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High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
Published on: May 21, 2018
Time-dependent interaction between lopinavir/ritonavir and fexofenadine
Rolf P G van Heeswijk1, Marc Bourbeau, Pearl Campbell
1Ottawa Hospital, Divisio of Infectious Diseaeses, Canada. rvheesw1@tibbe.jnj.com
Journal of Clinical Pharmacology
|July 1, 2006
Summary
This study shows that lopinavir/ritonavir significantly increases fexofenadine exposure by inhibiting P-glycoprotein. This drug interaction, though attenuated with repeated dosing, necessitates caution when coadministering P-glycoprotein substrates.
Area of Science:
- Pharmacology
- Drug Interactions
- Biochemistry
Background:
- P-glycoprotein (P-gp) is a key efflux transporter influencing drug bioavailability.
- Lopinavir/ritonavir is an antiretroviral medication known to interact with drug transporters.
- Fexofenadine serves as a probe substrate to assess P-gp activity.
Purpose of the Study:
- To evaluate the impact of single-dose and steady-state lopinavir/ritonavir on fexofenadine exposure.
- To quantify the effect of lopinavir/ritonavir on P-glycoprotein activity using fexofenadine as a marker.
- To assess potential time-dependent inhibition of P-glycoprotein by lopinavir/ritonavir.
Main Methods:
- A randomized study involving 16 volunteers receiving fexofenadine alone and with single-dose or steady-state lopinavir/ritonavir.
- Pharmacokinetic analysis of fexofenadine plasma concentrations to determine area under the curve (AUC) and elimination half-life.
- Comparison of fexofenadine exposure under different lopinavir/ritonavir dosing regimens.
Main Results:
- Single-dose ritonavir and lopinavir/ritonavir increased fexofenadine AUC(infinity) by 2.2- and 4.0-fold, respectively.
- Steady-state lopinavir/ritonavir increased fexofenadine AUC(infinity) by 2.9-fold.
- No significant changes in fexofenadine elimination half-life were observed.
Conclusions:
- Lopinavir/ritonavir inhibits P-glycoprotein, leading to increased fexofenadine bioavailability.
- The interaction effect was attenuated after repeated lopinavir/ritonavir administration but remained significant.
- Time-dependent P-glycoprotein inhibition by lopinavir/ritonavir should be considered during coadministration with P-gp substrates.
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