Strategies for long-acting drug design

doi:10.12122/j.issn.1673-4254.2025.01.24

Abstract

Abstract:

With advances of drug design and preparation technology, the development of long-acting drugs has become an important research focus in precision medicine and chronic disease management. These drugs are designed to improve the patients' compliance and quality of life by achieving prolonged maintenance of an effective drug concentration in the body with a reduced dosing frequency. Small molecule drugs, monoclonal antibodies and nucleic acid drugs all have their own difficulties in achieving long actions, which can be especially challenging for the latter two because of their structural complexity. This review provides an overview of the strategies for designing long-acting small molecule drugs, monoclonal antibodies, and nucleic acid drugs.

Key words: long-acting drugs, drug design, small molecule drugs, monoclonal antibodies, nucleic acid drugs

Muqi HUANG, Zheng CAI, Shuwen LIU. Strategies for long-acting drug design[J]. Journal of Southern Medical University, 2025, 45(1): 206-212.

Figures/Tables 1

References 46

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Drug type	Generic name (trade name)		Indication	Long acting strategy	Plasma half-life	Dosing method	FDA approval date
Small molecule drug	Paliperidone Palmitate (Invega Sustenna)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	25-49 d	qm, im	2009.7
	Paliperidone Palmitate (Invega Trinza)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	84-95 d	q3m,im	2015.5
	Aripiprazole Lauroxil (Aristada Initio)	Alkermes Inc	Schizophrenia	Nanocrystals	15-18 d	s, im	2018.6
	Risperidone (Perseris)	Indivior PLC	Schizophrenia	ATRIGEL delivery system	9-11 d	qm, sc	2018.7
	Baloxavir marboxil (Xofluza)	Shionogi	Influenza A and B	Prodrug technique	80-100 h	s, po	2018.10
	Cabotegravir/Rilpivirine (Cabenuva)	Viiv Healthcare Co	Treatment of HIV-1 infection	Nanocrystals	Cabotegravir:5.6-11.5w;Rilpivirine:13-28 w	qm or q2m, im	2021.1
	Paliperidone Palmitate (Invega Hafyera)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	148-159 d	q6m,im	2021.8
	Cabotegravir (Apretude)	Viiv Healthcare Co	Prophylaxis for HIV-1	Nanocrystals	25-54 d	q2m, im	2021.12
	Lenacapavir (Sunlenca)	Gilead Sciences	Treatment/Prevention of HIV-1 infection	10 Fluoride substituted, PEG solvent, subcutaneous extended-release	8-12 w	q6m, sc	2022.12
	Risperidone Microspheres for Injection(II) (Rykindo)	Luye Pharma Group	Acute and chronic schizophrenia and bipolar disorder type I	Microsphere technique	3-6 d, stable release:4-5 w	q2w, im	2023.1
Monoclonal antibody	Ravulizumab (Ultomiris)	Alexion	Paroxysmal nocturnal hemoglobinuria	Increased extent of terminal sialylation on N-glycosylation Fc: LS modification, two histidine substitutions in complementarity determining region	50 d	q8w, iv	2018.12
	Sotrovimab (Xevudy)	GSK/Vir Biotechnology	COVID-19 treatment	Fc: LS modification	61 d	s, im	2021.5
	Tixagevimab/Cilgavimab (Evusheld)	AstraZeneca	Prophylaxis for COVID-19	Fc: TM and YTE modification	Tixagevimab:87.9 d,Cilgavimab:77.9-92.0 d	s, im	2022.12
	Nirsevimab (Beyfortus)	AstraZeneca/Sanofi	RSV induced lower respiratory tract infection	Fc: YTE modification	63-73 d	s, im	2023.7
Nucleic acid drug	Nusinersen (Spinraza)	Ionis/Biogen	Spinal muscular atrophy(SMA)	PS, 2′⁃MOE	plasma:63-87 d,cerebrospinal fluid:135-177 d	q4w, it	2016.12
	Patisiran (Onpattro)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	2′⁃OH/2′⁃OMe/2′⁃H; LNP delivery	2-4 d, 12-20 d(elimination)	q3w, iv	2018.8
	Givosiran (Givlaari)	Alnylam	Acute hepatic porphyria	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	6 h, CL= 0.50 L·h^-1·kg^-1	qm, sc	2019.11
	Lumasiran (Oxlumo)	Alnylam	Primary hyperoxaluria type 1(PH1)	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	5.2 h, CL= 0.38 L·h^-1·kg^-1, liver: not detected	q3m, sc	2020.11
	Inclisiran (Leqvio)	Novartis	Heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease	Advanced ESC, PS, 2′-OMe/2′-F; GalNAc delivery	9 h, liver: 80-90 d	q6m, sc	2020.12
	Vutrisiran (Amvuttra)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	ESC, PS, 2′-OMe/2′-F; GalNAc delivery	5.2 h, CL= 0.30 L·h^-1·kg^-1, liver: not detected	q3m, sc	2022.6
	Tofersen (Qalsody)	Ionis/Biogen	Amyotrophic lateral sclerosis with SOD1 gene mutation	PS, 2′-MOE	Cerebrospinal fluid:4 w	q4w, it	2023.4
	Nedosiran (Rivfloza)	Novo Nordisk	Primary hyperoxaluria type 1(PH1)	PS, 2′-OMe/2′-F; GalXc technique	15 h, CL=0.08 L·h^-1·kg^-1 liver: not detected	qm, sc	2023.9
	Eplontersen (Wainua)	Ionis/AstraZeneca	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	PS/PO, 2′-MOE; GalNAc delivery	3 w	qm, sc	2023.12

