En cardiologie et en medecine vasculaire, les medecins sont de plus en plus confrontes aux difficultes de la gestion des evenements thromboemboliques veineux (ETEV) et de leur traitement prescrits aux patients fragiles. En effet, ces patients pourraient presenter au moins une de ces situations a risque : insuffisance renale chronique (IRC), insuffisance ponderale ou malnutrition, chutes, troubles cognitifs, polymedication, cancer et grossesse. Les recommandations proposent generalement de recourir a des anticoagulants dans le traitement ou la prophylaxie des ETEV. Ainsi, il est necessaire de prendre en charge ces patients fragiles lors de l’utilisation des anticoagulants, en tenant compte du risque thrombotique et du risque de saignement, mais egalement du suivi, de l’observance et de la polymedication. L’objectif de cette revue est d’etudier les risques et la gestion des anticoagulants chez ces patients fragiles.
Background. Acquired immunodeficiency syndrome (AIDS)-related kidney disorders concern 30% of those patients and can lead to end-stage renal disease (ESRD; 0.6 to 1%). Therefore, administration of antiretroviral drugs in human immunodeficiency virus (HIV) patients with nephropathy is not uncommon. Aim of the review. Since renal insufficiency is not uncommon among HIV-infected patients treated with antiretroviral drugs, guidelines on how to use these drugs in the pattern of an altered renal function are mandatory. This review provides such guidelines established on the basis of pharmacokinetic and clinical studies reported in the international literature. In addition, some of these drugs may be nephrotoxic. Mechanisms and clinical and / or biological manifestations are reviewed to help monitor renal tolerance in patients receiving these drugs. Conclusion. Antiretroviral drugs dosage in HIV-infected patients with altered renal function should be cautiously determined. Drug dosage should not be systematically reduced since dosage adjustment is not mandatory for all therapies (ie. protease inhibitors). Furthermore, when dose reduction is necessary, pharmacokinetic and clinical data from the literature allows to establish practical guidelines on how to use these drugs in such patients. Keywords: dosage adujstment, aids, hiv, nucleoside reverse transcriptase inhibitors, non nucleoside reverse transcriptase inhibitors, protease inhibitors, nucleotide reverse transcriptase inhibitors, fusion inhibitors, end-stage renal disease
ABT-378 (lopinavir) is a novel protease inhibitor (PI) that is currently under clinical development. When administered with low doses of ritonavir (ABT 378/r), this compound achieves plasma drug levels that are highly suppressive of HIV replication in vitro[1]. ABT 378/r is extensively and rapidly metabolized by liver microsomes with an auto-induction phenomenon. It has formerly been shown that even drugs in which elimination is predominantly hepatic may have altered pharmacokinetics in patients with renal impairment [2]. No lopinavir pharmacokinetic data are available in patients with renal failure. We report a pharmacokinetic study of ABT 378/r in one patient with renal insufficiency requiring haemodialysis. A 53-year-old HIV-infected man presented with a history of systemic leishmaniasis treated with amphotericin B 1 mg/kg a week for 5 years. The patient developed chronic renal insufficiency as defined by a serum creatinine level of 180 μmol/l. After the last injection of amphotericine B, the serum creatinine level rapidly increased to 450 μmol/l and the patient was placed on maintenance haemodialysis. Antiretroviral therapy consisted of stavudine, didanosine, lamivudine, nevirapine, efavirenz, and ABT-378/r. ABT-378 pharmacokinetics were performed after the oral administration of a three soft capsule single dose with the patient's consent. Blood samples were collected just before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 h after oral administration. The study was performed between and during dialysis sessions. Paired arterial and venous blood samples were also obtained simultaneously 2 h after starting haemodialysis. In addition, dialysate samples were collected at 2 h and at the end of the haemodialysis session from the influx and efflux lines of the dialysing unit. Haemodialysis was