No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches.
Metformin
/ pharmacokinetics
Humans
Drug Interactions
Organic Cation Transport Proteins
/ metabolism
Organic Cation Transporter 2
/ metabolism
Organophosphates
/ administration & dosage
Models, Biological
Animals
Organic Cation Transporter 1
/ metabolism
Anti-HIV Agents
/ administration & dosage
Octamer Transcription Factor-1
/ metabolism
HIV Infections
/ drug therapy
Piperazines
DDI with Metformin
Fostemsavir
PBPK model
Journal
Pharmacology research & perspectives
ISSN: 2052-1707
Titre abrégé: Pharmacol Res Perspect
Pays: United States
ID NLM: 101626369
Informations de publication
Date de publication:
Aug 2024
Aug 2024
Historique:
revised:
21
05
2024
received:
06
02
2024
accepted:
23
06
2024
medline:
11
7
2024
pubmed:
11
7
2024
entrez:
11
7
2024
Statut:
ppublish
Résumé
Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.
Substances chimiques
Metformin
9100L32L2N
Organic Cation Transport Proteins
0
Organic Cation Transporter 2
0
Organophosphates
0
fostemsavir
97IQ273H4L
SLC47A1 protein, human
0
SLC22A2 protein, human
0
Organic Cation Transporter 1
0
SLC47A2 protein, human
0
Anti-HIV Agents
0
Octamer Transcription Factor-1
0
POU2F1 protein, human
0
Piperazines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1238Informations de copyright
© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
Références
RUKOBIA (fostemsavir) [package insert]. ViiV HealthCare; 2020.
Study NCT02674581. An Open‐Label Study to Evaluate the Pharmacokinetics and Safety of BMS‐663068 in Subjects with Normal Renal Function and Subjects with Mild, Moderate, Severe, and End‐Stage Renal Dysfunction. ViiV Healthcare; 2016.
Study NCT02805556. Study of the Absolute Bioavailability of BMS‐626529 in Healthy Subjects Following Oral Dosing of BMS‐663068 and Intravenous Dosing of BMS‐626529. ViiV Healthcare; 2016.
Gorycki P, Magee M, Ackerman P, Miao X, Moore K. Pharmacokinetics, metabolism and excretion of radiolabeled fostemsavir administered with or without ritonavir in healthy male subjects. Xenobiotica. 2022;52:541‐554.
Zhu L, Hruska M, Hwang C, et al. Pharmacokinetic interactions between BMS‐626529, the active moiety of the HIV‐1 attachment inhibitor prodrug BMS‐663068, and ritonavir or ritonavir‐boosted atazanavir in healthy subjects. Antimicrob Agents Chemother. 2015;59:3816‐3822.
Butt AA, McGinnis K, Rodriguez‐Barradas MC, et al. HIV infection and the risk of diabetes mellitus. AIDS. 2009;23:1227‐1234.
Riyaten P, Salvadori N, Traisathit P, et al. New‐onset diabetes and antiretroviral treatments in HIV‐infected adults in Thailand. J Acquir Immune Defic Syndr. 2015;69:453‐459.
Hanke N, Turk D, Selzer D, et al. A comprehensive whole‐body physiologically based pharmacokinetic drug‐drug‐gene interaction model of metformin and cimetidine in healthy adults and renally impaired individuals. Clin Pharmacokinet. 2020;59:1419‐1431.
Nishiyama K, Toshimoto K, Lee W, Ishiguro N, Bister B, Sugiyama Y. Physiologically‐based pharmacokinetic modeling analysis for quantitative prediction of renal transporter‐mediated interactions between metformin and cimetidine. CPT Pharmacometrics Syst Pharmacol. 2019;8:396‐406.
Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996;30:359‐371.
Yang Y, Zhang Z, Li P, Kong W, Liu X, Liu L. A Whole‐Body Physiologically Based Pharmacokinetic Model Characterizing Interplay of OCTs and MATEs in Intestine, Liver and Kidney to Predict Drug‐Drug Interactions of Metformin with Perpetrators. Pharmaceutics. 2021;13:698.
Burt HJ, Neuhoff S, Almond L, et al. Metformin and cimetidine: physiologically based pharmacokinetic modelling to investigate transporter mediated drug‐drug interactions. Eur J Pharm Sci. 2016;88:70‐82.
EMA. Guideline on the investigation of drug interactions. 2013.
US FDA. Drug development and drug interactions: table of substrates, inhibitors and inducers. 2019.
Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J Pharm Sci. 2017;106:2245‐2250.
Zamek‐Gliszczynski MJ, Chu X, Cook JA, et al. ITC commentary on metformin clinical drug‐drug interaction study design that enables an efficacy‐ and safety‐based dose adjustment decision. Clin Pharmacol Ther. 2018;104:781‐784.
International Transporter Consortium, Giacomini KM, Huang SM, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9:215‐236.
