Comparative Bioavailability of Two Formulations of Biopharmaceutical Classification System (BCS) Class IV Drugs: A Case Study of Lopinavir/Ritonavir.
ADME
Anti-infective
Bioavailability
Bioequivalence
Biopharmaceutics Classification system (BCS)
Clinical pharmacokinetics
HIV
Lopinavir
Ritonavir
Journal
Journal of pharmaceutical sciences
ISSN: 1520-6017
Titre abrégé: J Pharm Sci
Pays: United States
ID NLM: 2985195R
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
19
03
2021
revised:
23
08
2021
accepted:
23
08
2021
pubmed:
17
9
2021
medline:
1
3
2022
entrez:
16
9
2021
Statut:
ppublish
Résumé
Lopinavir/ritonavir (LPV/r-A, Kaletra®), a fixed dose, co-formulated antiviral therapy for the treatment of HIV infection has been used worldwide for over two decades. Both active substances have low solubility in water and low membrane permeability. LPV/r-A tablets contain key excipients critical to ensuring acceptable bioavailability of lopinavir and ritonavir in humans. An established dog pharmacokinetic model demonstrated several generic LPV/r tablet formulations have significant oral bioavailability variability compared to LPV/r-A. Analytical characterizations of LPV/r-B tablets were performed and a clinical study was conducted to assess the relative bioavailability of Kalidavir® (LPV/r-B) 400/100 mg tablets relative to Kaletra® (LPV/r-A) 400/100 mg tablets under fasting conditions. The presence of active substances were confirmed in LPV/r-B tablets in an apparent amorphous state at essentially the labeled amounts, and dissolution profiles were generally similar to LPV/r-A tablets. Excipients in the tablet formulation were found to be variable and deviate from the labeled composition. Lopinavir and ritonavir exposures (AUC) following LPV/r-B administration were approximately 90% and 20% lower compared to that of LPV/r-A. LPV/r-B was not shown to be bioequivalent to LPV/r-A.
Sections du résumé
BACKGROUND
Lopinavir/ritonavir (LPV/r-A, Kaletra®), a fixed dose, co-formulated antiviral therapy for the treatment of HIV infection has been used worldwide for over two decades. Both active substances have low solubility in water and low membrane permeability. LPV/r-A tablets contain key excipients critical to ensuring acceptable bioavailability of lopinavir and ritonavir in humans. An established dog pharmacokinetic model demonstrated several generic LPV/r tablet formulations have significant oral bioavailability variability compared to LPV/r-A.
METHODS
Analytical characterizations of LPV/r-B tablets were performed and a clinical study was conducted to assess the relative bioavailability of Kalidavir® (LPV/r-B) 400/100 mg tablets relative to Kaletra® (LPV/r-A) 400/100 mg tablets under fasting conditions.
RESULTS
The presence of active substances were confirmed in LPV/r-B tablets in an apparent amorphous state at essentially the labeled amounts, and dissolution profiles were generally similar to LPV/r-A tablets. Excipients in the tablet formulation were found to be variable and deviate from the labeled composition. Lopinavir and ritonavir exposures (AUC) following LPV/r-B administration were approximately 90% and 20% lower compared to that of LPV/r-A.
CONCLUSIONS
LPV/r-B was not shown to be bioequivalent to LPV/r-A.
Identifiants
pubmed: 34530003
pii: S0022-3549(21)00458-5
doi: 10.1016/j.xphs.2021.08.037
pii:
doi:
Substances chimiques
Anti-HIV Agents
0
Biological Products
0
Drug Combinations
0
HIV Protease Inhibitors
0
Tablets
0
lopinavir-ritonavir drug combination
0
Lopinavir
2494G1JF75
Ritonavir
O3J8G9O825
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3963-3968Informations de copyright
Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.