Pharmacokinetics of ritonavir and nevirapine in peritoneal dialysis

Hassane Izzedine, Vincent Launay-Vacher and Gilbert Deray

Department of Nephrology, Pitié Salpétrière Hospital, Paris, France

Sir,

Hepatic clearance is the major route of elimination of ritonavir and nevirapine (<95% and 85%, respectively). Therefore it has been suggested that no dosage adjustment is necessary in patients with renal insufficiency [1,2]. However, no study is available on the influence of continuous ambulatory peritoneal dialysis (CAPD) on the pharmacokinetics of ritonavir. We report on the pharmacokinetics of ritonavir and nevirapine in an HIV-1 patient on CAPD.

Case.

A 40-year-old man with end-stage renal disease (ESRD), had been treated for 2 years with CAPD for an HIV-associated nephropathy. He was receiving oral ritonavir 600 mg every 12 h, nevirapine 200 mg every 12 h, zidovudine 100 mg every 8 h, and didanosine 100 mg every 24 h for 2 months.

Blood samples were collected just before and at 0.5; 1; 1.5; 2; 2.5; 3; 3.5; 4; 5; 6; 8 and 10 h after oral administration of the first two drugs. Paired blood and dialysate samples were collected at the start of dialysis and every hour during 12 h. CAPD was carried out with three isotonic and one hypertonic bags per day.

Pharmacokinetic parameters of our patient are summarized in Table 1Go. For ritonavir, pharmacokinetic parameters remained within a normal range compared with patients with normal renal function. Values of extraction ratio and dialysance were less than 1% and 3.4 ml/min respectively. The pharmacokinetic parameters of nevirapine were not modified compared to those in subjects with normal renal function except for the AUC (0-{infty}), which was increased in our patient. The values of extraction ratio and dialysance of nevirapine were 51.85% and 3.3 ml/min respectively.


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Table 1. Pharmacokinetic parameters of ritonavir (200 mg/12 h) and nevirapine (200 mg/12 h) in an HIV1-infected patient with end-stage renal disease (ESRD) undergoing CAPD and in patients with normal renal function (NRF)

 
No side-effects were observed, in particular no diarrhoea, abdominal pain, diabetes, hyperlipidaemia or hepatic toxicity. The patient's viral load decreased to undetectable levels (<200 copies/ml).

Comment.

Our data suggest that renal impairment and CAPD have no influence on the pharmacokinetics of ritonavir and nevirapine. Ritonavir does not cross the peritoneal membrane because it is tightly bound to plasma protein (98%) and because of its relatively large size (720.95 Da). In contrast, a non-negligible proportion of nevirapine was recovered in the dialysis fluid (half that in plasma) because of a smaller molecular weight (266.3 Da) and a lower protein binding (<60%). Therefore, no dosage adjustment is necessary in patients with ESRD undergoing CAPD.

References

  1. Jayasekara D, Aweeka FT, Rodriguez R, Kalayjian RC, Humphreys MH, Gambertoglio JG. Antiviral therapy for HIV patients with renal insufficiency. J Aids1999; 21: 384–395[ISI][Medline]
  2. Hilts AE, Fish DN. Dosage adjustment of antiretroviral agents in patients with organ dysfunction. Am J Health-Syst Pharm1998; 55: 25828–25833
  3. Wood AJJ. HIV-protease inhibitors. N Engl J Med1998; 338: 1281–1292[Free Full Text]
  4. Lacy CH. Nevirapine: drug information. UpToDate1999; 7