Plasma exchange significantly affects darunavir exposure.

Abstract

Sir, Plasma exchange (PE) is a therapeutic procedure aimed at reducing the amount of abnormal or toxic substances in the blood, e.g. immunoglobulins. It consists in removing a large volume of plasma from a patient and replacing it with some form of replacement fluid. PE is non-selective and may also remove circulating medications from blood (both protein-bound and unbound drug). Darunavir is a synthetic non-peptidic HIV protease inhibitor (PI) metabolized mainly by CYP3A4 isoenzymes and 95% bound by plasma proteins, primarily a-1-acid glycoprotein. Increased clearance of atazanavir, another PI, during PE has already been reported, but the effect of PE on darunavir disposition is unknown. Since darunavir exhibits concentration–effect relationships, knowledge of this effect is critical for treatment efficacy. We report here the case of a white woman in her 50s receiving highly active antiretroviral therapy (HAART) including darunavir and requiring PE treatment. Consent for publication was obtained from the patient. She was diagnosed HIV-1 positive in 2001 and started HAART in 2005. Viral load (VL) and CD4 count were 720956 copies/mL and 13 cells/mm, respectively, when she was hospitalized for visceral leishmaniasis with polyclonal hypergammaglobulinaemia. She then started a new HAART combination consisting of darunavir/ritonavir (600/100 mg twice daily) with emtricitabine/tenofovir (200/245 mg once daily). Despite good virological response (VL ,20 copies/mL), immunological restoration was not achieved (CD4 count1⁄4150 cells/mm and CD4/CD8 ratio1⁄40.08) and hypergammaglobulinaemia increased. Because of hyperviscosity syndrome, she underwent PE sessions twice a week during which darunavir pharmacokinetics (PK) were explored. Several blood samples were drawn over the dosing interval, i.e. just before, during and immediately after a 2 h PE session, in order to estimate the elimination rate constant during PE (keon); a plasma sample collected during PE was also assayed in order to determine the amount of darunavir eliminated by PE. Three additional samples were drawn after PE in order to estimate the darunavir elimination rate constant after a PE session (keoff). Plasma darunavir concentrations were determined using a validated HPLC-UV method and ke values were estimated as the slope from the linear regression of log-concentrations on sample times. Corresponding t1 2 were estimated as loge2 divided by ke. In order to demonstrate the impact of PE on steady-state darunavir PK profiles, PK simulations were performed using Nonmem population PK software (Monte Carlo simulation, n1⁄41000 concentration –time profiles). Calculated keon and mean estimated PK parameters obtained from the literature (CL/F1⁄410.7 L/h, V/F1⁄4198 L and ka1⁄40.95 h) were used for that purpose. PK analysis was performed during three PE sessions. The mean+SD plasma volume and darunavir amount removed per session were 2.51+0.03 L and 9.3+8.3 mg, respectively. Actual darunavir concentrations measured before, during and after PE sessions were 8802+4835, 4505+2930 and 3314+2103 ng/mL, respectively. Estimated keoff and keon were 0.10+0.1 and 0.53+0.13 h, respectively. These data