Atazanavir in plasma-exchange treatment

Abstract

Atazanavir is an HIV protease inhibitor (PI) with a pharmacokinetic profile that allows once daily oral administration. As with other PIs, atazanavir is primarily metabolized by CYP3A isoenzymes in the liver. Therefore, the drug is prone to drug–drug interactions. The terminal elimination half-life of atazanavir administered as a single agent is 6–7 h. Atazanavir is 86% bound to human serum protein. The recommended atazanavir doses are 400 mg once a day taken with food or 300 mg once a day when boosted with low-dose ritonavir (100 mg) [1]. Because atazanavir is a relatively new agent, published pharmacokinetic data on this compound are scarce thus far. No data are available on patients receiving plasma-exchange treatment. Plasma exchange is a procedure in which plasma is separated from blood cells, removed and exchanged for donor plasma before returning it to the patient. Plasma exchange can reduce the amount of abnormal protein in the blood, but may also significantly reduce levels of drugs in the blood (both protein-bound and unbound drug levels). We report a patient receiving antiretroviral medication including atazanavir and plasma-exchange treatment. In this patient we monitored atazanavir plasma concentrations before and after plasma-exchange treatment in order to study the influence of plasma exchange on the atazanavir pharmacokinetics. Atazanavir was assayed using a liquid chromatography–mass spectrometry assay with a lower limit of quantitation of 0.1 mg/l, as used in our hospital [2]. A 41-year-old man was admitted to our hospital with a diagnosis of thrombotic thrombocytopenic purpura (TTP), possibly related to an HIV infection diagnosed at the same time (HIV viral load 9.5 × 105 copies/ml, CD4 cells 190 × 106/l). The patient had an adequate liver test and slightly decreased renal function (creatinine 112 μmol/l, alanine aminotransferase 20 IU/l, aspartate aminotransferase 40 IU/l, gammaglutamyl transferase 21 IU/l). The patient started with antiretroviral treatment including atazanavir (300 mg once a day), ritonavir (100 mg once a day), tenofovir (245 mg once a day) and emtricitabine (200 mg once a day). On the same day, the patient started daily plasma-exchange treatment to treat TTP. Plasma exchange was performed by a continuous centrifugation technique. The amount of plasma removed per plasma-exchange session was 3000 ml, corresponding to 40 ml/kg of the patient's body weight. Volume replacement fluid was fresh frozen donor plasma. The amount substituted was equal to that of the removed plasma. Every day, the process of plasma exchange took approximately 2 h. From day 10 of treatment, blood samples were withdrawn for atazanavir monitoring just before and directly after three plasma-exchange sessions. The time between the two blood samples was approximately 3 h. Antiretroviral medication was given after the post-plasma-exchange sample was drawn, making the pre-plasma-exchange sample a ‘trough’ sample. At days 9, 11, 14, 15 and 16, no plasma-exchange treatment took place. The last plasma-exchange session was on day 17. That same day, atazanavir treatment was discontinued and replaced by efavirenz. From 2 days before the start of antiretroviral therapy, the patient received phenytoin for epileptic seizures, which were neurological complications of TTP (150 mg twice a day during the first 5 days; 75 mg twice a day during the following 4 days; 75 mg once a day on subsequent days). Phenytoin is known to be a potent inducer of CYP3A4 and may therefore enhance atazanavir metabolism. In Table 1 the results of the atazanavir plasma concentration measurements are shown. For comparison, phenytoin concentrations in the same samples are also reported. The results show that atazanavir plasma concentrations were reduced by one half during the 2-h process of plasma-exchange treatment as applied in this patient. As atazanavir half-life when administered in combination with ritonavir and tenovovir has been reported to be 8–10 h [3], plasma-exchange treatment appears to reduce the half-life of atazanavir approximately fourfold. This significant effect of plasma exchange on atazanavir concentrations was expected as a result of the low distribution of atazanavir in body fluids and a number of tissue compartments [1]. Therefore, the majority of atazanavir in the body will be present intravascularly, and will be removed and diluted with plasma-exchange treatment. In contrast, the volume of distribution of phenytoin is relatively large (0.5–1.0 l/kg). The effect of plasma-exchange treatment on phenytoin plasma concentrations is therefore expected to be minor, because replacement of the intravascular fluid will have a minor effect on the total amount of phenytoin in the body.Table 1: Atazanavir plasma concentration measurements.In conclusion, plasma-exchange treatment has a significant effect on atazanavir clearance. As concentration–effect relationships for atazanavir have been described [4], we suggest that when treating a patient using atazanavir with plasma exchange, atazanavir administration should take place directly after a plasma-exchange session.