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Raltegravir Levels May Drop With Lopinavir/Ritonavir
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9th International Workshop on Clinical Pharmacology of HIV Therapy
April 7-9, 2008
New Orleans
Mark Mascolini
Lopinavir/ritonavir lowered 12-hour concentrations of the integrase inhibitor raltegravir in a study of 15 healthy volunteers [1]. But the 12-hour raltegravir level almost always remained above an estimated 95% inhibitory concentration of 14.6 ng/mL for raltegravir, so the investigators concluded a dose adjustment probably is not needed when giving these drugs together.
Raltegravir metabolism does not depend on the major pathways used by protease inhibitors (PIs) and nonnucleosides, but PIs and nonnucleosides can interfere with raltegravir elimination via UGT 1A1-mediated glucuronidation. Also, raltegravir is a substrate for P-glycoprotein, which other drugs can inhibit or induce. Earlier work found that atazanavir (which inhibits UGT 1A1) increased raltegravir 12-hour area under the concentration-time curve (AUC) 41% and 12-hour concentration 77% [2]. Tipranavir (which induces UGT 1A1 and both induces and inhibits P-glycoprotein) lowered raltegravir 12-hour AUC 24% and lowered the 12-hour concentration 55% [3]. Ritonavir (which induces glucuronosyltransferases) lowered raltegravir 12-hour AUC 16% and lowered peak concentration 24% [4].
With colleagues at the University of Alabama, Frank Rhame (Abbott Northwestern Hospital, Minneapolis) recruited 15 healthy men and women and gave them raltegravir with or without lopinavir/ritonavir in the following sequence:
· Period 1: Raltegravir alone at 400 mg twice daily for 4 days (7 doses)
· Period 2: Lopinavir/ritonavir tablets alone at 400/100 mg twice daily for 10 days (19 doses)
· Period 3: Both drugs for 4 days (7 doses)
Rhame and coworkers measured drug levels before dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing on the last day of each period.
Three people did not complete the study, one because she became pregnant and one because Rhame discovered the person had a positive tuberculin skin test and could not quickly rule out active tuberculosis. One volunteer had grade 2 nausea and vomiting in period 2. Nine people had grade 1 headache, fatigue, and gastrointestinal problems, 2 of them in period 1 and 7 in period 2. The investigators detected no laboratory abnormalities while these healthy people were taking these drugs.
Raltegravir had no impact on concentrations of lopinavir or ritonavir. Comparing period 1 with period 3, Rhame found a 30% lower raltegravir 12-hour concentration and a 40% shorter raltegravir elimination half-life with lopinavir/ritonavir. Both changes were statistically significant (P < 0.05).
· Raltegravir 12-hour concentration: period 1, 49.4 ng/mL; period 3, 34.4 ng/mL; geometric mean ratio 0.70 (95% confidence interval 0.53 to 0.91)
· Raltegravir elimination half-life: period 1, 5.9 hours; period 3, 3.6 hours; geometric mean ratio 0.60 (95% confidence interval 0.42 to 0.88)
One of 13 people who completed the study (7.7%) had a raltegravir trough concentration of 10.9 ng/mL--below the estimated 95% inhibitory concentration for raltegravir of 14.6 ng/mL. Raltegravir troughs stayed above this cutoff in everyone else taking raltegravir with lopinavir/ritonavir. Rhame suggested that "the significance of this [one low trough] in the context of multiple drug therapy is unclear." In general, he proposed, raltegravir and lopinavir/ritonavir can be coadministered without dose adjustments.
Rhame appended several standard caveats to his report: This analysis involved healthy volunteers, not people with HIV infection. He did not measure glucuronide metabolites (the products of glucuronidation). There are no large, prospective clinical trials of people taking raltegravir with lopinavir/ritonavir that may shed more light on possible interactions between these drugs.
(Many complete slide sets and posters from this workshop will be available at www.hivpresentation.com shortly after the meeting ends.)
References
1. Rhame F, Long M, Acosta E. RAL-KAL: pharmacokinetics of coadministered raltegravir and lopinavir-ritonavir in healthy adults. 9th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2008. New Orleans. Abstract O19.
2. Mistry GC, et al. 8th International Congress on Drug Therapy in HIV Infection. November 2006. Glasgow. Abstract P291.
3. Wenning LA, et al. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 2006. San Francisco. Abstract A-0374.
4. Iwamoto Mo, et al. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 2006. San Francisco. Abstract A-0373.
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