Piperaquine

Identification

Generic Name
Piperaquine
DrugBank Accession Number
DB13941
Background

Piperaquine is an antimalarial agent first synthesized in the 1960's and used throughout China 1. Its use declined in the 1980's as piperaquine resistant strains of Plasmodium falciparum appeared and artemisinin derivatives became available. It has come back into use in combination with the artemisinin derivative Artenimol as part of the combination product Eurartesim Label. Eurartesim was first authorized for market by the European Medicines Agency in October 2011.

Type
Small Molecule
Groups
Approved, Experimental, Investigational
Structure
Weight
Average: 535.52
Monoisotopic: 534.2065505
Chemical Formula
C29H32Cl2N6
Synonyms
  • 1,3-bis[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propane

Pharmacology

Indication

For the treatment of uncomplicated Plasmodium falciparum infection in adults, children, and infants aged 6 months and up weighing over 5 kg Label. Used in combination with Artenimol.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatMalaria caused by plasmodium falciparumCombination Product in combination with: Artenimol (DB11638)••••••••••••••••••• ••••••• ••••••• •••• ••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Piperaquine inhibits the P. Falciparum parasite's haem detoxification pathway 4.

Mechanism of action

The mechanism of piperaquine inhibition of the haem detoxification pathway is unknown but is expected to be similar to that of Chloroquine.

Absorption

Piperaquine is slowly absorbed and exhibits multiple peaks in its plasma concentration curve suggestive of enterohepatic recycling occurring alongside the absorption process 4. Due to this complication there is no discreet value for bioavailability but piperaquine is highly absorbed into systemic circulation. When taken with food, Cmax increases by 217% and mean exposure increases by 177%. Tmax is not affected by food and remains around 5 h Label. Piperaquine has been observed to accumulate more in females to a degree of 30-50% more than males Label. It also collects in red blood cells similar to Artenimol.

Volume of distribution

Piperaquine is thought to distribute into a central compartment with an apparent volume of 26.7 L/kg, and two peripheral compartments with apparent volumes of 76.8 L/kg and 617 L/kg 4. These combine for a total volume of distribution of 720.5 L/kg.

Protein binding

Piperaquine's binding to plasma proteins is considered to be virtually complete 4. It has been measured to be >99% in humans, rats, and dogs.

Metabolism

Piperaquine undergoes N-dealkylation, separating its aliphatic bridge from one of the nitrogen-containing rings 3. The resulting aldehyde is then oxidized to a carboxylic acid to form metabolite 1 (M1). The same nitrogen-containing rings can also undergo hydroxylation at one of two sites to form M3 or M4. M2 is formed via N-oxidation of one of the nitrogens in the quinoline groups at either side of the molecule. M5 results when both of these nitrogens are oxidized. M1 and M2 are the major metabolism products Label. Each of these metabolites were observed in the urine.

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Route of elimination

Piperaquine is mainly excreted in the feces with a negligible amount in the urine Label.

Half-life

The terminal elimination half-life was observed to be 576h or 24 days 4. This is thought to be due to the extensive distribution of piperaquine.

Clearance

The mean apparent total clearance has been observed to be 1.12 L/h/kg in adult malaria patients 4.

Adverse Effects
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Toxicity

Studies of piperaquine in monkeys and dogs have shown some hepatotoxicity and reversible depression in white blood cells and neutrophils Label. Additional observations include infiltration of macrophages with intracytoplasmic basophilic granular material consistent with phospholipidosis and degenerative lesions in numerous organs and tissues. These effects were seen at exposure levels similar to clinical dosing in humans. At high doses, piperaquine can interfere with cardiac conduction and produce effects on blood pressure. Mild phototoxicity has been observed with piperaquine in rats exposed to UV light.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Piperaquine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Piperaquine can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Piperaquine.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Piperaquine.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Piperaquine.
Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Piperaquine tetraphosphateIHB5WLO51Q911061-10-4OAKKJVUSSVZQRF-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
EurartesimPiperaquine tetraphosphate (320 mg) + Artenimol (40 mg)Tablet, film coatedOralAlfasigma s.p.a.2021-01-27Not applicableEU flag
EurartesimPiperaquine tetraphosphate (320 mg) + Artenimol (40 mg)Tablet, film coatedOralAlfasigma s.p.a.2021-01-27Not applicableEU flag
EURARTESIMPiperaquine tetraphosphate (160 320) + Artenimol (40 MG)Tablet, film coatedOralAlfasigma s.p.a.2014-07-08Not applicableItaly flag
EurartesimPiperaquine tetraphosphate (320 mg) + Artenimol (40 mg)Tablet, film coatedOralAlfasigma s.p.a.2021-01-27Not applicableEU flag
EURARTESIMPiperaquine tetraphosphate (160 320) + Artenimol (40 MG)Tablet, film coatedOralAlfasigma s.p.a.2014-07-08Not applicableItaly flag

