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Probable interaction between efavirenz and cyclosporine

Tseng, Alicea,b; Nguyen, Mary E.a,c; Cardella, Carla,b; Humar, Atula,b; Conly, Johna,b

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aToronto General Hospital, Toronto, ON, Canada; bUniversity of Toronto, Toronto, ON, Canada; and cSt Michael's Hospital, Toronto, ON, Canada.

Received: 7 September 2001; accepted: 12 September 2001.

In vitro, efavirenz induces and inhibits cytochrome p450 isoenzymes, with induction effects being predominant [1]. Currently, data on the interaction between efavirenz and immunosuppressants are lacking. We would like to report an apparent drug interaction between efavirenz and cyclosporine in an HIV-infected patient.

The patient was a 39-year-old, newly diagnosed HIV-positive man whose previous medical history included depression, hypertension, pernicious anaemia, urinary tract infections, gout, and end-stage renal disease secondary to IgA nephropathy, requiring peritoneal dialysis in March 1995 and a living-related, human leukocyte antigen-identical kidney transplant in February 1996. The course of his post-transplant care was unremarkable, with no complications or rejection episodes. For the past few years, the patient had been receiving nifedipine XL 60 mg in the morning and 30 mg in the evening, with metoprolol 100 mg twice a day for hypertension and nefazodone 50 mg a day for depression. One month before admission, he was started on allopurinol 100 mg a day for gout. For rejection prophylaxis, he was maintained on prednisone 2.5 mg a day and cyclosporine (neoral), most recently at a dose of 200 mg twice a day since March 1999. The mean cyclosporine drug level using the fluorescence polarization immunoassay at this dose was 328 μg/l.

On 17 August 1999, the patient was admitted to our institution for fever of unknown origin, 20 lb weight loss, general malaise, and fatigue that had progressively worsened over the previous 6 months. A diagnosis of HIV was made shortly after admission. The patient's baseline CD4 cell count and viral load at that time was 352 × 106 and 5.38 log10, (Chiron 3 assay). On admission, the cyclosporine level was 307 μg/l. All standard medications were continued, and two doses of intravenous ciprofloxacin 500 mg every 12 h and two daily doses of prednisone 20 mg were given. Three days after admission, the patient's cyclosporine level was elevated at 372 μg/l. The cyclosporine dose was subsequently reduced to 175 mg twice a day and prednisone was changed to 2.5 mg a day. As a result, the cyclosporine levels gradually declined to an average of 203 μg/l (Fig. 1).

Fig. 1
Fig. 1
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On 25 August, nefazodone was discontinued and efavirenz 600 mg at bedtime, zidovudine 300 mg twice a day and lamivudine 150 mg twice a day were initiated. An initial rise in the cyclosporine level was noted for 2 days after antiretroviral initiation. The levels then proceeded to decline to 80 μg/l approximately 7 days after the first dose of efavirenz. In response, his cyclosporine was temporarily increased to 200 mg twice a day, and the patient was discharged on 4 September. Four days later, his cyclosporine was changed back to a maintenance dose of 175 mg twice a day. One month after antiretroviral initiation, his cyclosporine level had reached a nadir of 50 μg/l. At 2 years follow-up, the patient remains on the same medications, and is doing extremely well. His viral load has been continuously suppressed (< 50 copies/ml), his CD4 cell count is over 900 cells/mm3, and his renal function remains excellent (serum creatinine 119 μmol/l).

Cyclosporine is extensively metabolized by CYP3A4 isoenzyme, and is also a substrate and inhibitor of P-glycoprotein [2]. Drugs that are enzyme inducers or inhibitors would be expected to decrease or increase cyclosporine levels, and numerous interactions have been documented in the literature [3,4]. For instance, rifampin, phenytoin, and phenobarbital reduced cyclosporine concentrations by 39, 70, and 68.2%, respectively [5–7].

