Pharmacokinetics of nelfinavir and nevirapine in a patient with end-stage renal failure on continuous ambulatory peritoneal dialysis

Stephen Taylora, Jane Littleb, Kathryn Halifaxc, Susan Drakea,* and David Backd

a Departments of Sexual and b Renal Medicine, Hawthorn House, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS; c Roche Products Ltd, Welwyn Garden City AL7 3AY; d Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK

Sir,

Data concerning the administration of drugs with activity against human immunodeficiency virus (HIV) to patients with impaired renal function who require dialysis are limited. Choosing an effective and safe regimen for use in this setting is therefore difficult and giving a suboptimal regimen is potentially hazardous. We describe here the pharmacokinetic profiles of nelfinavir and nevirapine in such a patient.

The patient was a 34 year-old HIV-1-positive female with endstage renal failure secondary to chronic pyelonephritis. At the time of the study she had been receiving antiretroviral therapy comprising nevirapine 200 mg bd, nelfinavir 1250 mg bd and zidovudine 250 mg bd for 16 weeks without adverse effects. The patient had been established on continuous ambulatory peritoneal dialysis (CAPD) 20 weeks before the study was undertaken and she was oliguric, with a creatinine clearance of <10 mL/min. Her daily CAPD regimen consisted of four exchanges of 2 L of CAPD fluid containing 1.36% anhydrous glucose; the daytime dwell time was 4 h and the overnight dwell time was 8 h (allowing 1 h for exchanges). On the day of the study, samples of peritoneal dialysis fluid (PDF) and blood were obtained before drainage of the overnight bag. Two litres of fresh dialysate were drained into the peritoneal cavity and, at the same time, the patient took doses of all three antiviral agents. Samples of PDF and blood were obtained immediately before the doses, 30 min and 1 h after the doses and then hourly for the remainder of the 12 h dosing interval.

Nelfinavir and nevirapine concentrations were measured by HPLC techniques described previously;1 the lower limit of detection of both drugs was 50 µg/L. The peak serum concentration (Cmax), the trough serum concentration (Cmin) and the time to reach the peak serum concentration (Tmax) for each agent were determined and the area under the serum-concentration versus time curves (AUC) were derived by non-compartmental analysis with TOPFIT computer software (Gustav Fischer, Stuttgart, Germany). The amount of nevirapine cleared by a 4 h CAPD exchange was calculated by multiplying the concentration of the drug in the PDF at 4 h by the volume of PDF drained.

The nelfinavir and nevirapine concentrations are shown in the FigureGo. Nelfinavir was not detected in the PDF at any of the sampling times and the Cmax, Cmin and plasma AUC between 0 h and 12 h (AUC0–12) were 6 mg/L, 0.3 mg/L and 30.1 mg/L•h, respectively. Nevirapine, on the other hand, was detected in the PDF at concentrations that were approximately 50% of those in plasma. The Cmax, Cmin and AUC0–12 for this drug were 4.7 mg/L, 2.6 mg/L and 46.6 mg/L•h, respectively. The plasma AUC between 0 h and 4 h (AUC0–4) for nevirapine was 15.4 mg/L•h, whereas the PDF AUC0–4 was 7.3 mg/L•h. Approximately 4 mg of nevirapine were removed in a 2 L bag of CAPD fluid drained after 4 h. After 12 weeks of treatment with the antiretroviral regimen, the CD4+ lymphocyte count rose from 110 x 103 cells/L initially to 240 x 103 cells/L and the viral load fell from 88000 HIV RNA copies/mL at baseline to 1.3 x 105 copies/L at week 4 and <50 copies/mL at week 12.



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Figure. Plasma ({blacktriangleup}) and PDF ({square}) concentrations of (a) nelfinavir following a 1250 mg dose and (b) nevirapine following a 200 mg dose. (An MEC of nevirapine has not yet been recommended.)

 
The results of this study suggest that nelfinavir does not cross the peritoneal membrane and this may be attributed to its relatively large size and high degree of protein binding; a protein-corrected minimum effective concentration (MEC) of nelfinavir of 0.4 mg/L has been proposed.1 Although the plasma trough concentration fell below this threshold in our patient, the same observation has been made in some patients with normal renal function who were also taking nelfinavir twice daily.2 As plasma concentrations were similar to those found in patients with normal renal function3 and as nelfinavir was not recovered in the PDF, dosage alterations specifically for patients undergoing CAPD do not appear to be necessary.

In contrast, a considerable proportion of the nevirapine appeared in the PDF (the concentration of nevirapine in PDF being almost 50% of that in plasma), possibly because it is a smaller molecule and exhibits lower protein binding than nelfinavir. In the patient reported here, we estimate that approximately 16 mg of nevirapine were lost in the discarded PDF over a 24 h period. The plasma trough concentrations of nevirapine in our patient were similar to those documented in a study in which patients received 200 mg od.4 In that study, patients whose plasma trough concentrations exceeded 3.4 mg/L exhibited a more longlasting response to therapy. It may therefore be prudent to monitor nevirapine concentrations to optimize the efficacy of the drug.

In conclusion, we have successfully and safely used nelfinavir and nevirapine in a patient undergoing CAPD and have produced the first pharmacokinetic data for these drugs in such a patient. However, because the pharmacokinetic properties of a drug vary widely from subject to subject, it is not possible to draw reliable conclusions on the basis of data from a single patient. Additional data are clearly required but, for the time being, the plasma concentrations of nelfinavir and nevirapine in patients on CAPD should be closely monitored.

Acknowledgments

The CAPD studies were performed by R. Adkins and A. Dodds. We thank Dr G. M. Beards and S. Gibbons for their contributions to the study. Financial support was provided by Boehringer Ingelheim Ltd and Roche Products Ltd.

Notes

J Antimicrob Chemother 2000; 45: 716–717

* Corresponding author. Tel: +121-766-6611; Fax: +121-766-8752; E-mail: sdrake{at}hawthorn.co.uk Back

References

1 . Merry, C., Barry, B., Mulcahy, F., Ryan, M., Tjia, J. F., Halifax, K. L. et al. (1998). The pharmacokinetics of combination therapy with nelfinavir plus nevirapine. AIDS 12, 1163–7.[ISI][Medline]

2 . Peterson, A. & Johnson, M. (1998). Long term comparison of BID and TID dosing of nelfinavir in combination with stavudine and lamivudine in HIV patients. In Program and Abstracts of the Twelfth World AIDS Conference, Geneva, 1998. Abstract 12224, p. 56.

3 . Perry, C. M. & Benfield, P. (1997). Nelfinavir. Drugs 54, 81–7.[ISI][Medline]

4 . Havlir, D., Cheeseman, S. H., McLaughlin, M., Murphy, R., Erice, A., Spector, S. A. et al. (1995). High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. Journal of Infectious Diseases 171, 537–45.[ISI][Medline]