Evaluation of pharmacokinetic interactions between long-acting HIV-1 fusion inhibitor albuvirtide and lopinavir/ritonavir, in HIV-infected subjects, combined with clinical study and simulation results

Abstract

1. A clinical study to assess the interactions between albuvirtide (320 mg) and lopinavir/ritonavir (400/100 mg) was conducted in 10 HIV-1-infected subjects. Because albuvirtide requires a long period to achieve steady state, and extended monotherapy may lead to early resistance, it is unethical to take albuvirtide alone to achieve steady state. Therefore, a population pharmacokinetic model was developed to predict steady-state concentration-time curve of solely administered albuvirtide. 2. When albuvirtide and lopinavir/ritonavir were co-administered, the plasma concentration of albuvirtide when the infusion ended (C) increased by about 34%, but the geometric mean ratios and 90% confidence intervals (90% CIs) of AUC [1.09 (0.96-1.24)] and C [1.00 (0.83-1.20)] were within the range of 0.8-1.25. For lopinavir, the ratios (90% CIs) of AUC, C and C were 0.63 (0.49-0.82), 0.67 (0.53-0.86) and 0.65 (0.46-0.91); for ritonavir, those ratios (90% CIs) were 0.62 (0.42-0.91), 0.61 (0.38-0.99) and 0.72 (0.40-1.26), respectively. 3. Co-administration of albuvirtide with lopinavir/ritonavir has little effect on albuvirtide exposure, but it decreases the plasma exposures of lopinavir/ritonavir. However, the drug-drug interactions may not reduce the effectiveness of this co-therapy, the trough concentration of lopinavir may be sufficient and this combination could achieve similar clinical efficacy with marketed drugs. So, a phase 3 clinical trial without dose adjustment is underway to validate their effectiveness and safety.

A Review of Clinical Pharmacokinetic and Pharmacodynamic Profiles of Select Antiretrovirals: Focus on Differences among Chinese Patients

“…Ritonavir, a pharmacokinetic enhancer, inhibited the cytochrome P450 (CYP) metabolism of LPV, thereby providing increased plasma concentrations of LPV and allowing twice/day dosing . Compared with the results of previous reports (Table ), despite relatively large interpatient variability, C min and Cl/F appeared to be lower in Chinese patients than that in other populations.…”

Investigational drugs in HIV: Pros and cons of entry and fusion inhibitors (Review)

“…In patients treated with LPV/r and ABT, a decrease of LPV/r exposure was identified. However, this decrease did not lead to a change in the usual doses of these drugs (62). No other drug interactions are known at present.…”

Physiologically‐Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS‐CoV‐2

“…The predicted CL/F after repeated dosing in white healthy volunteers were greater than the Chinese populations (3.81 L/h), corresponding with observed clinical data. 2,22,25 Predicted C max and AUC 0-t were in turn greater in Chinese (20.00 µg/mL and 204.29 µg/ mL.h) in comparison to white healthy volunteers (13.02 µg/mL and 117.68 µg/mL.h).…”

“…Simulations were performed for an oral administration of single dose of lopinavir 400 mg, single dose of lopinavir/ritonavir 400/100 mg, and repeated dosing of 400/100 mg twice daily regimen for white and Chinese populations using the Simcyp Healthy Volunteers and Chinese Healthy Volunteers population database, respectively. Simulated results were visually inspected by overlaying clinical plasma concentration‐time profiles (extracted using WebPlotDigitizer, San Francisco, CA) with model predictions 2,22–28 . Thereafter, the PBPK models were validated using a two‐fold criterion to compare the clinically observed and model predicted PK parameters, such as the maximum plasma concentration (C max ), area under the plasma concentration‐time profile (AUC 0–t ), time needed to reach C max (T max ), oral clearance (CL/F), terminal half‐life, and minimum plasma concentration at steady‐state (C min ).…”

“…Simulated results were visually inspected by overlaying clinical plasma concentration-time profiles (extracted using WebPlotDigitizer, San Francisco, CA) with model predictions. 2,[22][23][24][25][26][27][28] Thereafter, the PBPK models were validated using a twofold criterion to compare the clinically observed and model predicted PK parameters, such as the maximum plasma concentration (C max ), area under the plasma concentration-time profile (AUC 0-t ), time needed to reach C max (T max ), oral clearance (CL/F), terminal half-life, and minimum plasma concentration at steady-state (C min ).…”