Drug-drug interactions can be either pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions are the primary concern with ARV drugs.
Pharmacokinetic interactions occur when one drug alters the absorption, distribution, metabolism or excretion of another drug, possibly increasing or decreasing its plasma concentration. For ARV drugs the interaction types of concern are absorption, metabolism and excretion.
Interactions affecting drug absorption
Drug absorption may be altered by a change in gastric acidity, by chelation, or by alterations in intestinal membrane transport or intestinal cytochrome P450 enzyme activity. Examples are:
- An increase in gastric pH due to proton pump inhibitors, H2 antagonists or antacids can reduce the absorption of acid-sensitive drugs such as atazanavir or rilpivirine.
- Polyvalent cations (e.g. magnesium, zinc, calcium, iron) in antacids, vitamin/mineral supplements or iron preparations can bind to integrase inhibitors and reduce their absorption.
- Induction of efflux transporters such as P-glycoprotein, and/or the cytochrome P450 3A4 enzyme (CYP3A4) (e.g. by rifampicin) in the intestinal wall may significantly decrease the absorption of a number of drugs, including some ARVs. In contrast, inhibition of P-glycoprotein (e.g. by ritonavir) and/or CYP3A4 (e.g. by ritonavir) may increase the absorption of some drugs including several ARV drugs.
Interactions affecting drug metabolism
Drug metabolism occurs though enzyme systems located primarily in the liver. The enzymes most commonly associated with drug interactions are those of the cytochrome P450 superfamily and the uridine diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes which are responsible for glucuronidation.
The cytochrome P450 enzyme system is the major mediator of drug metabolism, with CYP3A4 and CYP2D6 enzymes being the most active. Many ARV drugs are metabolised by (i.e. are substrates for) cytochrome P450 enzymes and may also independently induce and/or inhibit a number of other CYPs to varying degrees. The strength of the enzyme inhibition or induction is important with strong inducers and inhibitors more likely to produce a greater clinical effect. Induction of CYP450 enzymes can result in lower exposure of the affected drug, potentially reducing its efficacy, for example, efavirenz can reduce apixaban levels (by CYP3A4 induction). Inhibition of CYP450 enzymes can increase the exposure of the affected drug, potentially increasing the risk of toxicity, for example, protease inhibitors increase midazolam exposure (by CYP3A4 inhibition). When substrates of the same CYP450 enzyme are co-administered, their rates of metabolism can change. This may alter the plasma concentration/s of the drug/s and increase the risk of toxicity, for example, caution is advised when prescribing colchicine and simvastatin (both CYP3A4 substrates), as concomitant use may result in myopathy and rhabdomyolysis
UGT enzymes metabolise a small number of drugs with UGT1A1 being the most active enzyme. UGT enzymes can be induced or inhibited. Ritonavir induces glucuronidation, (as do some other drugs e.g. rifampicin) and may reduce levels of other drugs (e.g. thyroxine, lamotrigine). Integrase inhibitors are substrates of UGT1A1 and dose adjustment is required when an integrase inhibitor is co-prescribed with rifampicin
Ritonavir and cobicistat are both potent inhibitors of CYP3A4; when either drug is co-administered with an ARV agent that is metabolised by CYP3A4, such as a protease inhibitor or elvitegravir, the exposure to that ARV drug is increased. This effect is commonly referred to as “boosting”.
It is important to note that cobicistat and ritonavir are not selective in their “boosting” action and have different drug-drug interaction effects. Ritonavir has a much more complex interaction profile due to its effects on other CYP450 enzymes such as CYP2D6 (inhibition), CYP2C9 and CYP2C19 (induction), and UGT1A1 (induction) as well as being an inhibitor of various membrane transporters (e.g. P-glycoprotein). Cobicistat also inhibits CYP2D6 plus several membrane transporters including P-glycoprotein. Therefore, when checking for potential drug interactions with pharmacokinetically enhanced drugs it is important to consider the effects of both the drug and the enhancer.
Interactions affecting drug excretion
Transport proteins in the liver, biliary tree and kidney function in drug elimination. Drug transporter interactions may alter transport activity at these sites potentially affecting drug exposure by increasing or decreasing the rate of elimination of the affected drug. Knowledge and understanding of these drug transporter interactions is evolving. Drugs including a number of ARV drugs may be enzyme inducers, enzyme inhibitors, and/or substrates of drug transporters. For example, dolutegravir inhibits the organic cation transporter (OCT-2) in the kidney, so can decrease the clearance of metformin.