However, interaction data regarding the concomitant administration of cyclosporine and antiretroviral drugs are scarce. There has been one case report of an HIV-positive renal transplant patient whose cyclosporine levels tripled 3 days after the initiation of saquinavir; the postulated mechanism was competition for CYP3A metabolism and P-glycoprotein drug transport by saquinavir [8]. To date, there have been no other interaction reports involving antiretroviral agents and cyclosporine.

Efavirenz is a substrate of CYP3A4, and it predominantly exerts cytochrome p450 3A4 enzyme induction effects [9–13]. Although the initial effects of enzyme induction may be noticeable within a few days, the maximal effects would be expected after a few weeks, because of the time required for the synthesis of new metabolizing enzymes and the long half-life of efavirenz [14]. In our patient, cyclosporine levels began to decrease 5 days after efavirenz was added to a stable cyclosporine regimen, and reached a nadir (representing an 75% decrease from baseline) one month later.

In conclusion, we describe an apparently significant interaction between efavirenz and cyclosporine. Close monitoring of cyclosporine levels and serum creatinine is recommended when these agents are co-prescribed, and cyclosporine dosage adjustment may be required to maintain desired therapeutic levels in previously stable patients. The potential for a similar interaction may exist with nevirapine, which is also a potent enzyme inducer.

Alice Tsenga,b

Mary E. Nguyena,c

Carl Cardellaa,b

Atul Humara,b

John Conlya,b

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1. Dupont Pharma. Efavirenz (sustiva) product monograph. Mississauga, ON; 2000.

2. Novartis Pharmaceuticals. Neoral product monograph. Dorval, Quebec, Canada; 2001.

3. Lake KD. Management of drug interactions with cyclosporine. Pharmacotherapy 1991, 11: 110S–118S.

4. Campana C, Regazzi MB, Buggia I, Molinaro M. Clinically significant drug interactions with cyclosporin. An update. Clin Pharmacokinet 1996, 30: 141–179.

5. Freitag V, Skifton RD, Lake K. Effect of short-term rifampin on stable cyclosporine concentrations. Ann Pharmacother 1999, 33: 871–872.

6. Keown PA, Laupacis A, Carruthers G. et al. Interaction between phenytoin and cyclosporine following organ transplantation. Transplantation 1984, 38: 304–306.

7. Castelao AM, Sabate I, Grino JM. et al. Cyclosporine–drug interactions. Transplant Proc 1988, 20: 66–69.

8. Brinkman K, Huysmans F, Burger DM. Pharmacokinetic interaction between saquinavir and cyclosporine [Letter]. Ann Intern Med 1998, 129: 915–916.

9. Jorga K, Buss NE. Pharmacokinetic drug interaction with saquinavir soft gelatin capsule. In:39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA, 26–28 September 1999 [Abstract 339].

10. Benedek IH, Joshi A, Fiske WD, et al. Pharmacokinetic interaction studies in healthy volunteers with efavirenz and the macrolide antibiotics, azithromycin and clarithromycin. In:5th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 1–5 February 1998 [Abstract 347].

11. Sadler BM, Gillotin C, Chittick GE, Symonds WT. Pharmacokinetic drug interactions with amprenavir. In:12th World AIDS Conference. Geneva, Switzerland, 28 June–3 July 1998 [Abstract 12389].

12. Benedek IH, Fiske WD, White SJ, Stevenson D, Joseph JL, Kornhauser DM. Pharmacokinetic interaction between multiple doses of efavirenz and rifabutin in healthy volunteers [Abstract]. Clin Infect Dis 1998, 27: 1008.1008.

13. Tashima K, Bose T, Gormley J, Sousa H, Flanigan TP . The potential impact of efavirenz on methadone maintenance. In:9th European Congress of Clinical Microbiology and Infectious Diseases. Berlin, Germany, 21–24 March 1999 [Abstract P0552].

14. Tseng AL, Foisy MM. Management of drug interactions in patients with HIV. Ann Pharmacother 1997, 31: 1040–1058.

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