HALOFANTRINE

US Previously Marketed

Details

Stereochemistry	RACEMIC
Molecular Formula	C26H30Cl2F3NO
Molecular Weight	500.424
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCCCN(CCCC)CCC(O)C1=C2C=CC(=CC2=C3C=C(Cl)C=C(Cl)C3=C1)C(F)(F)F

InChI

InChIKey=FOHHNHSLJDZUGQ-UHFFFAOYSA-N

InChI=1S/C26H30Cl2F3NO/c1-3-5-10-32(11-6-4-2)12-9-25(33)23-16-22-21(14-18(27)15-24(22)28)20-13-17(26(29,30)31)7-8-19(20)23/h7-8,13-16,25,33H,3-6,9-12H2,1-2H3

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf
Curator's Comment: Description was created using several sources including: https://www.sri.com/newsroom/press-releases/sri-international-celebrates-50-years-drug-discovery-and-development-contrib; http://www.drugbank.ca/drugs/DB01218

Halofantrine is a blood schizonticidal antimalarial agent with no apparent action on the sporozoite, gametocyte or hepatic stages of the infection. It is used only to treat but not to prevent malaria. Has been marketed by GlaxoSmithKline as HALFAN (halofantrine hydrochloride) in 250 mg tablets indicated for the treatment of adults who can tolerate oral medication and who have mild to moderate malaria (equal to or less than 100,000 parasites/mm3) caused by Plasmodium falciparum or Plasmodium vivax. Among side effects is cardiac arrhythmia. It belongs to the phenanthrene class of compounds that includes quinine and lumefantrine. It was reported that halofantrine binds to hematin in vitro (crystal structure of the complex) and to to plasmpesin, a haemoglobin degrading enzyme unique to the malarial parasites.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Ferriprotoporphyrin IX 43 Target ID: CHEMBL613897 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18508124	Antagonist 2778		0.79 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Plasmodium vivax malaria 6 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf	Curative		Approved 8429	HALFAN Approved Use Halfan tablets are indicated for the treatment of adults who can tolerate oral medication and who have mild to moderate malaria (equal to or less than 100,000 parasites/mm3) caused by Plasmodium falciparum or Plasmodium vivax. Launch Date 1993
Plasmodium falciparum malaria 63 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf	Curative		Approved 8429	HALFAN Approved Use Halfan tablets are indicated for the treatment of adults who can tolerate oral medication and who have mild to moderate malaria (equal to or less than 100,000 parasites/mm3) caused by Plasmodium falciparum or Plasmodium vivax. Launch Date 1992

C_max

Value	Dose	Analyte	Population
114 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	DESBUTYLHALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
191 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	DESBUTYLHALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
79 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	DESBUTYLHALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1218 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: HIGH-FAT
185 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
345 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
546 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
3200 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf	500 mg 3 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FED

AUC

Value	Dose	Analyte	Population
17.33 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	DESBUTYLHALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
24.46 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	DESBUTYLHALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
8.76 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	DESBUTYLHALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
11.3 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: HIGH-FAT
3.92 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
7.86 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
9.36 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
81 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
98 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
72 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2775616/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
8 day DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf	500 mg 3 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HALOFANTRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FED

Doses

Dose	Population	Adverse events
500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	Disc. AE: Vomiting of medication, Consciousness decreased... Other AEs: Convulsions, Stomatitis... AEs leading to discontinuation/dose reduction: Vomiting of medication (3 patients) Consciousness decreased (2 patients) Other AEs: Convulsions (3 patients) Stomatitis (3 patients) Pulmonary edema (1 patient) Tetany (1 patient) Hypertensive crisis (1 patient) Cerebrovascular accident (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7

AEs

AE	Significance	Dose	Population
Cerebrovascular accident	1 patient	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7
Hypertensive crisis	1 patient	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7
Pulmonary edema	1 patient	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7
Tetany	1 patient	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7
Consciousness decreased	2 patients Disc. AE	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7
Convulsions	3 patients	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7
Stomatitis	3 patients	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7
Vomiting of medication	3 patients Disc. AE	500 mg 3 times / day single, oral Recommended Dose: 500 mg, 3 times / day Route: oral Route: single Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7	unhealthy, adult n = 933 Health Status: unhealthy Condition: malaria Age Group: adult Sex: unknown Population Size: 933 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf Page: 7

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP3A5 395 CYP1A2 1054 CYP2C8 693 CYP2C19 991 CYP2E1 667

