Lopinavir–Ritonavir Dramatically Affects the Pharmacokinetics of Irinotecan in HIV Patients With Kaposi's Sarcoma

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