Ritonavir and PI-boosting: Using Drug/Drug Interactions to Our Advantage
July 14, 2000
Background on Ritonavir
Ritonavir (Norvir®, RTV) is a type of antiretroviral medication called a protease inhibitor (PI), used in combination with other antiretroviral drugs to treat people infected with HIV. Like other antiretrovirals, RTV interferes with the life-cycle of HIV to stop it from reproducing. More specifically, RTV works by blocking an enzyme, called protease, which is involved in the last step of viral replication. Once protease is blocked, HIV is no longer able to successfully assemble itself and infect other CD4+ cells.
RTV is available in both capsules and liquid form. When taken as the sole PI in a combination, the recommended adult dosage is either 1200 mg daily, taken as two doses of six 100 mg capsules, with food or 7.5mL of the liquid twice a day. To reduce side effects caused by RTV, people can begin with 300 mg twice a day and increase each dose by 100 mg every two to three days, until the recommended dose is reached.
The most common side effects of RTV are nausea, diarrhea, vomiting, stomach pain, taste change, fatigue, mild to severe skin sensitivity, and numbness around the mouth (circumoral paresthesias). Not everyone has side effects, but when they occur they may be mild, moderate, or severe. Some people report that the side effects are worse during the first few weeks of taking the drug and then taper off. These side effects may be severe but can be treated using over-the-counter agents for diarrhea and stomach upset. Symptoms usually improve after a month of therapy, once the body has time to adjust to the medication.
RTV and Dual-PI Therapy
The most common way to use RTV today is as part of a dual-PI strategy. The activity of RTV has been extensively studied in clinical trials, initially as the only PI and later in combination with other PIs. More recent studies have looked at RTV in combination with other PIs for two main reasons. First, when used as the only PI, RTV is not tolerated well due to gastrointestinal side effects such as nausea, diarrhea, vomiting, weight loss, and abdominal pain. Second, RTV may increase the amount of other drugs within the body since it prevents the liver from eliminating drugs.
When RTV is used in reduced doses, in combination with another PI, side effects may be less severe for some. Unfortunately, of all the PIs, RTV is most likely to cause liver function problems and raise blood lipid (fat) levels. PIs have also been associated with long-term metabolic side effects such as lipodystrophy [loss of fat in the face, arms, and legs, or increased fat deposits on the back of the neck or inside the abdominal cavity (belly)], forms of diabetes, increased cholesterol, and osteoporosis.
Drug/Drug Interactions: The Basis for Dual PI Therapy
Ritonavir, like many medications, is broken down and processed by the liver through an enzyme pathway called cytochrome p450. Taking RTV with other drugs that are metabolized the same way can change blood levels of each drug. As a result of these drug interactions, blood levels of some drugs may drop too low to be of benefit, or they may rise so high they cause serious side effects. Dosages of other drugs may therefore have to be raised or lowered, or some drugs may have to be changed.
These drug-level interactions are the reason RTV is now so commonly used in combinations for antiretroviral therapy. When used in antiretroviral combinations, RTV can boost the levels of other drugs. This can reduce the number of pills taken daily, the food restrictions, and the cost. It also allows easier dosing schedules, improved adherence to the complex regimens, and possibly increased potency. For example, indinavir (Crixivan®) is usually taken as 800 mg every eight hours on an empty stomach, with at least 1.5L of clear fluid daily. Combining a low dose of RTV (100 mg or 200 mg, two times a day), reduces the dose of indinavir to 800 mg twice a day and allows indinavir to be taken with food. RTV is also being used in combination with the PIs amprenavir (Agenerase®), saquinavir (Fortovase®) and nelfinavir (Viracept®). In addition, RTV is a component of the new PI lopinavir (ABT-378, Kaletra®) now in expanded access. Table 1 illustrates the effects of RTV on drug levels and dosages of other PIs.
Data on long-term safety and effectiveness is limited for many RTV-containing combinations. Currently, only the RTV/saquinavir combination is recommended by the most recent Department of Health and Human Service guidelines. Other combinations, including indinavir/nelfinavir, RTV/nelfinavir, and amprenavir/RTV-based regimens, are still being evaluated. For further information, contact your healthcare provider or pharmacist.
The potentially important benefits of RTV boosting and dual-PI therapies need to be confirmed in larger and longer studies. Some possible downsides of combining two PIs are the possibility of a greater chance of short-term side effects (e.g., nausea) for some people and the metabolic irregularities associated with PIs.
Although it is sometimes advantageous that the levels of other PIs in the body are increased by RTV, it should always be remembered that this same effect may increase the levels of other drugs in the body to dangerous levels. Abbott Laboratories, the manufacturer of RTV, has compiled a list of about 200 drugs that may interact with RTV. (A PDF version of this list is available on the Web at http://www.rxabbott.com/product/nor/norpi.htm. Choose the link "Product Labeling".)
Anyone about to start a combination including RTV should review all the medications they are taking with their healthcare provider and pharmacist, since some of the drug interactions are potentially life-threatening. It is important to remember that over-the-counter medications and herbal products such as St. John's wort may have potential interactions with PIs. It is strongly recommended that recreational/street drugs such as amphetamines, ecstasy or GHB not be taken with RTV, as these combinations can lead to unintentional overdoses.
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Ezine.