Risk Factors for Arthralgias or Myalgias Associated With Quinupristin-Dalfopristin Therapy

Peggy L. Carver, Pharm.D., Emily Whang, Pharm.D., Heather L. VandenBussche, Pharm.D., Carol A. Kauffman, M.D., Preeti N. Malani, M.D.

Disclosures

Pharmacotherapy. 2003;23(2) 

In This Article

Discussion

Quinupristin is converted to two conjugated metabolites and dalfopristin to one nonconjugated metabolite.[2] We were concerned that some patients could exhibit higher plasma concentrations of quinupristin, dalfopristin, or their metabolites. Because the frequency of arthralgias and myalgias may be higher in these patient populations, we felt it important to look for this possible association. Although single-dose (7.5 mg/kg) studies[12] suggest that age, sex, and obesity appear to have no clinically significant effects on the pharmacokinetics of quinupristin-dalfopristin, limited pharmacokinetic data suggest that plasma concentrations of quinupristin and dalfopristin may be slightly impaired in patients with severe chronic renal failure.[12] However, no accumulation of the parent drugs or their metabolites was evident in patients with end-stage renal disease who received an infusion of quinupristin-dalfopristin 7.5 mg/kg twice/day.

In patients with cirrhosis, mean values for area under the curve (AUC) of quinupristin and dalfopristin in combination with their respective metabolites were approximately 2.8 and 1.5 times higher than in healthy volunteers. Also, patients with high bilirubin levels (> 3 times normal) have experienced a marked increase in exposure to quinupristin metabolites (up to a 4-fold increase in AUC) because of delayed elimination of the drug.[12]

Quinupristin-dalfopristin does not significantly inhibit the human CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, or 2E1.[12] However, although quinupristin-dalfopristin is not metabolized by CYP3A4, it inhibits the biotransformation rate of specific CYP3A4 substrates, such as nifedipine, midazolam, terfenadine, and cyclosporine. Thus, concurrent drugs chosen for evaluation in this study were primarily known or suspected substrates, inhibitors, and inducers of this enzyme.

We also evaluated drugs such as digoxin that are substrates, inhibitors, or inducers of P-glycoprotein, and commonly used agents that interact (through other CYP pathways) with numerous drugs. Of these other agents, the most commonly administered were digoxin and omeprazole. Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors was monitored specifically because of their metabolism by the CYP pathway and the arthralgias and myalgias observed with elevated plasma concentrations of these agents. No patients in our study received these agents.

Myalgias or arthralgias were significant adverse events among patients receiving quinupristin-dalfopristin at our medical center. The 50% occurrence rate is higher than that observed in other reports, which noted these symptoms in 0-10% of patients receiving quinupristin-dalfopristin,[4,5,6,7,8] but is similar to that noted in other series.[9,10,11] In one report, 47% of 32 patients experienced arthralgias or myalgias related to quinupristin-dalfopristin, and 60% of the group with these adverse effects had received a liver transplant, versus 36% of those without symptoms.[9] Perhaps because of the small number of patients studied, significant risk factors for development of arthralgias or myalgias (e.g., chronic liver disease, receipt of liver transplant, or elevated bilirubin level) could not be established.

A study with a group of patients similar to our population, most of whom had received a liver transplant, reported a 33% frequency of arthralgias or myalgias. The results also showed that the frequency was dose related and did not occur in patients who had received a lower dosage of 5 mg/kg every 8 hours.[11] Another study noted a 36% frequency of arthralgias or myalgias associated with quinupristin-dalfopristin in 56 patients with cancer, most of whom had leukemia.[10] None of these studies assessed the effects of concomitant drugs on development of arthralgias or myalgias.

The etiology of arthralgias or myalgias related to quinupristin-dalfopristin remains unknown. We found a strong association between the occurrence of arthralgias or myalgias and liver disease or liver transplantation. It is tempting to speculate that these effects could be related to increased levels of quinupristin-dalfopristin or its metabolites that accumulate with hepatic dysfunction. Decreasing the dosage might diminish the risk for development of arthralgias or myalgias.[11] Symptoms improved quickly in the two patients whose dosage was decreased in our study.

We anticipated that inhibitors or competitors of the metabolism of quinupristin-dalfopristin or its metabolites by CYP3A4 might result in elevated drug concentrations of quinupristin-dalfopristin or its metabolites. However, only two drugs -- mycophenolate and cyclosporine -- were associated with arthralgias or myalgias, and mycophenolate is not metabolized through the CYP3A4 route. Mycophenolate is metabolized completely to mycophenolic acid (the active form of mycophenolate), which subsequently is metabolized to mycophenolic acid glucuronide by hepatic glucuronosyl transferase.[13]

Although theoretical, competition for metabolism by hepatic glucuronosyl transferase could result in altered concentrations of quinupristin or dalfopristin; however, no data support such an interaction. Despite the similarity in routes of metabolism of cyclosporine and tacrolimus, we found no association between tacrolimus therapy and development of arthralgias or myalgias. Our data suggest that inhibition of metabolism by CYP3A4 leading to accumulation of quinupristin-dalfopristin metabolites is probably not the primary mechanism of development of arthralgias or myalgias.

Physicians' notes for several of our patients made no mention of pain, whereas nurses' notes clearly reported pain with movement. In these instances, the primary team caring for the patient did not associate the pain noted by the nurses with quinupristin-dalfopristin. Caregivers should be aware that quinupristin-dalfopristin causes arthralgias and myalgias, and that these adverse effects appear to be more common in patients who have underlying hepatic disease or are receiving cyclosporine or mycophenolate.

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