performed for 4 h every 2 days using a F60 polysulfone dialyser (surface area 1.6 m2) with a double-needle access to a double-lumen catheter, with a constant dialysate flow rate of 500 ml/min and blood flow rate between 250 and 300 ml/min. Urine collection was performed for 24 h after administration over the study. Pharmacokinetic parameters were compared with those of individuals with normal renal function. Gwilt and Perrier [3] indices of haemodialysability, which consists of the ratio of free fraction (%) to volume of distribution (l/kg), Fu/Vd, was calculated. The significance of haemodialysis clearance compared with total body clearance fHD[4] (CLHD/(CLHD + CLER)), where CLHD is haemodialysis clearance and CLER is ‘extra-renal’ clearance, was calculated. Neither clinical (rash, diarrhoea or abdominal pain, rhabdomyolysis) nor biological (hyperlipaemia, serum amylase and creatinine phosphokinase) side-effects were observed. Our pharmacokinetic parameters are summarized in Table 1. As healthy volunteer pharmacokinetic parameters are scarce, only maximum and minimum plasma concentrations (Cmax and Cmin, respectively) and area under the concentration-time curve (AUC) were compared with reference values obtained for patients with normal renal function. On dialysis day, Cmax, Cmin, and AUC were 14.21 mg/l, 8.83 mg/l, and 76.95 mg.h/l, respectively, from time 0 until 8 h after administration. Cmax, Cmin, and AUC off-dialysis day values were 15.11 mg/l, 7.86 mg/l, and 116.23 mg.h/l, respectively, until 12 h after administration. On dialysis day (off-dialysis day), values of time to reach maximum plasma concentration Tmax, apparent elimination half-life T1/2, apparent total body clearance CL/F, and apparent volume of distribution Vd/F were 2 (3 h), 12 (17.5 h), 28.8 (20.4 ml/min), and 30.2 (30.8 l), respectively. Urine volume and lopinavir urinary concentrations were 1000 ml and 2.05 mg/l, respectively, on haemodialysis day, and 2000 ml and 4.22 mg/l, respectively, on off-dialysis day. Renal clearance of lopinavir CLR was 0.18 and 0.72 ml/min, on haemodialysis and non-haemodialysis day, respectively (Table 1). Serum lopinavir concentrations were 7.86 and 8.45 mg/l before and after haemodialysis, respectively. Two hours after the start of haemodialysis, arterial and venous concentrations were 14.21 and 11.43 mg/l, respectively. The extraction ratio and haemodialysis clearance of lopinavir were 19.5% and 1.76 ml/min, respectively. fHD was 7.9%. Lopinavir protein binding was 98%. Lopinavir volume of distribution was 0.5 l/kg. Gwilt and Perrier indices were 4.Table 1: Pharmacokinetic parameters of ABT 378/r in an HIV-1-infected haemodialysed patient. In normal individuals, ABT-378/r metabolism has been shown to be predominantly by the liver. As expected, Cmax and Cmin were only slightly increased in our patient. As reference values were calculated at steady state in individuals with normal renal function and our patient received only two doses, it should be considered that in our patient auto-induction did not occur, resulting in slightly elevated plasma concentrations. Our patient's AUC was decreased compared with reference values. We did not observe either a rapidly decreasing distribution phase, or enterohepatic recirculation rebound in plasma concentrations at the end of the sampling period. Therefore, the AUC decrease may be explained by a slightly delayed absorption in the early time of sampling, which could not be assessed because no reference Tmax was available. Other pharmacokinetic parameters did not significantly differ from dialysis to off-dialysis days, suggesting that the haemodialysis session had no influence on the pharmacokinetics of lopinavir. Indeed, lopinavir showed a low extraction ratio in haemodialysis. Furthermore, Gwilt and Perrier indices of haemodialysability were less than 20 and the value of fHD was below the 25% limit value from which haemodialysis clearance should be considered clinically significant. From these data, we suggest that lopinavir (ABT-378) should be administered at normal dosages in patients with renal insufficiency undergoing haemodialysis, regardless of the haemodialysis schedule. Hassane Izzedinea Vincent Launay-Vachera Mayeule Legrandb Deborah Lieberherra Eric Caumesc Gilbert Deraya
