Efavirenz (EFV; Sustiva) is a non-nucleoside reverse transcriptase inhibitor that shows good inhibitory activity against HIV-1 . The mean half-life of the drug is 40–76 h. Long-term administration of 600 mg every day, in phase II studies , resulted in a peak plasma concentration of 4.1 mg/l (2–5 h after administration) and a trough concentration of 1.8 mg/l. Because only 1% of the dose is recovered in the urine as parent compound, it has been suggested that kidney function is not the principal determinant of the elimination of EFV . However, no data are available on patients with end-stage renal disease (ESRD), a situation in which not only renal clearance but also hepatic drug metabolism may be modified . We report on the pharmacokinetics of EFV between sessions of haemodialysis and during the procedure in one patient with ESRD.
In 1995, a 38-year-old HIV-infected man with anuric ESRD treated with haemodialysis had the AIDS-related complex. He was then treated with zidovudine, lamivudine and didanosine. In November 1998, he was shifted to lamivudine 150 mg twice a day, nelfinavir 750 mg three times a day and EFV 600 mg once a day. His viral load decreased from 17 500 copies/ml to undetectable levels (< 200 copies/ml).
Studies of the pharmacokinetics of EFV in plasma, conducted between haemodialysis sessions, were performed 6 months after the start of EFV treatment. Paired arterial and venous blood samples were also obtained simultaneously 2 h after the start of an haemodialysis session.
The peak (observed at 4 h) and the trough concentration of EFV were 2.58 mg/l and 0.65 mg/l, respectively. The area under the curve and half-life were 28.8 mg.h/l per hour and 10 h, respectively.
EFV concentrations were 1.12 mg/l and 0.99 mg/l before and after haemodialysis, respectively, with an haemodialysis clearance of 20 ml/min.
During the first 6 months of treatment no clinical or biological effects were observed; in particular headache, dizziness, insomnia, fatigue and maculopopular rash. Platelet count, leukocyte count and liver enzymes remained stable.
The half-life of EFV was four times lower in our patient than in normal individuals. Those results may be explained by an alteration in EFV metabolism. EFV has been reported to induce CYP3A4 in vivo. In in-vitro studies, EFV inhibited the isoenzymes CYP2G9, 2C19 and 3A4. EFV may thus alter the metabolism of drugs by these enzymes. Similarly, the metabolism of EFV may be increased by drugs that induce CYP3A4, and EFV may also induce its own metabolism.
Studies have shown that hepatic drug metabolism is predominantly decreased in patients with ESRD . However, these findings should be interpreted with caution because concurrent drug intake, age, smoking habit and alcohol intake were not controlled. Prediction of the effect of renal impairment on the metabolism of a particular drug is thus difficult; for example, although nifedipine, nitrendipine and nisoldipine are all apparently metabolized in vivo by CYP3A4, the metabolism of nifedipine is increased , that of nitrendipine decreased and that of nisoldipine is unaffected by renal failure.
It has now been clearly shown that patients with HIV infection do not necessarly have a short expectancy on maintenance dialysis, and that survival for a year or longer is possible. When EFV is given to such patients, not only dosage reduction is necessary but EFV serum level monitoring is also desirable to determine that the concentrations are not lower than the required effective level. Haemodialysis does not affect the pharmacokinetics of EFV.
1. Adkins JC, Noble S. Efavirenz.
Drugs 1998, 56: 1055 –1066.
2. Tachette MA, Slaughter RL. The effect of renal failure on hepatic drug clearance.
DCIP Ann Pharm 1991, 25: 1214 –1224.
3. Van Bortel L, Boher R, Mooi JJ. et al
. Total and free steady state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure.
Eur J Clin Pharmacol 1989, 37: 185 –189.