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Lopinavir–Ritonavir Dramatically Affects the Pharmacokinetics of Irinotecan in HIV Patients With Kaposi's Sarcoma
Author(s) -
Corona G,
Vaccher E,
Sandron S,
Sartor I,
Tirelli U,
Innocenti F,
Toffoli G
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100330
Subject(s) - pharmacokinetics , ritonavir , lopinavir , irinotecan , pharmacology , lopinavir/ritonavir , drug , medicine , metabolite , human immunodeficiency virus (hiv) , chemistry , cancer , virology , viral load , antiretroviral therapy , colorectal cancer
The coadministration of protease inhibitors with anticancer drugs in the management of human immunodeficiency virus‐related malignancies can cause potential drug–drug interactions. The effect of lopinavir/ritonavir (LPV/RTV) on the pharmacokinetics of irinotecan (CPT11) has been investigated in seven patients with Kaposi's sarcoma. Coadministration of LPV/RTV reduces the clearance of CPT11 by 47% (11.3±3.5 vs 21.3±6.3 l/h/m 2 , P =0.0008). This effect was associated with an 81% reduction ( P =0.02) of the AUC (area under the curve) of the oxidized metabolite APC (7‐ethyl‐10‐[4‐ N ‐(5‐aminopentanoic‐acid)‐1‐piperidino]‐carbonyloxycamptothecin). The LPV/RTV treatment also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio (5.9±1.6 vs 9.2±2.6, P =0.002) consistent with UGT1A1 inhibition by LPV/RTV. This dual effect resulted in increased availability of CPT11 for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase ( P =0.0001) in SN38 AUC in the presence of LPV/RTV. The clinical consequences of these substantial pharmacokinetic changes should be investigated. Clinical Pharmacology & Therapeutics (2008); 83 , 4 601–606. doi: 10.1038/sj.clpt.6100330