Ideally, a drug dose should be strong enough to have a therapeutic effect against a disease or condition, yet not so strong that it causes toxicity. Finding a correct range is complicated because the same dose of a drug will not produce the same concentration of drug in each individual who uses it.
There are differences in how each person’s body processes a drug. Despite this variation among individuals, an effective drug dose or range is usually determined through clinical trials in which large numbers of people volunteer to test an investigational drug. The dosing level that produces the best balance between safety, tolerability, and efficacy for the greatest number of people guides the decision-making process in establishing dosing levels.
When one drug is taken with another, an effect other than that achieved with each single agent can result. The interaction may lower or heighten the effectiveness of either one or both drugs and the results can be therapeutic, harmful, or neutral.
Pharmacodynamics describes what a drug does to the body: its biochemical and physiological effects, the correlation of action and effects of a drug with its chemical structure, and the mechanisms of the drug’s actions.
Pharmacokinetics (PK) looks at what the body does to the drug, examining its absorption, distribution, metabolism, and elimination. Many individual factors influence the amount of drug that actually gets into the bloodstream. The term PK refers both to the study of this process and to the process itself.
A drug interaction occurs when the pharmacodynamics or pharmacokinetics of a drug is altered by the intake of one or more other agents (other drugs, food, and/or drink). Studying the pharmacodynamic interaction of two or more agents used together establishes whether the results are additive, antagonistic, synergistic, or neutral in effect.
A pharmacokinetic interaction can change the absorption, distribution, metabolism, or excretion of one or all of the substances involved in the interaction. Looking at the interaction reveals whether the expected plasma level of one drug is altered through the interaction with another.
In itself, a drug interaction is neither good nor bad. Sometimes, it can be very useful. A good example of this is found with the anti-HIV drug ritonavir. Adding a small amount of ritonavir (a boosting dose) to saquinavir affects the absorption level of saquinavir, the length of time it works in the body, and its elimination.
When a boosting dose of ritonavir is added to indinavir, it does not significantly affect absorption or elimination, but does extend the length of time indinavir works in the body, meaning the person taking it can go longer between doses and the drug will still be working at a therapeutic level. The same is true of ritonavir added to amprenavir. Adding ritonavir to nelfinavir does not seem to have this effect. In this case, the drugs are using different pathways when they are metabolised in the body. The presence of one drug neither inhibits nor enhances the performance of the other.
An understanding of drug interactions is essential for those administering highly active antiretroviral therapy (HAART) and those receiving it. Drug interactions can range from insignificant changes in the plasma levels to changes large enough to cause major toxicities or virological failure.
Clinically significant drug interactions are common amongst patients
taking antiretroviral therapy, and research suggests that prescribing physicians may frequently be unaware of them.1 Potential PK interactions should be evaluated whenever a drug is to be added or withdrawn from therapy. Similarly, whenever an opportunistic illness occurs or there is a change in viral load, the possibility of a drug interaction taking place should be considered. Drug interactions can be helpful, deleterious, or neutral; what they should not be is ignored.
The HIV-Drug Interactions website created and managed by the University of Liverpool is an online resource for information on drug interactions. Interactive charts are available where users can enter the name of a drug and receive information on drug metabolism, transport and toxicity. It is also possible to search by specific toxicity or by gene. This site can be accessed at www.hiv-druginteractions.org.The website has also recently launched an interaction chart as an app for iPhones.