Lopinavir-ritonavir (Kaletra) Dramatically Affects the Pharmacokinetics of the Anti-cancer Agent Irinotecan (Camptosar) in HIV Patients with Kaposi's Sarcoma

The co-administration of HIV protease inhibitors with anti-cancer drugs in the management of HIV-related malignancies can result in drug-drug interactions.

In the current study, published online ahead of print in Clinical Pharmacology and Therapeutics, researchers assessed the effect of lopinavir/ritonavir (Kaletra) on the pharmacokinetics of irinotecan (Camptosar; CPT11) in 7 patients with Kaposi's sarcoma.

Irinotecan is a injectible cytotoxic chemotherapy drug, classified as a plant alkaloid and topoisomerase I inhibitor. It is FDA-approved for the treatment of metastatic colon or rectal cancer.

Results

• Co-administration of lopinavir/ritonavir reduced the clearance of irinotecan by 47% (P=0.0008).

• This effect was associated with an 81% reduction of the area under the curve (AUC) of the oxidized metabolite APC (7-ethyl-10-[4-N- (5-aminopentanoic-acid)-1-piperidino]-carbonyloxycamptothecin) (P=0.02).

• Treatment with lopinavir/ritonavir also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio (P=0.002).

• This dual effect resulted in increased availability of irinotecan for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase in SN38 AUC in the presence of lopinavir/ritonavir (P=0.0001).

Conclusion

Based on these results, the study authors concluded, "The clinical consequences of these substantial pharmacokinetic changes should be investigated."

According to the drug's FDA labeling, "Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available."

08/28/07

References

G Corona, E Vaccher, S Sandron, and others. Pharmacokinetics of Irinotecan in HIV Patients With Kaposi's Sarcoma. Clinical Pharmacology and Therapeutics. August 22, 2007 [Epub ahead of print].

U.S. Food and Drug Administration (FDA). Camptosar Warnings.