Pharmacokinetic of nevirapine in haemodialysis

Hassane Izzedine, Vincent Launay-Vacher, Guy Aymard, Mayeuie Legrand and Gilbert Deray

Departments of Nephrology and Pharmacology, Pitié Salpétrière Hospital, Paris, France

Sir,

Nevirapine is a potent and selective non-competitive inhibitor of reverse transcriptase [1] which is always administered in combination with at least one additional antiretroviral agent. Renal elimination of the drug is <3% of parent compound [2]. Not surprisingly it has been suggested that no dosage adjustment is necessary in patients with end-stage renal disease (ESRD). However, no pharmacokinetic study of the drug is available in patients with renal failure. We report here on the pharmacokinetics of nevirapine in HIV1-infected patients with ESRD undergoing haemodialysis (HD).

Cases.

Case 1. A 55-year-old man with moderate renal insufficiency (creatinine clearance 60ml/min) was treated with daily abacavir 600 mgx2, nevirapine 200 mgx2, ritonavir 200 mgx2, and saquinavir 600 mgx2 for 6 months. His viral load decreased from 22 710 copies/ml to 1500 copies/ml.

Case 2. A 40-year-old man with anuric ESRD undergoing haemodialysis was treated with daily didanosine 250 mg, stavudine 60 mg, nevirapine 200 mg, ritonavir 400 mgx2 and saquinavir 600 mgx2 for 1 month. His viral load decreased from 30 670 copies/ml to 14 000 copies/ml.

Blood samples were collected just before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 h after oral administration. Patient no. 2 was studied between and during dialysis sessions. Paired arterial and venous blood samples were also performed simultaneously 2 h after start of haemodialysis. In addition, dialysate samples were collected at 2 h and at the end of haemodialysis sessions from the influx and efflux lines of the dialysing unit. Haemodialysis was performed for 4 h using a F60 polysulphone dialyser (surface area 1.4 m2) every 2 days with a double-needle access to an arteriovenous fistula with a consstant dialysate flow rate of 500 ml/min and blood flow rate between 250 and 300 ml/min.

Neither clinical (rash, diarrhoea, abdominal pain, or peripheral neuropathy) nor biological (neutropenia, thrombocytopenia, anaemia) side-effects were observed. Liver enzymes remained stable.

In our haemodialysed patient, the pharmacokinetic analysis of the concentration-time profile on a non-dialysis day led to original observations. The initial decrease of nevirapine plasma concentrations in the early time periods of sampling was related to a lag-time phenomenon in the absorption. Furthermore, concentrations never decreased during studies time period (until 10 h after administration) suggesting a flip-flop [3] phenomenon. Flip-flop occurs when the absorption phase is markedly slowed down. It covers the distribution and/or the elimination phases and then forbids any non-compartmental analysis. We therefore performed a pharmacokinetic modelling of the concentration values vs time of sampling and obtained a good correlation between calculated and observed values. Pharmacokinetic parameters were then generated.

The pharmacokinetic parameters obtained in our patients are summarized in Table 1Go. T1/2 and Tmax were close to values observed in subjects with normal renal function, except for the non-dialysis day of patient no. 2 where Tmax was not a controlled value because of the flip-flop phenomenon. AUC (0-infinity) of patient no. 2 on a non-dialysis day was slightly increased, which is consistent with the large increase of the absorption time due to the flip-flop phenomenon. Apparent volume of distribution ranged from 24.7 to 39.1 litres. Total apparent body clearance was slightly, but not significantly, increased in these patients as compared with subjects with normal renal function [4]. After 2 h of haemodialysis, arterial and venous concentrations were 5.74 and 3.07 mg/l for nevirapine. The values of extraction ratio and dialysance of nevirapine were 46.5% and 100.5 ml/min respectively. Thus, administration should be performed after the haemodialysis session.


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Table 1. Pharmacokinetic parameters of nevirapine in HIV1-infected patients with ESRD undergoing haemodialysis

 

Comment.

Results in patient no. 1 show that there are only minor modifications in the pharmacokinetics of nevirapine in patients with moderate renal insufficiency and that no dosage adjustment should be necessary in those patients.

Results in patient no. 2 show that oral bioavailability of nevirapine may be significantly modified in haemodialysed patients, as it was previously observed for other drugs in patients with end-stage renal disease.

References

  1. Barry M, Mulcahy F, Merry C, Gibbons S, Back D. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet1999; 36: 289–304[ISI][Medline]
  2. Riska P, Lamson M, MacGregor T et al. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos1999; 27: 895–901[Abstract/Free Full Text]
  3. Melvin GC, Ellison SR, Monk CM, Bates TR. Existence of a flip-flop kinetic model for zidovudine (AZT) after oral administration. Res Commun Chem Pathol Pharmacol1990; 70: 193–204[ISI][Medline]
  4. Zhou HJ, Sheiner LB, D'Aquila RT et al. Population pharmacokinetics of nevirapine (NVP), zidovadine (ZDV) and didanosine (ddI) in human immunodeficiency virus-infected patients. The National Institute of Allergy and Infectious Diseases, AIDS Clinical Trials Group Protocol 241 Investigators. Antimicrob Agents Chemother1999; 43: 121–128[Abstract/Free Full Text]