Drug type	Generic name (trade name)		Indication	Long acting strategy	Plasma half-life	Dosing method	FDA approval date
Small molecule drug	Paliperidone Palmitate (Invega Sustenna)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	25-49 d	qm, im	2009.7
	Paliperidone Palmitate (Invega Trinza)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	84-95 d	q3m,im	2015.5
	Aripiprazole Lauroxil (Aristada Initio)	Alkermes Inc	Schizophrenia	Nanocrystals	15-18 d	s, im	2018.6
	Risperidone (Perseris)	Indivior PLC	Schizophrenia	ATRIGEL delivery system	9-11 d	qm, sc	2018.7
	Baloxavir marboxil (Xofluza)	Shionogi	Influenza A and B	Prodrug technique	80-100 h	s, po	2018.10
	Cabotegravir/Rilpivirine (Cabenuva)	Viiv Healthcare Co	Treatment of HIV-1 infection	Nanocrystals	Cabotegravir:5.6-11.5w;Rilpivirine:13-28 w	qm or q2m, im	2021.1
	Paliperidone Palmitate (Invega Hafyera)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	148-159 d	q6m,im	2021.8
	Cabotegravir (Apretude)	Viiv Healthcare Co	Prophylaxis for HIV-1	Nanocrystals	25-54 d	q2m, im	2021.12
	Lenacapavir (Sunlenca)	Gilead Sciences	Treatment/Prevention of HIV-1 infection	10 Fluoride substituted, PEG solvent, subcutaneous extended-release	8-12 w	q6m, sc	2022.12
	Risperidone Microspheres for Injection(II) (Rykindo)	Luye Pharma Group	Acute and chronic schizophrenia and bipolar disorder type I	Microsphere technique	3-6 d, stable release:4-5 w	q2w, im	2023.1
Monoclonal antibody	Ravulizumab (Ultomiris)	Alexion	Paroxysmal nocturnal hemoglobinuria	Increased extent of terminal sialylation on N-glycosylation Fc: LS modification, two histidine substitutions in complementarity determining region	50 d	q8w, iv	2018.12
	Sotrovimab (Xevudy)	GSK/Vir Biotechnology	COVID-19 treatment	Fc: LS modification	61 d	s, im	2021.5
	Tixagevimab/Cilgavimab (Evusheld)	AstraZeneca	Prophylaxis for COVID-19	Fc: TM and YTE modification	Tixagevimab:87.9 d,Cilgavimab:77.9-92.0 d	s, im	2022.12
	Nirsevimab (Beyfortus)	AstraZeneca/Sanofi	RSV induced lower respiratory tract infection	Fc: YTE modification	63-73 d	s, im	2023.7
Nucleic acid drug	Nusinersen (Spinraza)	Ionis/Biogen	Spinal muscular atrophy(SMA)	PS, 2′⁃MOE	plasma:63-87 d,cerebrospinal fluid:135-177 d	q4w, it	2016.12
	Patisiran (Onpattro)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	2′⁃OH/2′⁃OMe/2′⁃H; LNP delivery	2-4 d, 12-20 d(elimination)	q3w, iv	2018.8
	Givosiran (Givlaari)	Alnylam	Acute hepatic porphyria	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	6 h, CL= 0.50 L·h^-1·kg^-1	qm, sc	2019.11
	Lumasiran (Oxlumo)	Alnylam	Primary hyperoxaluria type 1(PH1)	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	5.2 h, CL= 0.38 L·h^-1·kg^-1, liver: not detected	q3m, sc	2020.11
	Inclisiran (Leqvio)	Novartis	Heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease	Advanced ESC, PS, 2′-OMe/2′-F; GalNAc delivery	9 h, liver: 80-90 d	q6m, sc	2020.12
	Vutrisiran (Amvuttra)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	ESC, PS, 2′-OMe/2′-F; GalNAc delivery	5.2 h, CL= 0.30 L·h^-1·kg^-1, liver: not detected	q3m, sc	2022.6
	Tofersen (Qalsody)	Ionis/Biogen	Amyotrophic lateral sclerosis with SOD1 gene mutation	PS, 2′-MOE	Cerebrospinal fluid:4 w	q4w, it	2023.4
	Nedosiran (Rivfloza)	Novo Nordisk	Primary hyperoxaluria type 1(PH1)	PS, 2′-OMe/2′-F; GalXc technique	15 h, CL=0.08 L·h^-1·kg^-1 liver: not detected	qm, sc	2023.9
	Eplontersen (Wainua)	Ionis/AstraZeneca	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	PS/PO, 2′-MOE; GalNAc delivery	3 w	qm, sc	2023.12

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