Have you ever wondered why a 210-pound man takes the same dose of a protease inhibitor as does a 110-pound woman, or questioned the difference between a dosage to be taken every eight hours versus one taken three times a day? Why do some drugs have to be taken with food and others on an empty stomach? Why do you have terrible side effects from your cocktail, but your friend takes the same drugs with no problems?
In the future, many of these contradictions will be resolved with the use of Therapeutic Drug Monitoring (TDM), the next big test to be used in HIV.
In order for anti-retroviral drugs to inhibit HIV replication, enough drug must be in the blood at all times to be effective, but not so much drug that it will cause side effects and possibly more serious long term problems. This is called the therapeutic range. We now use an average of levels found in clinical trials volunteers. The promise of TDM is that if we could determine the best blood level of a drug for a particular person, we could then customize an exact dosage for each drug for that patient's regimen. A blood test called a phenotypic assay (measuring drug resistance) could tell doctors which drugs may or may not be effective in suppressing viral replication in an individual.
From the results of the phenotypic test, a clinician could calculate the exact dose of that drug that would be necessary to be effective. This dosage would be designed to achieve that drug level for the correct amount of time, therefore optimizing the benefits of drug therapy and reducing side effects specifically for an individual. The dose will differ for every particular (drug) combination. A person's Crixivan dose for one combo would differ from his or her Crixivan dose in a different combo. All in all, we would therefore optimize the benefits of the combinations and reduce the risks of over-medicating.
TDM is used today in many other diseases with success. For example, treatments for asthma, epilepsy, and bacterial infections all use TDM to determine the correct dosage regimens and improve the desired outcome of therapy for an individual.
In order to understand how this all works, let's go over some terminology. When a drug is taken "by mouth," the amount of drug in the blood increases as it is absorbed in the body to the maximum concentration (Cmax), and then gradually is eliminated (metabolized) from the body over time (called the half-life, or T-1/2). Most anti-retroviral drugs, especially the protease inhibitors, are eliminated from the bloodstream by the liver and kidneys. The rate at which this clearance happens is very important because it affects the amount of drug in the blood and the length of time it is there.
The Therapeutic Range is the section of time where the drug level is above the amount needed to be effective and below the level that is risking side effects. TDM's goal is to keep drug levels in this range at all times, although the Therapeutic Range has yet to be determined in most of the anti-retroviral drugs we are using. For most research that is available about HIV Therapeutic Range at this time, concentrations used are the researcher's "best guesses." Moreover, the range is believed to be very narrow, with less room for error than seen with other medications. If you consider all the people who tested an HIV drug, you find that some of them achieved optimal blood levels of the drug and others didn't. Their level was above or below. The dosage that is finally approved is an average. For many of you, this dose is too high or too low. That's where TDM comes in.
Here is where it gets complicated.
There are challenges to using these concepts in practice.
Bioavailability is the fractional amount of drug that eventually gets into the blood after taking an oral dose of medication as compared to the same dose of medicine that is injected intravenously. Bioavailability varies from drug to drug and is sometimes difficult to measure, and would make a significant difference in measuring the Therapeutic Range accurately. Saquinavir HGC (Invirase hard gel capsule), for example, has a 4% bioavailability -- 96% does not make it to the blood. Reformulated saquinavir SGC (Fortovase soft gel capsule) is 20% bioavailable, giving much higher blood levels than the original formula.
Genetics play a role, so everybody's different. Is there a difference in the amount of drug needed for a person with a high viral load versus a person who is undetectable? Variations exist in a patient's ability to absorb and metabolize medications. Different people have different abilities to absorb and metabolize medications, based on this and other differences. Differences can be seen between men and women, adults and adolescents, and among the races. Since most existing pharmaceutical research is done using adult white men, much more information is needed.
Does every tablet or capsule that is manufactured in a particular batch dissolve at exactly the same rate? The FDA does regulate this very closely, but it is possible that the dosage form of drug products can affect drug responses.
Impaired liver or kidney functions will definitely affect the measurement of Therapeutic Drug Monitoring. Co-infection with hepititis could be a factor as well.
Let's not forget about everyone's favorite topic, adherence. The precise manner in which the anti-retroviral drugs are taken will still be critical when accessing Therapeutic Drug Monitoring. For example, nelfinavir (Viracept) will still need to be taken with food for better absorption, despite the availability of TDM.
Drug interactions (both good ones and harmful ones) can drastically change the pharmacokinetics (a drug's action inside the body). Studies evaluating TDM have generally been done on individual drugs, not on drugs used in combination. The Therapeutic Range for Crixivan and Norvir together may be different than that of Crixivan and Norvir used separately.
Money is always an issue. TDM is available here and in England now at a cost of about $50-$75 per patient, per drug. Who will pay for these tests? Will these lab tests be covered by Medicaid programs or state ADAPs (AIDS Drug Assistance Program)? Some suggest that the pharmaceutical companies should foot the bill, since they will benefit from the patient's ability to stay on their drug regimens for a longer period of time. Early reports seem to suggest that the drug companies have responded positively to that idea.
Let's imagine for a moment that we can work out all of these issues. We still have to deal with the logistical aspects of applying all of this new information at the clinic in real patients. In reality, Therapeutic Drug Monitoring is no different than viral load testing was years ago and phenotypic and genotypic tests are today. More information and time are needed to improve the technical skills of clinicians to use this new tool in clinical practice. We will be using Therapeutic Drug Monitoring in the management of HIV/AIDS; it's just a question of when.
Glen Pietrandoni is director Clinical Pharmacy Services for the Walgreen Specialty Pharmacy, focusing on HIV, located in the Howard Brown Health Center of Chicago.