Matthias Leyh¹, Sven Zipperich², Ralf Winzer³, Philipp Drechsel¹, Johannes Bogner⁴, Andreas Trein⁵, Lothar Schneider⁶, Hartwig Klinker¹ and Peter Langmann⁷

¹Department of Internal Medicine II, Division of Infectious Diseases, University of Wuerzburg, 97070 Wuerzburg, Germany. ²Department of Internal Medicine II, Zentralklinikum, 98527 Suhl, Germany. ³Department of Internal Medicine, Outpatient Clinic for Infectious Diseases, University of Duesseldorf, 40225 Duesseldorf, Germany. ⁴Department of Internal Medicine, Division of Infectious Diseases, University of Munich, 80336 Munich, Germany. ⁵Clinic for Infectious Diseases, 70197 Stuttgart, Germany. ⁶Clinic for Infectious Diseases, 90762 Fuerth, Germany. ⁷Clinic for Infectious Diseases, 97753 Karlstadt, Germany.

Abstract

The protease inhibitor Lopinavir (LPV) combined with low dose ritonavir (r) in the formulation of a soft gelatine capsule (SGC) has been widely used in antiretroviral therapy and has been shown to produce safe therapeutic plasma levels. In June 2006, the LPV/r combination was approved as a tablet (TBL) in Germany and since then has replaced the capsule form. The purpose of this study was to analyze and compare pharmacokinetics of Lopinavir both in the new meltrex tablet formulation and the LPV/r soft gelatine capsule during long-term treatment of HIV.

Methods:  Included in this study were all patients followed at multiple study centers between January 2003 and August 2007 for whom LPV plasma levels were archived during therapeutic drug monitoring. A total of 4010 LPV plasma levels from 721 patients met these inclusion criteria. From these, those patients for whom complete data sets were missing were excluded from the study. Complete data sets were defined as those data that included information regarding cumulative daily dose, the patient’s anti-retroviral drug regimen, and the time of measurement after drug intake. A total of 571 LPV plasma levels from 138 patients met the full criteria for inclusion in this retrospective study. Additionally, a small prospective study of LPV plasma levels in 6 patients with 24 data points was conducted in order to increase the reliability of this report.

Results:  At 3 h after dosing, plasma levels of LPV were significantly higher in patients who had received the meltrex tablet (Mdn = 10030 ng/ml, min = 3323, max = 17280) compared to those who had received the soft gelatine capsule (Mdn = 7964 ng/ml, min = 120, max = 17900). This difference was statistically significant (p < 0.05). There were no statistically significant differences between the LPV plasma levels of the tablet and the capsule at 6, 9 and 12 h after dosing. Additionally, there were no differences between the trough levels of LPV in the two formulations. However, great variances of plasma levels were detected at time 12 h after dosing for both treatment groups (s(capsule) = 3213 ng/ml, s(tablet) = 2273 ng/ml).

Conclusion:  The LPV/r tablet formulation is able to produce equivalent to significantly higher plasma levels of LPV when compared with the SGC formulation at time 3 h after drug intake. In addition, the known sex difference in the pharmacokinetic profile of the tablet formulation was verified in this study.