Pharmacokinetics of tenofovir in haemodialysis

Hassane Izzedine1, Vincent Launay-Vacher1, Vincent Jullien2, Guy Aymard3, Claudine Duvivier4 and Gilbert Deray1

1 Department of Nephrology, Pitié Salpêtrière Hospital, Paris, 2 Department of Pharmacology, Saint Vincent de Paul Hospital, Paris, 3 Department of Pharmacology, Pitié Salpêtrière Hospital, Paris and 4 Department of Infectious Diseases, Pitié Salpêtrière Hospital, Paris, France

Correspondence and offprint requests to: Vincent Launay-Vacher, PharmD, Nephrology Department Pr. Deray, Pitié Salpêtrière Hospital, 47–83 Boulevard de l’Hôpital, F-75013 Paris, France. Email: vincent.launay-vacher{at}psl.ap-hop-paris.fr

Keywords: end-stage renal disease; haemodialysis; hepatitis B virus; tenofovir



   Introduction
 Top
 Introduction
 Case
 Results
 Discussion
 References
 
Tenofovir is an antiviral nucleotide with activity against human immunodeficiency virus type I (HIV-1). Tenofovir is extensively and rapidly excreted in the urine by the kidneys [1]. There are no available data on tenofovir pharmacokinetics in patients with renal failure. We report here on the clinical effects and the pharmacokinetics of tenofovir in one patient with end-stage renal disease (ESRD) undergoing haemodialysis.



   Case
 Top
 Introduction
 Case
 Results
 Discussion
 References
 
The patient was a 46-year-old Caucasian man co-infected with HIV-1 and hepatitis B virus (HBV) who was undergoing haemodialysis twice a week for end-stage renal failure (ESRD) secondary to autosomal polycystic kidney disease. At the time of the study, his creatinine clearance was 10 ml/min with a urinary output of 1 l/day. He weighed 60 kg, his height was 1.75 m, resulting in a body surface area of 1.73 m2. His antiretroviral therapy included efavirenz, didanosine and lamivudine (3TC), against a CD4 lymphocytes count of 450/mm3 and an undetectable serum HIV-1RNA. Furthermore, in spite of the 3TC therapy the patient had developed a severe post-hepatitis B cirrhosis and had liver pain, an alanine transferase level more than 10 times the upper normal limit, hypoalbuminaemia at 28 g/l and prothrombin time of 68%. HBV-DNA measured at 2100 copies/ml. Tenofovir 300 mg/day was then started [2]. A complete analysis of tenofovir pharmacokinetics was performed in order to: (i) study tenofovir pharmacokinetics in ESRD in comparison with patients with normal renal function, and (ii) evaluate tenofovir’s dialysability.

Blood samples were collected on a non-haemodialysis day just before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7, 9, 13, 17, 21 and 24 h after oral administration of tenofovir and at 0, 1, 3, 4, 5, 6, 7, 8, 10, 12 and 24 h after oral administration on a dialysis day, the haemodialysis being performed during hours 3–7 of the pharmacokinetic study. Paired arterial and venous blood samples were also obtained 2 h after starting haemodialysis. Haemodialysis was performed via an arteriovenous fistula using an F60 polysulfone dialyser (surface area 1.6 m2), with a constant dialysate flow rate of 500 ml/min and a blood flow rate of 250 ml/min. Tenofovir dialysability was calculated using FHD, which is the ratio expressed in per cent of the haemodialysis clearance of a drug vs its total body clearance during a specified period, that being defined as the sum of the drug clearance effected by the patient’s body and its clearance by the dialyser—i.e. total body clearance on a non-haemodialysis day plus the haemodialysis clearance. was thus calculated using the formula: FHD (%) = [CLHD/(CLHD + CLER)] x 100 where CLHD is the haemodialysis clearance of the drug and CLER is the extrarenal clearance [3]. CLHD was calculated as follows CLHD (ml/min) = [(Ca - Cv)/Ca] x [Qb x(1 - Ht)] where Ca and Cv, respectively, are the arterial and venous plasma concentrations of the drug and [Qb x(1 - Ht)] represents the plasma flow rate at the entry of the dialyser, with Qb the blood flow rate and Ht the haematocrit of the patient at that time. Actually, CLER was estimated based on the total body clearance of the drug measured in the patient, on a non-dialysis day.



