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.
Corona
G
G
Division of Experimental and Clinical Pharmacology, Department of Molecular Oncology and Translational Research, National Cancer Institute, Aviano, Italy.
Vaccher
E
E
Sandron
S
S
Sartor
I
I
Tirelli
U
U
Innocenti
F
F
Toffoli
G
G
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D019259:Lamivudine / Q000494:pharmacology; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D000068698:Tenofovir; D044465:White People
D019380:Anti-HIV Agents; D000972:Antineoplastic Agents, Phytogenic; D063065:Organophosphonates; D011744:Pyrimidinones; C100720:RPR 121056; C106003:SN38-Glu; D061466:Lopinavir; D019259:Lamivudine; D000077146:Irinotecan; D000068698:Tenofovir; D000225:Adenine; D019438:Ritonavir; D002166:Camptothecin