HIV: Treatment, interactions

Safe to use in combination with HAART

Many interactions between protease-inhibitors and other drugs have been described. When in doubt, an up to date table should be consulted. It is however useful to have some idea of which drugs cause no major interactions. The following are likely to be safe:

Cytochrome 450

Metabolism is an important elimination pathway for lipophilic drugs. The biotransformation of drugs takes place mainly in the liver, but also in the intestinal mucosa and lungs. A number of drugs undergo partial or complete biotransformation in the liver and/or the intestine before they get into the systemic circulation. This is the first-pass metabolism. Oxidation is often an important stage in the biotransformation and takes place via mono-oxygenases or “mixed-function” oxidases. Cytochrome P450 is the key enzyme in these reactions. The enzyme uses NADPH and oxygen. The term cytochrome P450 (CYP) in fact covers a large number of isoenzymes which are subdivided into families and subfamilies based on similarities in amino acid composition. These families are designated with a number (e.g. CYP3). Subfamilies are designated with a letter (e.g. CYP3A). Individual isoenzymes are again designated with a number (e.g. CYP3A4).

More than 30 CYP-isoenzymes have been identified in man. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are especially important for biotransformation of many clinically used drugs. There is also a substantial variability in the enzyme activity of cytochrome P450. This may be responsible for the variability in pharmacokinetic parameters and for the therapeutic response. Genetic factors and interactions with drugs or other substances (inhibition or induction) are two important causes of this variability. For many drugs the expression of the enzymes responsible for the biotransformation is polygenetically controlled. This means that several genes control their metabolism. This is responsible for part of the unpredictable “spontaneous” interindividual variability in biotransformation. For some medicines the expression of enzymes responsible for the metabolism is monogenetically controlled. This means that only one gene controls the metabolism. For these medicines the interindividual differences in pharmacokinetic parameters and in therapeutic response are much more clearly identifiable. If there are two or more variants with different activity (genetic polymorphism) for such a gene, there must be at least three genotypes and two phenotypes at the population level, e. g. homozygotes, heterozygotes; rapid metabolisers and slow metabolisers. Genetic polymorphism for cytochrome P450 has hitherto been reported for oxidative reactions catalysed by CYP2D6 and CYP2C19. Between 5 and 10% of the Caucasian population are slow metabolisers of medicines metabolised by CYP2D6 (dextromethorphan for example). Approximately 2 to 5% are slow metabolisers of medicines metabolised by CYP2C19. In a slow metaboliser, administration of the usual dose can lead to excessively high plasma levels of the drug, due to a decreased elimination or first-pass metabolism. On the other hand the effectiveness of the drug can be reduced in a slow metaboliser when the effect of a medicine is due to its metabolite. This is demonstrated, for example, by codeine which, under the influence of CYP2D6 is normally metabolised to morphine which causes the analgesic effect. In slow metabolisers, in whom the gene coding for CYP2D6 is defective or absent, this transformation does not take place, resulting in a reduction of the analgesic effect.

Treatment, cytochrome P450 inhibition

Some medicines are potent inhibitors of a certain isoenzyme. For instance, all protease inhibitors inhibit cytochrome P450. Ritonavir is an important inhibitor of CYP2D6 and CYP3A4. Hence, a low dose of ritonavir can be used in order to reduce the dose of another protease inhibitor (basis of the combination Norvir®-Crixivan® and Kaletra®). Competition can occur when two drugs that are substrates for the same CYP isoenzyme are administered simultaneously. This can lead to inhibition of the metabolism of one or both medicines. Some medicines inhibit the activity of a certain CYP isoenzyme without themselves being a substrate for it. An example is quinidine, which is a potent inhibitor of CYP2D6, but which is itself metabolised by CYP3A4. Foodstuffs can also interfere with the metabolism of medicines. Certain constituents in grapefruit juice inhibit CYP3A4, thereby increasing the bioavailability of terbinafine, calcium antagonists of the dihydropyridine group and cyclosporine, among others.

Treatment, enzyme induction

Some medicines can selectively intensify the synthesis of one or more isoenzymes of CYP, though not all CYP isoenzymes are inducible. Induction can substantially reduce the efficacy of a medicine. An example is the induction by rifampicin of the metabolism of oestrogens in oral contraceptives, which can lead to failure of “the pill”. Barbiturates and rifampicin are known inducers of several CYP families. Oestradiol (oral contraceptive) blood levels are lowered by nevirapine, ritonavir, nelfinavir, rifampicin, rifabutin and possibly by amprenavir, which can reduce the effectiveness of “the pill”.