   Results
 Top
 Introduction
 Case
 Results
 Discussion
 References
 
The pharmacokinetic parameters of tenofovir for our patient and for patients with normal renal function [4] are summarized in Table 1. The maximum plasma concentration (Cmax) and the area under the concentration–time curve from 0 to 24 h after the oral administration of tenofovir [AUC(0–24 h)] were dramatically increased in our patient, by 8.7 and 15.6, respectively, and the apparent total body clearance (CL/F) was correlatively decreased 11-fold. We therefore decided to reduce tenofovir dosage for our patient. A wash-out period was allowed (no tenofovir given during five times the elimination half-life determined for our patient), after which tenofovir was re-introduced at 300 mg twice a week administered after each haemodialysis session. When tenofovir was resumed, its first trough level was 57 ng/ml, and 154 ng/ml after 2 weeks, which was slightly above the upper limit of the normal therapeutic range [3]. During the haemodialysis session, tenofovir clearance was high (129 ml/min) with an FHD of 73.9% while its elimination half-life (T1/2) was only 1.9 h as compared with 27.9 h on a non-haemodialysis day. This increase in tenofovir elimination during the session is seen on the plot of plasma concentrations vs time (Figure 1). Furthermore, a prolonged and large rebound in tenofovir plasma concentration was observed after the haemodialysis session. Unfortunately, the length of this rebound could not be determined as the plasma concentration of tenofovir at hour 24 could not be determined due to a technical problem.


View this table:
[in this window]
[in a new window]
 
Table 1. Pharmacokinetic parameters of tenofovir in a hemodialysis patient with HIV-1

 


View larger version (13K):
[in this window]
[in a new window]
 
Fig. 1. Tenofovir plasma concentrations vs time in our patient on a non-haemodialysis day and on a haemodialysis day. HD, haemodialysis; HDD, haemodialysis day; NHDD, non-haemodialysis day.

 


   Discussion
 Top
 Introduction
 Case
 Results
 Discussion
 References
 
The clinical course of our patient demonstrated that tenofovir was a safe and effective treatment for lamivudine-resistant hepatitis B infection even if started at the cirrhotic stage of the disease. Furthermore, tenofovir was efficiently antiviral in our patient, for HBV-DNA levels were still undetectable 6 months after its administration was stopped.

As expected, since tenofovir is almost exclusively excreted unchanged in urine, its pharmacokinetics were significantly altered in our patient with ESRD compared with patients with normal renal function (Table 1), leading to an accumulation of the drug and to drastically increased drug exposure. As a result, adjusting tenofovir doses in such patients is mandatory. With regards to our results, tenofovir 300 mg twice a week still seems to be too high a dose for ESRD patients, as in our patient accumulation occurred as early as 2 weeks after initiation of therapy. We suggest, therefore, that tenofovir be administered once a week in patients with ESRD. Furthermore, tenofovir should be considered dialysable as its FHD was higher than 25%. This was confirmed by the comparison of tenofovir AUC(0–12 h) on non-haemodialysis and haemodialysis days, which showed that it was reduced significantly, by almost 40%, with dialysis (26324 and 16164 ng h/ml, respectively) in spite of the post-dialysis rebound of its plasma concentrations. This rebound could also have an adverse impact on treatment efficacy, as the drug may recirculate away from the interior of vira and lymphocytes, where it exhibits its pharmacological activity, in addition to perhaps recirculating away from plasma protein binding sites. For these reasons, we recommend that tenofovir be administered to patients after their dialysis session. However, data on larger and more varied groups of ESRD patients are needed in order to establish formal and definitive guidelines on how to adjust the dosage of this drug according to the degree of renal impairment.



   Acknowledgments
 
We thank Gilead Sciences Inc. for their help in perfecting the analytical technique for tenofovir determination in plasma samples.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Case
 Results
 Discussion
 References
 

  1. Deeks SG, Barditch-Crovo P, Lietman PS et al. Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-(2-(R)-(phosphonomethoxy)propyl)adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults. Antimicrob Agents Chemother 1998; 42: 2380–2384[Abstract/Free Full Text]
  2. van Bommel F, Wunsche T, Schurmann D, Berg T. Tenofovir treatment in patients with lamivudine-resistant hepatitis B mutants strongly affects viral replication. Hepatology 2002; 36: 507–508[CrossRef][ISI][Medline]
  3. Izzedine H, Launay-Vacher V, Baumelou A, Deray G. An appraisal of anti-retroviral drugs in hemodialysis. Kidney Int 2001; 60: 821–830[CrossRef][ISI][Medline]
  4. Braditch-Crovo P, Deeks SG, Collier A et al. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2001; 45: 2733–2739[Abstract/Free Full Text]
Received for publication: 16. 1.03
Accepted in revised form: 9. 4.03