A population based, retrospective cohort study conducted by Richard Kim PhD, David G.Bailey PhD, Salimah Z. Shariff PhD, Muhammad Mamdani Pharm.D MPH, showed that the administration of statins with antibiotics could heighten the risks of ADRs especially in elderlies because statins are mostly prescribed to such patients and they are more susceptible to drug-drug interactions and side effects due to these interactions.
Clarithromycin: a semisynthetic macrolide antibiotic used for treatment of various respiratory conditions like acute exacerbation of chronic bronchitis, acute maxillary sinusitis, myobacterial infections and is also given for indications like peptic ulcer disease, skin/skin structure diseases. It is a potent inhibitor of Cytochrome P450 3A4 (CYP3A4).
CYP3A4: present in our liver and intestines is an important member of the cytochrome P450 family of oxidizing enzymes, involved in oxidizing foreign organic molecules (xenobioitics) such as toxins or drugs for the removal of such substances from the body.
Statins: are the cholesterol lowering drugs showing their mode of action by inhibiting the enzyme HMG-CoA reductase in the liver which is responsible for producing cholesterol.
Although statins possess a very secure profile of their safety, but still certain internet surveys which were conducted in 2012 revealed these drugs not to be very risk free or ADR free. One-third of the statin users were found to be experiencing noxious effects due to these agents. This drug was seen to be able to cause acute kidney injury (AKI), hyperkalemia, rhabdomyolysis (a syndrome caused because of the injury to skeletal muscles involving leakage of large quantities of potentially toxic intracellular contents into plasma).
It was believed that statins whose metabolism is not dependent on the CYP3A4 pathway can be easily given with the drugs that do interact with CYP3A4, but the recent study opposes this idea and suggests that this might not be the case and even non CYP3A4 metabolizing statins may be capable of producing toxicity and adverse drug events with CYP3A4 inhibiting agents like Clarithromycin due to a completely different pathway and mechanism.
Statin toxicity: when statins are administered with drugs which alter the functioning of enzymes involved in the pharmacokinetics of statins can lead to an increased risk of statin toxicity. The inhibition of CYP3A4 plays a significant role in the toxicity by elevating the levels of statins.
Recent studies have shown that the toxicity can also be take place due to the reduced drug transporter mediated hepatic uptake of statins e.g. several haplotypes in liver — specific organic anion- transporting polypeptides 1B1 (OATP 1B1) increases the blood concentrations of statins like Rosuvastatin and Pravastatin which are not CYP3A4 metabolized statins.
Clarithromycin is an inhibitor of OATP1B1 and OATP1B3 which was observed in hepatocyte cell cultures.
Study:was published in CMAJ December 22, 2014.
Objective: to find out if a concurrent use of clarithromycin with non CYP3A4 metabolized statins is possible for increasing the risks of adverse drug events.
The risks of ADRs… rhabdomyolysis, AKI, hyperkalemia and death by co administration of statins and clarithromycin were compared with the coadministration of statins with azithromycin (macroide antibiotic which is not an OATPs inhibitor). Azithromycin was used as a control group because Clarithromyci and Azithromycin independently are used for almost indetical indications and they are very close to each other in respect of clinical use patterns and rates of ADRs.
Statins used in the study were rosuvastatin, pravastatin and fluvastatin.
Method: data of patients of at least 66 years or older were collected between June 2002 and March 2013. All of these patients were on continuous therapy of non CYP3A4 metabolized statins and had also received a co-prescription for either clarithromycin or azithromycin. The date of first co-prescription of a study antibiotic served as the index date.
104041 patients were involved out of which 51523 were in clarithromycin group and 52518 were in the azithromycin one. The median doses were… clarithromycin 1000mg/d for 10 days and azithromycin 300mg/d for 5 days.Common prescriptions with statins were rosuvastatin 70% > pravastatin 21% > fluvastatin 3%.
Exclusion criteria: those patients were not included in the study who;
- had an incomplete medical records.
- had severe infections.
- received any antibiotic in 30 days before the index date.
- had a prescription for a potent CYP3A4 inhibitor ( e.g. chloramphenicol, antifungal, protease inhibitor etc) dispensed in 6 months before the index date.
- had received a prescription for more than one type of antibiotic or statin on the index date.
Follow up: 30 days after the index date.
Result: co prescription of clarithromycin with these statins showed an increased risk of;
- hospitalization with AKI ( adjusted relative risk 1.46)
- hospital admission with hyperkalemia (RR 1.87)
- all cause mortality (RR 1.32)
- the hospitalization with rhabdomyolysis was less (RR 2.27).
The co adminstration of clarithromycin with a non CYP3A4 metabolizing statin can cause modest but statistically important increase in the adverse drug events.
Reason of ADRs: not because of CYP3A4, but due to lessened functioning of OATP1B1 & OATP1B3 leading to increased systemic levels of non CYP3A4 metabolizing statins, because statins are a substrate for this polypeptide and 30% of statins get transported into liver by the help of this certain polypeptide. This study also suggests that invivo inhibitory effects may not only be present on just OATP1B1 & OATP1B3 but also on NTCP ( sodium taurocholate co transporting peptide, a liver specific bile acid transporting polypeptide) which is a binding site for the transportation of statins.
US FDA recommends non CYP3A4 metabolized statins as a safer alternative with CYP3A4 inhibitors, but researchers now believe that these findings are showing that non desired ADRs can still occur with non CYP3A4 metabolized statins and clarithromycin because of drug- drug interactions independent of CYP3A4 pathway.
Use of azithromycin or other antibiotics which donot interact with statins is a safer alternative.
According to Dr Kevin Marzo, chief of cardiology at Winthrop University Hospital, N.Y… physicians now need to be made aware of newly discovered interactions that can prove detrimental to a patient’s health & they should start considering the use of safer alternative antibiotics.
The study’s author Dr Amit believes that for every 100 patients, there is a one patient suffering from these ADRs. He also said ” many people stop taking statins because they are concerned about the harfmful effects of it & this study is providing an opportunity to improve their safety.”
According to David Bailey PhD, although the frequency in the study shown is low but administration of clarithromycin with statins can cause adverse events as an outcome of accidental statin overdose toxicity.
Proper use: Researchers are now stating that
- its better to only use clarithromycin when highly required
- or to give a break to statins while using clarithromycin for a short duration
- or entirely prescribe an alternative antibiotic.
My thoughts on topic: this means that with the increasing demand and use of statins, the various drug interactions with these agents should not be neglected & should be properly emphasized as certain side effects can prove more problematic in elderly patients than any other patients and that this study is opening a gateway to consider that administrating a CYP450 iso enzyme inhibitor with an agents which do not undergo metabolism via that specific enzyme may not always prove beneficial.
- CMAJ December 22, 2014