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.