Description: PDE4 (phosphodiesterase-4) inhibitors block the action of the enzyme phosphodiesterase-4. PDE4 inhibitors specifically block inflammation, so they are used to treat a variety of inflammatory diseases from asthma and chronic obstructive pulmonary disease (COPD) to psoriatic arthritis and ulcerative colitis. (British Journal of Pharmacology “PDE4 inhibitors: current status,” Oct 2008). Some of these diseases can be treated with topical drugs, which makes the PDE4 inhibitors side effects less common. On the other hand, oral formulations are associated with substantial PDE4 inhibitors side effects.The two major oral PDE4 inhibitors are Otezla (apremilast) and Daliresp (roflumilast). Apremilast is specified for the treatment of psoriatic arthritis or plaque psoriasis. Roflumilast is designated for the treatment of COPD. (Apremilast (Otezla)
National Drug Monograph, January 2015; Roflumilast drug label as reported by the FDA).
Common Side Effects
The most common side effects associated with Otezla (apremilast) include: various forms of headaches, weight loss, diarrhea, nausea, gastrointestinal issues, back and muscle pains, and upper respiratory issues. (Otezla drug label). The most common side effects associated with roflumilast include: headache, substantial weight loss, gastrointestinal issues, weight loss, diarrhea, nausea, headache, dizziness, back pain, and insomnia. (Roflumilast drug label as reported by the FDA, 2011).
Liver Metabolism May Underlie PDE4 Inhibitors Side Effects
Both apremilast and roflumilast are major substrates of the cytochrome P450 enzyme 3A4 (CYP3A4). These medications require the CYP3A4 liver enzyme to break down the active medication. Thus, CYP3A4-metabolized drugs can affect, and be affected by, PDE4 inhibitors; which causes potential drug-drug interactions and PDE4 inhibitors side effects.
For example, strong CYP3A4 inducers may decrease the serum concentration of apremilast or roflumilast – to such a degree, that prescribing instructions suggest avoiding these combinations. Even “moderate” CYP3A4 inducers can lower the serum concentration of PDE4 inhibitors. On the other hand, strong CYP3A4 inhibitors including certain classes of antibiotics, some antifungals, and protease inhibitors may increase the serum concentrations of PDE4 inhibitors. Higher-than-expected concentrations these drugs may be responsible for key PDE4 inhibitors side effects. (International Journal of Chronic Obstructive Pulmonary Disease “Treating COPD with PDE4 inhibitors,” Dec 2007).
Understand Your Risk for Side Effects with the Rxight® Genetic Test
If you currently take one of the PDE4 inhibitors, or any other medications you or your prescriber(s) have concerns about, consider pharmacogenetic testing. Rxight® pharmacogenetic testing provides a full assortment of genotyping for various metabolic enzymes, including CYP3A4. This genotype will provide useful information for you and your healthcare provider(s)regarding you current medication regimen and may reveal actionable information about any PDE4 inhibitors side affects you may be experiencing. Additionally, Rxight® tests for over 200 other types of medications (both OTC and prescription) across over 50 pharmacological classes. It thus provides a “medication blueprint” for life which can be used to guide prescribers in current and future pharmacotherapy.
Contributors to this Article:
Michael Sapko, MD, PhD; Deborah Kallick, PhD, Medicinal Chemistry