Adherence, Pharmacokinetics, and Metabolic Changes in Treatment-naive Patients Receiving Once-daily or Twice-daily Lopinavir/ritonavir (Kaletra): Study M05-730

Researchers have explored several strategies for making antiretroviral therapy more convenient and promoting improved adherence, including once-daily dosing. A series of posters at the 9th International Congress on Drug Therapy in HIV Infection (HIV9) this week in Glasgow, Scotland, presented data from studies of soft-gel capsule (SGC) and tablet formulations of the boosted protease inhibitor lopinavir/ritonavir (Kaletra) taken either once-daily (QD) or twice-daily (BID).

A brief summary of some of these studies is presented below. The full posters can be viewed online via the HIV9 Library of Slides and Posters.

Adherence

M05-730 is an ongoing Phase 3, open-label, randomized study designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of lopinavir/ritonavir tablets dosed QD or BID through 48 and 96 weeks in combination with QD tenofovir/emtricitabine (the NRTIs in the Truvada coformulation pill) in treatment-naive patients.

The study also compared the safety, tolerability, and pharmacokinetics of the newer lopinavir/ritonavir tablet versus the older SGC formulation over the first 8 weeks of administration (after 8 weeks, everyone switched to the tablet). Electronic monitoring pill bottle (MEMS) were used to track 3 aspects of adherence: whether pills were taken, correct dose, and timing (within 3 hours of prescribed interval).

Most participants (about 80%) were men, 75% were white, 18% were black, and the mean age was about 39 years. At baseline, the mean viral load was about 5 log10 copies/mL and the mean CD4 count was about 215 cells/mm3.

Among 606 participants with available MEMS data, adherence to QD lopinavir/ritonavir dosing was significantly better than for BID dosing (P < 0.001). Adherence declined significantly over time, but between-arm differences remained consistent over 12 weeks. Patient sex, age, and race were significant predictors of early adherence. Adherence was similar for patients taking the tablet and SGC formulations.

Clinical outcomes at week 48 did not differ for patients receiving QD or BID dosing, however, indicating that differences in early adherence did not appear to predict outcomes in this study.

Pharmacokinetics

A total of 633 patients were included in an analysis of population pharmacokinetics (PK) and pharmacodynamics (PD) in the same study. About half took lopinavir/ritonavir QD and half BID. Intensive PK samples were obtained for 69 patients, but all had some PK data collected through 48 weeks.

Patient sex, age, race, weight, body surface area, creatinine clearance, dosing regimen (QD versus BID), hepatitis B or C coinfection, and alcohol use did not affect ritonavir PK. Only weight had a small -- statistically significant, but not judged clinically relevant -- effect on lopinavir clearance (a 10 kg increase in weight led to a 4% increase in clearance).

Lopinavir concentrations did not correlate with virological response, indicating that the drug effectively suppressed HIV even at the lowest levels measured in this trial.

Metabolic Changes

In a third study, investigators looked at changes in metabolic parameters associated with QD or BID dosing of lopinavir/ritonavir in the same study. Use of some protease inhibitors, including lopinavir/ritonavir, has been linked to elevated blood lipid and glucose levels, which may raise the risk for cardiovascular disease in treated patients.

This analysis included 664 patients. Metabolic evaluations were performed at baseline and at week 48 (and will be continued through week 96). Mean changes in lipid parameters, lipid ratios, HOMA insulin resistance values, and cardiovascular risk according to National Cholesterol Education Program (NCEP) guidelines were calculated.

Through week 48, 15% of patients in the QD group and 17% in the BID group discontinued treatment prematurely for various reasons, but only 2 patients did so due to elevated triglycerides (TG) or total cholesterol (TC).

Increases in all lipid parameters were observed through 48 weeks, including HDL ("good") cholesterol. While statistically significant differences were observed between mean changes in total and non-HDL cholesterol in the QD and BID arms, these were not deemed clinically significant. Among all patients combined, there was a statistically significant decrease in the ratio of LDL ("bad") to HDL cholesterol (LDL:HDL), but no change in TC:HDL ratio through 48 weeks.

Median lipid values for TC, TG, and LDL stayed within the acceptable NCEP ranges through 48 weeks. 72% of patients who started with normal TC at baseline maintained this level, as did 87% with normal LDL and 80% with normal TG. However, the proportion with undesirably low HDL levels decreased from 60% to 33%. Men were more likely to experienced TG elevations, while women were more likely to have increased TC.

Looking at Framingham risk equation estimates, the mean 10-year cardiovascular risk score remained unchanged over 48 weeks when LDL criteria were used. When TC criteria were used instead, the mean 10-year risk increased from 4.25% to 5.02%.

Based on these findings, the investigators concluded, "In subjects treated with a lopinavir/ritonavir-based regimen through 48 weeks, there was minimal impact on 10-year cardiovascular risk as measured by TC:HDL and LDL:HDL ratios and Framingham risk score." They added that "HOMA did not change through 48 weeks of lopinavir/ritonavir-based treatment, suggesting no increase in insulin resistance."

11/14/08

References

TJ Podsadecki, RA Rode, C Naylor, and others. Adherence with lopinavir/ritonavir (LPV/r) tablet and SoftGel (SGC) capsule based antiretroviral regimens and predictors of early treatment compliance. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):P170. November 10, 2008.

J Ng, CE Klein, P Diderichsen, and others. Population pharmacokinetic/pharmacodynamic analysis of lopinavir and ritonavir in subjects receiving the tablet formulation. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):P245. November 10, 2008.

BA Da Silva, DE Cohen, TM Marsh, and others. Metabolic evaluation of Study M05-730: LPV/r tablets QD vs. BID, co-administered with tenofovir DF + emtricitabine in ARV-naïve HIV-1 infected subjects. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):P110. November 10, 2008.