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Potential hazard drug–drug interaction between boosted protease inhibitors and vinblastine in HIV patients with Hodgkin's lymphoma

2013; Lippincott Williams & Wilkins; Volume: 27; Issue: 6 Linguagem: Inglês

10.1097/qad.0b013e32835e0777

1473-5571

Giuseppe Corona, Emanuela Vaccher, Michele Spina, Giuseppe Toffoli,

Viral-associated cancers and disorders

Highly active antiretroviral therapy (HAART) has significantly increased life expectancy in patients with HIV infection [1,2]. However, cancer is still a substantial problem in this population. The aging HIV patients are now at increased risk for a multitude of non-AIDS malignancies, including Hodgkin's lymphoma [3,4]. Management of drug–drug interactions remains a critical component of HIV and cancer care [5]. Increased haematological and non-haematological toxicity of vinblastine (VBL) has been reported in HIV patients with cancer receiving VBL-based chemotherapy regimes in combination with HAART [5–8]. It was believed that such unexpected toxicity could be related to pharmacokinetic interactions with protease inhibitors. These latter share with VBL the same clearance pathways mainly represented by CYP3A4 and ABCB1; thus, when they are co-administered with VBL, they may compete and/or inhibit its clearance leading to an increased drug exposure. This drug interaction gained in importance with the introduction of second-generation protease inhibitors, boosted with ritonavir (Rtv), which is one of the most important inhibitors of CYP3A4 activity [9]. Concurrent ABVD regimen (25 mg/m2 doxorubicin, 10 U/m2 bleomycin, 6 mg/m2 VBL, 375 mg/m2 dacarbazine) and HAART are standard treatments in HIV patients with Hodgkin's lymphoma [10–12]. However, no pharmacokinetic study has been performed in this setting. In this report, we would like to share the preliminary results of an exploratory study on the effect of boosted protease inhibitors on pharmacokinetics of VBL in three consecutive patients with HIV-associated Hodgkin's lymphoma. The patients gave their informed consent prior to their participation in the investigation in accordance with the Declaration of Helsinki. The pharmacokinetics of VBL in presence and in absence of boosted protease inhibitors were performed in agreement with a cross-over scheme at the first and second cycles of ABVD administration. The pharmacokinetic of VBL alone was preceded by 7 days washout of boosted protease inhibitors. The VBL plasma levels were monitored up to 48 h from administration by liquid chromatography tandem mass spectrometry [13], whereas the pharmacokinetic parameters were evaluated by a non-compartmental model. The pharmacokinetic profile of VBL in presence or in absence of boosted protease inhibitors are reported in Fig. 1 with the corresponding pharmacokinetic parameters. During the co-administration of atazanavir (ATV)/Rtv 300/100 mg (q24 h) and darunavir (DRV)/Rtv 600/100 mg (q24 h) in case 1 and case 2, the VBL Cmax was incremented by 25% and 62.4%, whereas the VBL area under curve (AUC) was increased by 131% and 101%, respectively. This indicates that ATV and DRV in association with Rtv effectively influence the pharmacokinetic profile of VBL by lowering systemic clearance by 25.0% and 56.7%. These two patients during the cycle of ABVD and boosted protease inhibitor-based HAART regimens experienced only moderate side effects (WHO grade G2 Toxicity), suggesting that the increment of VBL exposure is well tolerated. A higher VBL AUC was reported for the case 3 patients when VBL was given in conjunction with lopinavr (LPV)/Rtv (Fig. 1). In these patients, the VBL AUC was 270 μgL/h which is about 1.6-fold higher than that observed in patients receiving ATV/Rtv and DRV/Rtv. After the ABVD administration, the patients experience severe (WHO grade G4 Toxicity) and persistent toxicity, including autonomic neuropathy (paralytic ileus) and febrile neutropaenia. The patient refused to continue the same cancer chemotherapy and, in order to reduce the risk of further toxicity, the patient was moved to a regime that did not include VBL without compromising the response. The severe side effects observed during the treatment of ABVD and LPV/Rtv in these patients were clear signs of high VBL exposure coherent with a possible reduction of the clearance of VBL consequent to the co-administration of LPV/Rtv. However, we were unable to demonstrate a direct contribution of the LPV/Rtv on determining the higher level of VBL systemic exposure observed because of the lack of the pharmacokinetic profile of VBL alone. Alert can be give for potential hazard toxicity of the ABVD treatment when administered in combination with LPV/Rtv in agreement with the previous observation that indicated, for this specific boosted formulation, an increment of haematological and severe neurotoxicity [5–7].Fig. 1: Pharmacokinetic profile of VBL alone and in presence of boosted protease inhibitors.(a) atazanavir/Rtv (300/100 mg, q24 h), case 1, (b) darunavir/Rtv (600/100 mg, q24 h), case 2 and (c) lopinavir/Rtv (300/100 mg, b.i.d.), case 3. In the insert are reported the principal VBL pharmacokinetics parameters. VBL, vinblastine.In conclusion, this exploratory investigation reveals for the first time that an increase of VBL exposure can occur when ATV-Rtv and DRV-Rtv are administered concurrently with VBL. The potential hazard of severe haematological and neurological toxicity observed for LPV/Rtv is consistent with a detrimental effect of boosted protease inhibitors on VBL clearance. Patients receiving a combination of ABVD and HAART should carefully be monitored and a therapeutic drug monitoring strategy should be further developed to define the optimal dose reduction of VBL when used in association with HAART regimes that incorporate boosted protease inhibitors. Acknowledgements Conflicts of interest There are no conflicts of interest.