Departments of Clinical Pharmacy, Nephrology and Internal Medicine, Bicêtre Hospital, Le Kremlin Bicêtre, France
Sir,
Antiretroviral treatment combining inhibitors of HIV-1 protease with nucleoside analogues reduces morbidity and increases survival in HIV-infected patients as a result of the sustained suppression of viral replication [1]. Because the majority of these agents went through a relatively rapid development process, often little is known about their pharmacokinetics, in special patient populations. Although recommendations for nucleoside analogues dosing in patients with renal impairment treated by haemodialysis are now available, there is a lack of recommendations in the dosing for protease inhibitors in patients with renal impairment treated by haemodialysis. The results obtained in one patient treated with a triple therapy including nelfinavir are reported.
Case.
A 45-year-old HCV-HIV co-infected patient on antiretroviral therapy was treated by haemodialysis for end-stage renal failure related to an active thrombotic microangiopathy. The daily doses of drugs were as follows: stavudine 30 mg day (evening dose), lamivudine 150 mg day (evening dose), nelfinavir 750 mg twice a day. The daily dose of nelfinavir was lowered because of hepatic dysfunction related to HCV infection. Clinical and biological signs of liver impairment were anicteric cholestasis and cytolysis and marked increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by fourfold, and gammaglutamyl transferase (-GT) by 10-fold, although plasma bilirubin remained within the normal range. The nelfinavir dose was administered at 8.00 a.m., 6 h before starting haemodialysis. Nelfinavir plasma concentrations measured before and 3 h after drug intake during the interdialytic period were 2203 and 2314 ng/ml respectively, and were considered to be within effective antiviral concentrations, but were higher than those obtained in patients with normal livers receiving the recommended dose [1]. The active metabolite M8 could not be detected in this patient. The haemodialysis was performed for 4 h, using a double-needle access to an arteriovenous fistula, polyamide 170 membrane dialyser (Gambro) and a single-pass dialysate delivery system, with a constant dialysate (bicarbonate fluid) flow rate of 500 ml/min. The blood flow entering the dialyser was 300 ml/min and the ultrafiltration rate was 1250 ml/h. Nelfinavir concentrations were monitored before and after dialysis to check for drug accumulation. Venous blood samples were collected hourly during the session. Arterial and venous blood entering and leaving the dialyser were sampled simultaneously at mid-dialysis. Plasma concentrations of nelfinavir were assayed by high-performance liquid chromatography according to a method previously reported [2]. The 4-h haemodialysis clearance (Clhd) was calculated by the following formula [3]:
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The dialyser extraction ratio (E) was calculated from Qb and Clhd: E=Clhd/Qb.
Nelfinavir concentrations at the beginning and at the end of the 4-h dialysis were 3421 and 2538 ng/ml respectively. At mid-dialysis, arterial and venous concentrations were 3458 and 3320 ng/ml respectively. The haemodialysis extraction coefficient ratio was 7.8% and the haemodialysis clearance was 23.4 ml/min. Those parameters indicate that nelfinavir is poorly removed during a 4-h haemodialysis session despite the use of a high-permeability dialyser membrane. The observed dialysis clearance and extraction ratio of nelfinavir were low, which is in agreement with nelfinavir pharmacokinetic properties: large volume of distribution (>1 l/kg) and high plasma protein binding mainly on alpha-acid-glycoprotein (90%) [4]. Consequently, the haemodialysis index [3] defined as the ratio of unbound fraction to volume of distribution is 10, which is <20 in the range of poorly removed drugs. These data are in contrast to those of Armbruster et al. [5], who reported a rapid decrease in nelfinavir concentrations in an HIV-infected female patient. However, concentrations of nelfinavir were measured during a short interval of time (5 h) and not at steady state, which makes calculation of half-life difficult. Lack of production of metabolite M8 is probably related to liver impairment, leading to a decrease in the rate of nelfinavir metabolism [6], although genetic polymorphism has been described in some patients. [4]. As a consequence of decreased metabolism in a patient with liver impairment, there is a significant increase in nelfinavir exposure, as already described [7].
Comment.
In conclusion, poor removal of nelfinavir during a haemodialysis session indicates that supplemental nelfinavir need not be routinely given to patients following haemodialysis. However, patient-to-patient variability could occur, and hence further data should be collected before definitive dosage recommendations can be proposed.
References