Pharmacokinetics of Once-daily Lopinavir/Ritonavir and the Influence of Dose Modifications

Dutch researchers studied the pharmacokinetics of lopinavir/ritonavir (Kaletra) dosed at 800/200 mg a day in 20 HIV positive patients and evaluated the effect of dose modifications in the case of trough concentration (Ctrough) levels less than 1.0 mg/l. The study results appear in a Research Letter published in the July 1, 2005 issue of AIDS.

Ctrough levels after the daily administration of lopinavir/ritonavir were lower than with twice daily administration, according to the authors of the study. Dose modifications in four patients with Ctrough levels less than 1.0 mg/l succeeded in only one patient.

Background

A study comparing lopinavir/ritonavir dosed at 800/200 mg a day with 400/100 mg twice a day in 38 antiretroviral-naive HIV-infected patients has recently been published [Eron et. al. J Infect Dis 2004]. A number of patients receiving lopinavir/ritonavir daily had lower lopinavir trough concentrations (C _trough) compared with patients receiving lopinavir/ritonavir twice a day.

No statistically significant differences were observed in antiviral activity between the twice daily and once a day treatment groups, up to 72 weeks of treatment [Feinberg et al XIVth International AIDS Conference. Barcelona, 2002 (Ab TuPeB4445).  

Based on the inhibitory quotient as a predictor of virological response to HIV therapy, for antiretroviral-naive patients a target lopinavir C _trough of 1.0 mg/l has been proposed. One could hypothesize that a daily dose of lopinavir/ritonavir of 800/200 mg should have a target C _trough of at least 1.0 mg/l to ensure antiviral activity, say the authors of the study.

The objectives of the current study were to determine the pharmacokinetics of lopinavir/ritonavir dosed at 800/200 mg once a day and the effect of a dose increase in patients with lopinavir C _trough plasma concentrations below 1.0 mg/l.

In this open-label, uncontrolled, multicentre study 20 HIV-1-infected patients were treated with lopinavir/ritonavir at 800/200 mg a day in combination with two daily nucleosides. After at least 14 days of treatment, blood samples were drawn up to 24 h after observed drug intake after breakfast.

A dosage increase by one lopinavir/ritonavir 133/33 mg capsule, in addition to the daily dosage, was made when the target 24-h concentration (C ₂₄) level of 1.0 mg/l was not reached. After another 2 weeks a morning trough level at approximately 24 h after intake (C _trough) was measured again. If the C _trough was again below 1.0 mg/l the procedure of dosage adjustment could be repeated up to three times.

The main finding of this study was that the pharmacokinetic profile of once daily lopinavir/ritonavir 800/200 mg in 20 HIV-infected patients was similar to data presented on once daily lopinavir/ritonavir with nucleosides administered twice a day.

More importantly, the present study gives insight into the effect of dose adjustment in patients who did not reach the predefined lopinavir C _trough of 1.0 mg/l³.  The researchers found lopinavir C ₂₄ levels less than 1.0 mg/l in six out of 20 patients, compared with three out of 18 patients previously reported.

Tenofovir (Viread) was used by one of the patients with lopinavir trough levels less than 1.0 mg/l exposure. Tenofovir has been shown to cause a 34% decrease in the lopinavir minimum concentration. Nevertheless, the combination of lopinavir/ritonavir with tenofovir did not result in C ₂₄ levels less than 1.0 mg/l in the majority of patients.

After dose adjustments, only one out of four patients finally reached a lopinavir C _trough greater than 1.0 mg/l. This success rate seems to be rather low. For the protease inhibitor nelfinavir (Viracept) dosed at 1250 mg twice a day we reported that dose adjustments in the case of low nelfinavir plasma concentrations were only effective in a minority of patients.

This observation indicates that dose adjustments also may not have the desired effect for other protease inhibitors. Another explanation could be that absorption from the gastrointestinal tract is limited.

In some patients this limitation might result in a decreasing bioavailability of lopinavir at higher dosages. In a multiple dose escalating study, in healthy subjects, increasing lopinavir or ritonavir doses provided less than dose proportional increases in lopinavir concentrations.

Although the mechanism of this remains unclear, the occurrence of diarrhea at higher dosages could be an important factor.

There were several limitations to this study. First, adherence was not measured in the study. Although the intensive pharmacokinetic blood sampling was performed after an observed medication intake, follow-up trough levels were obtained from unobserved intakes. The same applies for food intake. The second limitation was the small sample size of patients requiring dose adjustments. Although some data could be presented on this topic, a larger study would be necessary to reveal the effects of dose adjustments.

In conclusion, the authors write, “When dosing lopinavir/ritonavir at 800/200 mg once a day in this study similar pharmacokinetics were found, compared with a previous study with this dosage. In addition, we found that 30% of patients had a C ₂₄ less than 1.0 mg/l, and dose adjustment in four patients resulted in a C _trough greater than 1.0 mg/l in only one patient.”

“Therefore, it remains important to establish the best way to manage these patients in clinical practice. Also, dose escalation might induce more side-effects, higher pill burden and subsequent non-compliance. Therapeutic drug monitoring can be a tool to detect patients with lower-than-average exposure.

“Further studies are needed that address the question of to what extent lopinavir pharmacokinetic parameters, i.e. C _trough, are predictors of sustained virological suppression.”

Department of Clinical Pharmacy, Department of General Medicine, Radboud University Medical Centre, University Centre for Infectious Diseases, Department of Infectious Diseases, Leiden University Medical Center, Erasmus Medical Centre, Walcheren Hospital, Leyenburg Hospital, the Netherlands.

06/22/05

Reference
C la Porte and others. Pharmacokinetics of once-daily lopinavir/ritonavir and the influence of dose modifications (Research Letter). AIDS 19(10):1105-1107, July 1, 2005.

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