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2D6 1891	inhibitor 3277 Sources: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2125.1995.tb04559.x	yes [IC50 1.06 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	major	yes (co-administration study) Comment: grapefruit juice increased halofantrine area under the plasma concentration versus time curve (AUC) and peak plasma concentration by 2.8-fold Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	minor
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	minor
CYP2C8 693	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	minor
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	minor
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	minor
CYP2E1 667	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	minor
CYP3A5 395	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10385214/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1572249/

Sourcing

Vendor/Aggregator	ID	URL
3B Scientific (Wuhan) Corp	3B2-0827	http://www.3bsc.com/index/pro_info.php?id=20183
AA Blocks	AA005U0E	https://www.aablocks.com/goods/Goods/detail?id=AA005U0E
AHH Chemical co.,ltd	API-1799	http://www.ahhchemical.com/product/API-1799.html
AHH Chemical co.,ltd	MT-00040	http://www.ahhchemical.com/product/MT-00040.html
AK Scientific, Inc. (AKSCI)	K173	http://www.aksci.com/item_detail.php?cat=K173
Achemtek	0104-011826	http://www.achemtek.com/69756-53-2
Angene	AGN-PC-0TWMOP	http://www.angenechemical.com/productshow/AGN-PC-0TWMOP.html
Aurora Fine Chemicals LLC	A13.111.973	http://online.aurorafinechemicals.com/info?ID=A13.111.973
BLD Pharm	BD42604	http://www.bldpharm.com/products/69756-53-2.html
BioChemPartner	BCP13777	http://www.biochempartner.com/69756-53-2-BCP13777
Boerchem	BC219545	http://www.boerchem.com/?product_37027.html
CSNpharm	CSN16806	https://www.csnpharm.com/products/halofantrine.html
ChemMol	30109003	http://www.chemmol.com/chemmol/30109003.html
ChemMol	44006023	http://www.chemmol.com/chemmol/44006023.html
ChemMol	49409571	http://www.chemmol.com/chemmol/49409571.html
Chemspace	CSSB00000053387	https://chem-space.com/CSSB00000053387
Clearsynth	CS-O-01632	http://www.clearsynth.com/en/CS-O-01632.html
Finetech	FT-0601579	http://www.finetechnology-ind.com/prod/detail/pub/69756-53-2.html
Parchem	29094	http://www.parchem.com/chemical-supplier-distributor/Halofantrine-019094.aspx
Smolecule	S529738	http://www.smolecule.com/products/s529738
THE BioTek	bt-269289	https://www.thebiotek.com/product/inhibitors/bt-269289
eNovation Chemicals	D537196	https://www.enovationchem.com/ProductDetails.asp?ProductID=D537196

PubMed

Title	Date	PubMed
A new high-performance liquid chromatography (HPLC) method for the analysis of halofantrine (HF) in pharmaceuticals.	2002 Jul 31	12093524

Sample Use Guides

In Vivo Use Guide

The recommended treatment consists of 2 courses of 1500 mg. One course dosage is 500 mg (2 x 250 mg tablets) given every 6 hours for 3 doses, repeated in 7 days. Halofantrine is administered at least 1 hour before or 2 hours after food.

Route of Administration: Oral

In Vitro Use Guide

Antimalarial activity of halofantrine against 33 strains of P. falciparum isolated from naturally acquired malaria infections in Thailand was determined using a radioisotope microdilution method. 0.2-25 ng/ml of halofantrine was added to test isolates of P. falciparum. Susceptibility response ID50 was 0.63-0.73 ng/ml.

Name

Type

Language

HALOFANTRINE

Official Name

English

9-PHENANTHRENEMETHANOL, 1,3-DICHLORO-.ALPHA.-(2-(DIBUTYLAMINO)ETHYL)-6-(TRIFLUOROMETHYL)-

Systematic Name

English

(±)-HALOFANTRINE

Common Name

English

HALOFANTRINE [VANDF]

Common Name

English

Halofantrine [WHO-DD]

Common Name

English

DL-WR-171669

Code

English

HALOFANTRINE [MI]

Common Name

English

1,3-DICHLORO-.ALPHA.-(2-(DIBUTYLAMINO)ETHYL)-6-(TRIFLUOROMETHYL)-9-PHENANTHRENEMETHANOL

Systematic Name

English

halofantrine [INN]

Common Name

English

Classification Tree Code System Code

WHO-ATC

P01BX01