US FDA. In vitro drug interaction studies—cytochrome P450 enzyme‐ and transporter‐mediated drug interactions guidance for industry. 2020.
Guo Y, Chu X, Parrott NJ, et al. Advancing predictions of tissue and intracellular drug concentrations using in vitro, imaging and physiologically based pharmacokinetic modeling approaches. Clin Pharmacol Ther. 2018;104:865‐889.
Taskar KS, Pilla Reddy V, Burt H, et al. Physiologically‐based pharmacokinetic models for evaluating membrane transporter mediated drug‐drug interactions: current capabilities, case studies, future opportunities, and recommendations. Clin Pharmacol Ther. 2020;107:1082‐1115.
Ball K, Jamier T, Parmentier Y, Denizot C, Mallier A, Chenel M. Prediction of renal transporter‐mediated drug‐drug interactions for a drug which is an OAT substrate and inhibitor using PBPK modelling. Eur J Pharm Sci. 2017;106:122‐132.
Pan Y, Hsu V, Grimstein M, et al. The application of physiologically based pharmacokinetic modeling to predict the role of drug transporters: scientific and regulatory perspectives. J Clin Pharmacol. 2016;56(Suppl 7):S122‐S131.
Study NCT02666053. A Study to Assess the Effect of High Fat Meal and Increased Gastric pH on the Bioavailability of an Extended Release Formulation of BMS‐663068 in Healthy Subjects. ViiV Healthcare; 2016.
Study NCT02467335. Single‐dose pharmacokinetics of BMS‐626529, administered as BMS‐663068, in Subjects with Hepatic Impairment Compared to Healthy Subjects. ViiV Healthcare; 2015.
Study NCT02164045. Study to Evaluate the Effect of Food on the Pharmacokinetics of BMS‐626529. ViiV Healthcare; 2014.
Lagishetty C, Moore K, Ackerman P, Llamoso C, Magee M. Effects of Temsavir, active moiety of antiretroviral agent fostemsavir, on QT interval: results from a phase I study and an exposure‐response analysis. Clin Transl Sci. 2020;13:769‐776.
Brown J, Chien C, Timmins P, et al. Compartmental absorption modeling and site of absorption studies to determine feasibility of an extended‐release formulation of an HIV‐1 attachment inhibitor phosphate ester prodrug. J Pharm Sci. 2013;102:1742‐1751.
Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95:1238‐1257.
Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Alprazolam‐ritonavir interaction: implications for product labeling. Clin Pharmacol Ther. 2000;67:335‐341.
Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23:545‐551.
Wang ZJ, Yin OQ, Tomlinson B, Chow MS. OCT2 polymorphisms and in‐vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet Genomics. 2008;18:637‐645.
Grun B, Kiessling MK, Burhenne J, et al. Trimethoprim‐metformin interaction and its genetic modulation by OCT2 and MATE1 transporters. Br J Clin Pharmacol. 2013;76:787‐796.
Muller F, Pontones CA, Renner B, et al. N(1)‐methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin‐trimethoprim interaction. Eur J Clin Pharmacol. 2015;71:85‐94.
Cho SK, Kim CO, Park ES, Chung JY. Verapamil decreases the glucose‐lowering effect of metformin in healthy volunteers. Br J Clin Pharmacol. 2014;78:1426‐1432.
Peng Y, Cheng Z, Xie F. Evaluation of pharmacokinetic drug–drug interactions: a review of the mechanisms, in vitro and in silico approaches. Metabolites. 2021;11:75.
Shebley M, Liu J, Kavetskaia O, et al. Mechanisms and predictions of drug‐drug interactions of the hepatitis C virus three direct‐acting antiviral regimen: Paritaprevir/ritonavir, Ombitasvir, and dasabuvir. Drug Metab Dispos. 2017;45:755‐764.
Yu J, Ragueneau‐Majlessi I. In vitro‐to‐in vivo extrapolation of transporter inhibition data for drugs approved by the US Food and Drug Administration in 2018. Clin Transl Sci. 2020;13:693‐699.
USPI. RUKOBIA‐ Fostemsavir Tromethamine Tablet, Film Coated, Extended Release. ViiV Healthcare Company; 2020.
Greenblatt DJ, Peters DE, Oleson LE, et al. Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4‐dimethyl‐benziso‐(2H)‐selenazine (ALT‐2074), an experimental catalytic mimic of glutathione oxidase. Br J Clin Pharmacol. 2009;68:920‐927.
Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD. Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos. 2011;39:1070‐1078.
Ouellet D, Hsu A, Granneman GR, et al. Pharmacokinetic interaction between ritonavir and clarithromycin. Clin Pharmacol Ther. 1998;64:355‐362.
Kharasch ED, Bedynek PS, Walker A, Whittington D, Hoffer C. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P‐glycoprotein activities. Clin Pharmacol Ther. 2008;84:506‐512.
Culm‐Merdek KE, von Moltke LL, Gan L, et al. Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir. Clin Pharmacol Ther. 2006;79:243‐254.