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https://pubchem.ncbi.nlm.nih.gov/

Lopinavir and Ritonavir LAI

Developer(s)

University of North Texas Health Science Center

Originator
https://www.unthealth.edu/index.html

United States of America

Founded in 1970 as a private osteopathic college, UNT Health Fort Worth became a state institution in 1975. It expanded into a comprehensive graduate medical center by 1993. The 33-acre Fort Worth campus features the high-tech Interdisciplinary Research Building and the Center for BioHealth, which houses advanced imaging suites and virtual reality simulation labs.

Drug structure

Schematic Structure of Ritonavir (C37H48N6O5S2) & Lopinavir (C37H48N6O5S2)

Schematic Structure of Ritonavir (C37H48N6O5S2) & Lopinavir (C37H48N6O5S2)

https://pubchem.ncbi.nlm.nih.gov/

Drug information

Associated long-acting platforms

Based on other organic particles, Micellar suspension

Administration route

Subcutaneous

Therapeutic area(s)

HIV

Use case(s)

Treatment

Use of drug

Ease of administration

Administered by a community health worker
Administered by a nurse
Administered by a specialty health worker

Frequency of administration

Weekly

User acceptance

Not provided

Dosage

Available dose and strength

Dose: Lopinavir (LPV): 50 mg; Ritonavir (RTV): 12.5 mg (LPV:RTV = 4:1 w/w). Strength: 100 mg/kg LPV and 25 mg/kg RTV

Maximum dose

N/A

Recommended dosing regimen

The dosing regimen used in preclinical studies shows: 100 mg/kg LPV + 25 mg/kg RTV (4:1 w/w) administered as a single subcutaneous injection in rats. Each preparation contains 50 mg LPV, 12.5 mg RTV, 50 mg oleic acid, and 100 mg TPGS.

Additional comments

Not provided

Dosage link(s)

Not provided

Drug information

Drug's link(s)

Not provided

Generic name

Lopinavir and Ritonavir nanoparticle suspension

Brand name

Lopinavir and Ritonavir nanoparticle suspension

Compound type

Small molecule

Drug class/category

HIV protease inhibitors

Summary

long-acting subcutaneous injectable formulation of lopinavir (LPV) and ritonavir (RTV) was developed with in situ self-assembly nanoparticle technology (ISNP) to address adherence challenges associated with daily HIV therapy. The formulation combines LPV and RTV (4:1 w/w) with oleic acid and TPGS, forming nanoparticles upon contact with physiological fluids. Pharmacologically, co-formulated RTV enhances LPV exposure by inhibiting CYP3A4-mediated metabolism. The ISNPs demonstrated high entrapment efficiency (>98%), particle size of ~168 nm, and drug loading of 23.5% (LPV) and 5.9% (RTV). Pharmacokinetic studies in rats showed sustained systemic exposure following a single subcutaneous dose, maintaining LPV trough concentrations >160 ng/mL and RTV >50 ng/mL for 6 days, with t1/2=22 and 44 h.

Approval status

Under preclinical investigation, not approved yet.

Regulatory authorities

Under preclinical investigation, not approved yet.

Safety

1) No injection-site irritation or inflammation 2) No redness, swelling, or skin hypersensitivity reactions 3) No signs of illness, dehydration, hypothermia, pain, or distress during the 6-day observation period.

Efficacy

1) LPV exhibited controlled release, with only ~20% released by Day 5 and sustained release extending beyond 14 days. LPV trough concentration (Ctrough) >160 ng/mL at Day 6. 2) RTV showed a biphasic release profile, releasing faster than LPV during the first 5 days and more slowly thereafter. RTV trough concentration ≈50 ng/mL at Day 6. 3) Approximately 60% of LPV and 40% of RTV were released over 14 days, demonstrating prolonged drug retention in the formulation.

Evidence Summary

The ISNP-based long-acting lopinavir/ritonavir (LPV/RTV) injectable formulation demonstrated a favorable preliminary safety profile and sustained drug exposure in rats. No injection-site irritation, inflammation, redness, swelling, or hypersensitivity reactions were observed following subcutaneous administration. In addition, animals showed no signs of illness, dehydration, hypothermia, pain, or distress during the 6-day observation period, indicating good local and systemic tolerability. The formulation provided controlled and prolonged drug release, supporting its potential as a long-acting HIV therapy. LPV exhibited slow release, with only ~20% released by Day 5 and sustained release beyond 14 days, maintaining trough plasma concentrations above 160 ng/mL at Day 6. RTV showed an initial faster release followed by slower release thereafter, with trough concentrations of approximately 50 ng/mL at Day 6. Overall, LPV + RTV LAI has favourable preclinical results.

Delivery device(s)

Not provided

Scale-up and manufacturing prospects

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Not provided

Manufacturing

ISO Class 9 cleanroom: Aseptically manufactured lipid-surfactant injectable made by simply heating and mixing LPV/RTV with oleic acid and TPGS (Sterile hot-melt mixing of LPV, RTV, oleic acid, and TPGS at 50°C for 10 min, followed by cooling; nanoparticles self-assemble only upon exposure to saline/body fluids after administration). No preformed nanoparticles, no lyophilization, room-temperature storage possible, and readily scalable using standard pharmaceutical manufacturing equipment.

Specific analytical instrument required for characterization of formulation

Not provided

Clinical trials

Not provided

Excipients

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

1) Oleic acid 2) D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS)

Residual solvents used

Not provided

Patent info

There are either no relevant patents or these were not yet submitted to LAPaL

Supporting material

Publications

Tanaudommongkon, I., Tanaudommongkon, A., & Dong, X. (2021). Development of In Situ Self-Assembly Nanoparticles to Encapsulate Lopinavir and Ritonavir for Long-Acting Subcutaneous Injection. Pharmaceutics, 13(6), 904. https://doi.org/10.3390/pharmaceutics13060904

Irin Tanaudommongkon — Pharmaceutics - MDPI — 2021-07-18

Summary: Acute Preclinical studies of the fixed drug combination of Lopinavir and Ritonavir investigated the pharmacokinetics and safety profile of the in situ forming nanoparticle subcutaneous injection.

Most antiretroviral medications for human immunodeficiency virus treatment and prevention require high levels of patient adherence, such that medications need to be administered daily without missing doses. Here, a long-acting subcutaneous injection of lopinavir (LPV) in combination with ritonavir (RTV) using in situ self-assembly nanoparticles (ISNPs) was developed to potentially overcome adherence barriers. The ISNP approach can improve the pharmacokinetic profiles of the drugs. The ISNPs were characterized in terms of particle size, drug entrapment efficiency, drug loading, in vitro release study, and in vivo pharmacokinetic study. LPV/RTV ISNPs were 167.8 nm in size, with a polydispersity index of less than 0.35. The entrapment efficiency was over 98% for both LPV and RTV, with drug loadings of 25% LPV and 6.3% RTV. A slow release rate of LPV was observed at about 20% on day 5, followed by a sustained release beyond 14 days. RTV released faster than LPV in the first 5 days and slower than LPV thereafter. LPV trough concentration remained above 160 ng/mL and RTV trough concentration was above 50 ng/mL after 6 days with one subcutaneous injection. Overall, the ISNP-based LPV/RTV injection showed sustained release profiles in both in vitro and in vivo studies.

Additional documents

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Useful links

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Additional information

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