Categories

ATC Codes
P01BF07 — Artemisinin and piperaquineP01BX02 — Arterolane and piperaquineP01BF05 — Artenimol and piperaquine
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
A0HV2Q956Y
CAS number
4085-31-8
InChI Key
UCRHFBCYFMIWHC-UHFFFAOYSA-N
InChI
InChI=1S/C29H32Cl2N6/c30-22-2-4-24-26(20-22)32-8-6-28(24)36-16-12-34(13-17-36)10-1-11-35-14-18-37(19-15-35)29-7-9-33-27-21-23(31)3-5-25(27)29/h2-9,20-21H,1,10-19H2
IUPAC Name
7-chloro-4-(4-{3-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propyl}piperazin-1-yl)quinoline
SMILES
ClC1=CC2=C(C=C1)C(=CC=N2)N1CCN(CCCN2CCN(CC2)C2=CC=NC3=C2C=CC(Cl)=C3)CC1

References

General References
  1. Davis TM, Hung TY, Sim IK, Karunajeewa HA, Ilett KF: Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65(1):75-87. [Article]
  2. Hoglund RM, Workman L, Edstein MD, Thanh NX, Quang NN, Zongo I, Ouedraogo JB, Borrmann S, Mwai L, Nsanzabana C, Price RN, Dahal P, Sambol NC, Parikh S, Nosten F, Ashley EA, Phyo AP, Lwin KM, McGready R, Day NP, Guerin PJ, White NJ, Barnes KI, Tarning J: Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. PLoS Med. 2017 Jan 10;14(1):e1002212. doi: 10.1371/journal.pmed.1002212. eCollection 2017 Jan. [Article]
  3. Tarning J, Bergqvist Y, Day NP, Bergquist J, Arvidsson B, White NJ, Ashton M, Lindegardh N: Characterization of human urinary metabolites of the antimalarial piperaquine. Drug Metab Dispos. 2006 Dec;34(12):2011-9. doi: 10.1124/dmd.106.011494. Epub 2006 Sep 6. [Article]
  4. EMA: Eurartesim Assessment Report [Link]
ChemSpider
109031
ChEBI
91231
ChEMBL
CHEMBL303933
ZINC
ZINC000026251015
PharmGKB
PA166104279
Wikipedia
Piperaquine
FDA label
Download (904 KB)
MSDS
Download (107 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingPreventionMalaria2
4Active Not RecruitingPreventionMalaria in Pregnancy1
4Active Not RecruitingPreventionMalaria / Parasitic Diseases1
4Active Not RecruitingTreatmentMalaria1
4CompletedNot AvailableUncomplicated Malaria1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral
Tablet, solubleOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0167 mg/mLALOGPS
logP5.53ALOGPS
logP5.27Chemaxon
logS-4.5ALOGPS
pKa (Strongest Basic)8.47Chemaxon
Physiological Charge3Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area38.74 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity153.42 m3·mol-1Chemaxon
Polarizability59.56 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0000090000-5d8ecfac3e116a0fe237
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9000030000-d10158c067f048b7e785
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0000090000-fd731547b14635f55563
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-8000090000-ba1dfa716be5b79a4f76
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-000f-0692010000-8991c411c0d2741aa910
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-003r-2974040000-bfde0fcc9f74e66111d9
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-216.75377
predicted
DeepCCS 1.0 (2019)
[M+H]+219.14932
predicted
DeepCCS 1.0 (2019)
[M+Na]+225.06184
predicted
DeepCCS 1.0 (2019)

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Drug is a moderately sensitive substrate for CYP3A4 (change in AUC >2 fold with enzyme inhibitor).
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. EMA: Eurartesim Assessment Report [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Hanboonkunupakarn B, Ashley EA, Jittamala P, Tarning J, Pukrittayakamee S, Hanpithakpong W, Chotsiri P, Wattanakul T, Panapipat S, Lee SJ, Day NP, White NJ: Open-label crossover study of primaquine and dihydroartemisinin-piperaquine pharmacokinetics in healthy adult thai subjects. Antimicrob Agents Chemother. 2014 Dec;58(12):7340-6. doi: 10.1128/AAC.03704-14. Epub 2014 Sep 29. [Article]
  2. EMA: Eurartesim Assessment Report [Link]
  3. Eurartesim EMA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. EMA: Eurartesim Assessment Report [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. EMA: Eurartesim Assessment Report [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. EMA: Eurartesim Assessment Report [Link]

Drug created at January 04, 2018 21:59 / Updated at April 16, 2021 04:48