Pharmacokinetic interactions occur when one drug alters the serum or tissue concentration of another by changing its absorption, distribution, metabolism or elimination. Such interactions can result in clinically significant changes in drug concentration which may require the dose of one or more drugs to be modified or may necessitate the use of an alternative drug or drugs. Annexes 8B and 8C list antiretroviral drug interactions that are of importance in resource-poor countries. Not all interactions are are listed, and the product insert information should be consulted. In comparison with the NNRTIs and PIs the NsRTIs have very limited drug interactions and they are therefore not included in the tables. Clinically significant pharmacokinetic interactions for the NsRTIs are primarily related to ddI buffer-associated decreases in the absorption of some drugs (see below).

Changes in drug absorption

Alteration of gastric pH

If a drug changes the gastric pH it can affect the absorption and hence the concentration of other drugs that have specific pH requirements for absorption. For example, ddI requires a higher gastric pH for optimal absorption; ddI is administered with an antacid buffer that raises the gastric pH. Thus, ddI decreases the absorption of drugs whose absorption requires low gastric pH, such as ketoconazole, itraconzole, tetracyclines, quinolone antibiotics, IDV and LPV/r. If coadministration occurs these drugs should be given two hours apart from ddI.

Presence or absence of food

Food can enhance or decrease the bioavailability of a drug, often bcause of its effect on gastric acidity. It is therefore recommended that some drugs, e.g. ddI and IDV, be administered one hour before or two hours after eating. Additionally, the bioavailablity of lipid-soluble drugs, such as efavirenz, may be enhanced when administered with a high-fat meal.

Chelation

The binding of two drugs/compounds to form insoluble complexes that cannot be absorbed can change the absorption of a drug. For example, the absorption of the fluoroquinolone drugs is significantly decreased by chelation with calcium in milk products or with cations such as those of aluminum, magnesium, iron or zinc found in antacids or multivitamins.

Changes in distribution

Protein-binding

Things that alter the protein-binding of a drug affect the amount of free drug that is available to produce a therapeutic effect. For example, warfarin is 99% protein-bound and if given with other protein-bound drugs, such as EFZ, it can be displaced from its protein sites. This places the patient at risk for bleeding and requires the prothrombin time to be monitored.

Hypoalbuminaemia

Patients with low albumin levels can experience an increased therapeutic effect and/or a risk for toxicity of drugs that are highly protein-bound, such as warfarin or phenytoin.

Changes in metabolism

Metabolism in the liver cytochrome P450 system

The induction or inhibition of various P450 enzymes by one drug can significantly alter the serum concentration of another drug that is metabolized by the same P450 enzyme. The PIs and NNRTIs are primarily metabolized by the P450 CYP3A4 isoenzyme and can inhibit or induce this isoenzyme, resulting in increases or decreases in the concentration of concomitantly administered drugs. Moreover, other drugs that inhibit or induce this isoenzyme can bring about increases or decreases in the concentration of concomitantly administered PIs and/or NNRTIs. Each PI and NNRTI has a different drug interaction profile, depending primarily on its potency as an inducer or inhibitor of the CYP3A4 and/or other P450 isoenzymes.

Of all the PIs, RTV is the most potent inhibitor of CYP3A4 and other isoenzymes, and consequently the largest amount of drug interactions and contraindications are associated with it. This property of RTV has been exploited through its use at low dose as a pharmacological booster with other PI drugs in order to raise their serum concentration, thus allowing lower doses and/or decreased frequency of administration of the boosted PIs. IDV and NFV inhibit the CYP3A4 isoenzyme with similar potency. They are less potent inhibitors than RTV and present a smaller risk of drug interactions. SQV exhibits the smallest amount of drug interactions. NVP is a potent enzyme inducer, and EFZ is both an inducer and an inhibitor of CYP3A4. The many drug interactions associated with PIs and NNRTIs require that a careful review of medication be conducted before therapy is started, with attention to the potential need either to modify the drug dose or doses of the antiretroviral drug and/or the non-antiretroviral drug or to substitute an alternative drug.

Rifamycins have significant interactions with other drugs in relation to hepatic metabolism. Rifampicin is a potent inducer of hepatic metabolism and significantly decreases the concentration of PIs to subtherapeutic levels; the concomitant administration of PIs with rifampicin is not recommended, except possibly for SQV/r (see Chapter XII). Rifabutin is a less potent inducer of hepatic metabolism than rifampicin. However, rifabutin levels can be markedly increased with concomitant administration of some PIs, and this can result in an increased risk of, for example, myalgias, uveitis and neutropenia. The rifabutin dose may therefore have to be decreased if this drug is concomitantly administered with some PIs.

NFV, RTV and the NNRTIs can significantly decrease the estrogen concentration in oral contraceptives. Consequently, women taking these drugs cannot rely on oral contraceptives and should use another or an additional method of contraception. IDV and SQV do not affect estrogen levels unless RTV-boosting drugs are given (i.e. SQV/r). It is important to counsel women about the need for additional or alternative contraception if they are treated with these drugs.

PIs and EFZ can raise the serum concentration of cisapride and non-sedating antihistamines (astemizole, terfenadine), which can lead to cardiotoxicity. They can also increase the serum concentration benzodiazapines, and this can result in prolonged sedation. PIs and these other drugs should not, therefore, be administered concomitantly.

Changes in elimination

Kidney function

The inhibition of the tubular secretion of one drug by another that is eliminated by the kidney can result in changes in drug concentration. For example, probenecid can increase levels of ZDV.