Kaletra: could upping the dose overcome resistance?

Keith Alcorn
Estimated reading time 2 minutes
This article is more than 21 years old.

Increasing the dose of lopinavir/ritonavir (Kaletra from 400/100mg to 667/167mg twice daily results in a 73% increase in trough levels, and the effect of this dose increase is substantially greater than the effect of increasing the amount of ritonavir used alongside lopinavir to therapeutic levels. The findings, presented at the Second International AIDS Society Conference on HIV Pathogenesis and Treatment this week in Paris by Charles Flexner of Johns Hopkins University School of Medicine, are preliminary and come from the 049 study of high dose lopinavir, a 48 week study being carried out in France, Spain and the United States.

There is some evidence to suggest that resistance to lopinavir can be overcome with higher levels of the drug, an effect known as the inhibitory quotient, or IQ. The 049 study is testing whether higher drug levels can overcome resistance, although it does not have a control group that will receive the standard lopinavir dose.

The 049 study is comparing lopinavir/ritonavir 667/167mg bid (five 133/33mg capsules twice daily) with lopinavir/ritonavir 400/300mg (three 133/33mg capsules plus two 100mg ritonavir capsules twice daily). Thirteen patients are receiving an increased lopinavir dose and eighteen an increased ritonavir dose. Patients underwent intensive 12 hour sampling after three weeks on treatment, and were multiple PI-experienced, with NNRTI resistance, a CD4 count below 200 cells/mm3 and viral load above 1,000 copies/ml.

Glossary

log

Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

virologic response

Reduction in viral replication in response to treatment, especially achievement of an undetectable viral load.

 

pharmacokinetics (PK)

How drugs are processed and used in the body, including how they are absorbed, metabolised, distributed and eliminated.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

antiviral

A drug that acts against a virus or viruses.

Preliminary results show that a higher lopinavir dose increases the trough level by 72%, the AUC12 (total drug exposure over 12 hours) by 88% and the peak level (Cmax) by 88% compared with standard dosing. In comparison, a higher ritonavir dose increases the trough by 56% compared with standard dosing, the AUC by 59% and the peak level by 46%.

This study will continue to follow patients for 48 weeks to determine the durability of effects on viral load and the tolerability of higher drug doses. After three weeks viral load had already fallen by –1.2 log in the boosted lopinavir arm and –1.5 log in the ritonavir 300mg arm.

Reference

Flexner C et al. Steady state pharmacokinetics and short-term virologic response of two lopinavir/ritonavir (LPV/r) high dose regimens in multiple antiretroviral-experienced subjects (study 049). Antiviral Therapy 8 (Suppl 1): S421, 2003.

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