Mixing and Matching Meds: ICAAC Update
At the 41st Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) held in Chicago in December 2001, there were presentations discussing therapeutic drug monitoring (TDM) in HIV. What researchers and some clinicians are doing now is conducting studies, or in some cases select sampling of plasma (the part of the blood that is without cells), of their patient populations. They are doing this to determine if the amount of drug getting into a person's blood is not what is expected nor desired. This may allow the clinician to adjust the dose of the antiretroviral, as in some cases when another drug the patient is taking may be causing the drug level to be an undesirable one.
Many of the ICAAC presentations focused on: 1) how drug-to-drug and drug-to-food interactions may alter plasma levels of various drugs and 2) how plasma levels may relate to viral load suppression or resistance. Only a few focused on the actual monitoring of drug levels, primarily protease inhibitors, and how the process can significantly affect the results. Outcome data are not being discussed in this article and more details on how these persons faired while on these medicines are available at the conference web site: www.icaac.org.
Flaherty, et al., Abstract # 1791, presented much anticipated data on the interaction between Videx (didanosine, ddI) and Viread (tenofovir). Viread is the new kid on the block, and is only taken once a day. So a big question was: how does it function when taken with Videx, the only other nucleoside analog that can also be taken once a day. Together, they might make a good nucleoside base for HIV therapy. It's a tricky question, because Viread can be taken with food, but both Videx and Videx-EC (the newer, non-buffered capsule) must be taken on an empty stomach.
The jury is still out on what is the best way to construct a pill regimen with these two medicines in the same patient, but there are studies being done that may give us this answer. However, this research has yet to be completed. In this pharmacokinetic analysis using non-HIV infected persons, didanosine and tenofovir were given to 15 (8 male/7 female) for 7 days. The plasma levels obtained were compared to when the same subjects took each drug individually. The Gilead Science study (makers of Viread) demonstrated an increase in both the total drug exposure (AUC) and the maximal drug level in the plasma (Cmax) of didanosine of about 44% and 20%, respectively, when ddI was taken one hour before tenofovir. All medications were administered in the fasting state. This should not affect the results when applied to the clinical setting, as when tenofovir is administered with food it would not likely cause much greater changes in didanosine pharmacokinetics.1 This should also not be any different in HIV infected persons as Kearney, et al., presented the effect of demographic variables on the pharmacokinetics of tenofovir in 56 HIV positive persons getting nearly identical tenofovir levels (Abst. 504).
In a related research study, Bristol-Myers Squibb presented data showing that when Videx-EC (didanosine EC) was administered with food (high and low fat) compared to fasting in a total of 99 HIV negative persons (Abst. 499). The authors reported that the extent of absorption was lower when given at the same time with either a low or high fat meal by 27% and 19%, respectively. Additionally, it was reinforced that Videx-EC needs to be taken at least 1 hour prior to any food as a 24% decrease in total drug exposure was seen when it was given only 1 hour before a light meal.
Several combination protease inhibitor pharmacokinetic profiles were presented. Can the popular Fortovase/Norvir combination be taken only once a day? Research presented here suggests that it can -- but more research needs to be done to prove that the once-daily dose is actually effective. Montaner, et al., showed data on 20 HIV positive African Americans (11 men/9 women) receiving Fortovase (saquinavir soft-gel) 1,600 mg with 100 mg of Norvir (ritonavir) once daily (Abst. 1920). After four weeks of therapy, the trough level was drawn (the amount of drug in plasma at the end of a dosing period -- in this case it was done at 24 hours after the previous dose). Good news: the average drug plasma level was about 9.4 times greater than what an acceptable trough level would be. Shelton, et al., presented data on 12 (5 male/7 female) methadone patients taking 1,600 mg saquinavir/100 mg ritonavir once daily (Abst. 492). In this patient population, somewhat lower troughs were seen compared to Montaner's data, yet 83% of these persons still had levels that would be expected to suppress viral replication (lower the viral load).
The optimal Agenerase (amprenavir) dose to be used with ritonavir was being researched by Garraffo, et al. (Abst. 489). Here, researchers provided scientific evidence for combination doses that were already widely prescribed by HIV specialists.
Using 10 (9 male/1 female) HIV-infected persons, plasma levels of amprenavir were obtained and compared to various dosage regimens. Each patient took amprenavir at full FDA-approved dosage (8 100 mg capsules twice daily), then 600 mg amprenavir with 100 mg of ritonavir twice daily and then finally, 1,200 mg amprenavir with 200 mg ritonavir once daily. Each dose was taken for 10 days prior to 8-10 plasma levels being taken. The elimination of amprenavir (APV) from the body was decreased by 50% when given with either dose of ritonavir (RTV). The trough levels of amprenavir were higher when subjects received the 600 mg APV/100 mg RTV compared to 1,200 mg APV/200 mg RTV, but both of these were much higher than that seen with 1,200 mg APV twice daily. Since this conference, the FDA has approved the 600 mg APV/100 mg RTV dosing regimen.
Correlating the levels of Viracept (nelfinavir) to future regimen failure was the intent of Le Moing, et al. (Abst. 1733). These researchers examined single time point plasma levels of 407 patients taking successful regimens (viral load <500 copies/mL) containing indinavir (240 subjects) or nelfinavir (167 subjects) for at least 4 months. As you would expect, the researchers found a correlation between lower than expected plasma concentrations of nelfinavir levels as well as lower levels of its active metabolite (M8) and failure of therapy (at least one viral load >500 copies/mL after the fourth month). (In the past few years research has found that a drug's metabolite -- the form it takes inside the body -- is often more important than the drug itself, for all diseases. This is one of the earliest studies looking at an HIV drug metabolite.) The authors did point out weaknesses of the study and stress the need for further studies to be done in a controlled, research environment prior to any recommendations being made about monitoring plasma levels of any antiretroviral.
This point was reinforced by DiCenzo et al. (Abst. 751 and 487). This collaboration of notable researchers presented two posters that examined what information could be learned from different sampling methods. Basically, they took single time samples (at any point during the day when the patient came into the clinic and was taking the medicine) and compared how accurate and reproducible the results were when compared to a full day's worth of blood draws. The results are important in helping clinicians understand how to best utilize and interpret TDM data. These researchers found that taking less than two blood samples during one dosing period was not informative. The recommendation was that for the most precise and unbiased estimates to be obtained, at least 2 to 3, but seeking 4 to 6 samples would give the best data. The likelihood of a clinic being able to fiscally, physically or emotionally have every patient on antiretrovirals get this intensive sampling procedure done is small.
To summarize, the data presented at ICAAC that displayed research on the use of measuring antiretroviral blood levels do not support this being done as a part of routine clinical practice. This is not meant to dissuade clinicians from measuring plasma levels when legitimate concerns arise regarding absorption, interactions or other clinical scenarios. Obtaining plasma levels of antiretrovirals at this time point should continue to be pursued in prospective, randomized, controlled research environments in order to provide infected and affected persons, clinicians and third-party payors (insurance) with consistent, clear and indisputable results. With upcoming conferences in 2002 (4th International Workshop on Antiretroviral Clinical Pharmacology, World AIDS, 42nd ICAAC, etc.) where more TDM studies are surely to be presented, it is hoped these answers are forthcoming.
Patrick G. Clay, Pharm.D. is an Assistant Professor of Pharmacy Practice at the University of Missouri-Kansas City School of Pharmacy. He is also the HIV Clinical Specialist at the KC Free Health Clinic, 3515 Broadway, Kansas City, MO 64111. Clay can be reached by phone: (816) 777-2721; fax: (816) 753-0804; or email: firstname.lastname@example.org.
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