negative impact on the reliability of TDM.
Nephrotoxicity and Indinavir Pharmacokinetics
A study by Burger and colleagues shed some light on the relationship between indinavir (IDV) PK parameters and nephrotoxicity [Abstract 730]. Nineteen HIV-infected Thai patients on AZT/3TC/IDV 800 mg q8h, underwent 8 hour PK curves four weeks after starting antiretroviral treatment. Nephro-toxicity was defined as hematuria, flank pain, or an increase in serum creatinine of 25% or greater. Results revealed that an AUC of 30 mg-hour/L per hour and a Cmax of 10 mg/L were predictors of nephrotoxicity. This is the first study that identifies specific PK parameters as predictors of IDV-associated nephrotoxicity. One implication of this study is that dual PI regimens with very high IDV Cmax and AUC values, like IDV 800 mg/RTV 200 mg b.i.d., may be more prone to produce nephrotoxicity.
NRTI Naïve and Treatment Experienced Patients: Is Phosphorylation Important for NRTI Sequencing?
NRTIs are prodrugs that require intracellular phosphorylation in order to be activated. Previous data suggested that NRTI sequencing may affect treatment outcome, specifically that prior use of AZT may reduce subsequent phosphorylation of d4T. In order to better understand this issue, Parsons and coworkers studied peripheral blood mononuclear cells (PBMCs) of NRTI naïve and experienced patients who were on a suppressive regimen or were experiencing treatment failure [Abstract 257]. Results showed that the phosphorylation of AZT was lower in NRTI-experienced patients compared to NRTI naïve patients. However, no difference was found in the phosphorylation levels of AZT, d4T, or abacavir in patients on suppressive or non-suppressive regimens. These results suggest that AZT and d4T sequencing will not impact the level of phosphorylation and treatment outcome and failure. Treatment failure involving these agents is likely to be secondary to poor adherence or broad class genotypic resistance, and is not likely to reflect poor phosphorylation as a consequence of NRTI sequencing.
The Effect of Cannabinoids on Antiretroviral Therapy
Cannabinoids such as marijuana and dronabinol are commonly used drugs for appetite stimulation in the HIV-infected population. Like the PIs, cannabinoids undergo extensive first pass metabolism in the liver and currently it is unknown whether these agents interfere with antiretroviral metabolism. Kosel et al [Abstract 745] reported the results of a randomized placebo-controlled trial to investigate whether there is a potential for metabolic drug interactions involving PIs and cannabinoids. Twenty-eight HIV-infected subjects on nelfinavir 750 mg TID and 34 on indinavir 800 mg q8h for at least 8 weeks, were randomized to one of three treatment arms for 21 days: 3.95% marijuana cigarettes, dronabinol 2.5 mg capsules, or placebo capsules. PK studies were done prior to cannabinoid administration and after 14 days of concomitant treatment with cannabinoids and PIs. Results revealed a large variability of both indinavir and nelfinavir pharmacokinetics among study participants. Patients receiving indinavir and using marijuna cigarettes had a 14% and 34% decrease in indinavir Cmax and Cmin, respectively. Only Cmin values reached statistical significance. No statistically significant changes were observed in nelfinavir pharmacokinetics. Overall, alterations in the PIs pharmacokinetic parameters were greater with the inhaled than with the oral cannabinoid formulation, regardless of the PI used. The greater difference observed in indinavir PK parameters in study subjects receiving cigarettes compared to dronabinol capsules could reflect different cannabinoid concentrations in these two formulations. It is unclear whether these effects would be more pronounced in patients consuming larger doses of cannabinoids. At his point it is unclear whether the reduction in indinavir levels observed with concomitant use of inhaled marijuana will have clinical implications in the treatment of HIV, but the authors made no specific recommendations for curtailing cannabinoid use in patients taking PIs.
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