HALOFANTRINE

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

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

Molecular Formula	C26H30Cl2F3NO
Molecular Weight	500.424
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description

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	Antagonist 2,778		0.79 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Plasmodium vivax malaria 6	Curative		Approved 8,429	HALFAN
Plasmodium falciparum malaria 63	Curative		Approved 8,429	HALFAN

C_max

Value	Dose	Analyte	Population
114 μg/L	500 mg single, oral	DESBUTYLHALOFANTRINE plasma	Homo sapiens
191 μg/L	1000 mg single, oral	DESBUTYLHALOFANTRINE plasma	Homo sapiens
79 μg/L	250 mg single, oral	DESBUTYLHALOFANTRINE plasma	Homo sapiens
1218 μg/L	250 mg single, oral	HALOFANTRINE plasma	Homo sapiens
185 μg/L	250 mg single, oral	HALOFANTRINE plasma	Homo sapiens
345 μg/L	500 mg single, oral	HALOFANTRINE plasma	Homo sapiens
546 μg/L	1000 mg single, oral	HALOFANTRINE plasma	Homo sapiens
3200 ng/mL	500 mg 3 times / day multiple, oral	HALOFANTRINE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
17.33 mg × h/L	500 mg single, oral	DESBUTYLHALOFANTRINE plasma	Homo sapiens
24.46 mg × h/L	1000 mg single, oral	DESBUTYLHALOFANTRINE plasma	Homo sapiens
8.76 mg × h/L	250 mg single, oral	DESBUTYLHALOFANTRINE plasma	Homo sapiens
11.3 mg × h/L	250 mg single, oral	HALOFANTRINE plasma	Homo sapiens
3.92 mg × h/L	250 mg single, oral	HALOFANTRINE plasma	Homo sapiens
7.86 mg × h/L	500 mg single, oral	HALOFANTRINE plasma	Homo sapiens
9.36 mg × h/L	1000 mg single, oral	HALOFANTRINE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
81 h	250 mg single, oral	HALOFANTRINE plasma	Homo sapiens
98 h	500 mg single, oral	HALOFANTRINE plasma	Homo sapiens
72 h	1000 mg single, oral	HALOFANTRINE plasma	Homo sapiens
8 day	500 mg 3 times / day multiple, oral	HALOFANTRINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
500 mg 3 times / day single, oral Recommended	unhealthy, adult n = 933	Disc. AE: Vomiting of medication, Consciousness decreased... Other AEs: Convulsions, Stomatitis...

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AEs

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AE	Significance	Dose	Population
Cerebrovascular accident	1 patient	500 mg 3 times / day single, oral Recommended	unhealthy, adult n = 933
Hypertensive crisis	1 patient	500 mg 3 times / day single, oral Recommended	unhealthy, adult n = 933
Pulmonary edema	1 patient	500 mg 3 times / day single, oral Recommended	unhealthy, adult n = 933
Tetany	1 patient	500 mg 3 times / day single, oral Recommended	unhealthy, adult n = 933
Consciousness decreased	2 patients Disc. AE	500 mg 3 times / day single, oral Recommended	unhealthy, adult n = 933

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	substrate 1,037	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP3A5 395 CYP1A2 1,054 CYP2C8 693 CYP2C19 991 CYP2E1 667

Drug as perpetrator

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP2D6 1,891	inhibitor 3,277	yes [IC50 1.06 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
CYP1A2 1,054	substrate 3,367	minor
CYP2C19 991	substrate 3,367	minor
CYP2C8 693	substrate 3,367	minor
CYP2C9 1,037	substrate 3,367	minor

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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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

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PubMed

PubMed

Title	Date	PubMed
No data available in table

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.