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
Structure for Piperaquine (DB13941)
- 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.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Malaria caused by plasmodium falciparum Combination Product in combination with: Artenimol (DB11638) •••••••••••• ••••••• ••••••• ••••••• •••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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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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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Piperaquine can be increased when it is combined with Abametapir. Abatacept The metabolism of Piperaquine can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Piperaquine. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Piperaquine. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Piperaquine. - Food Interactions
- Not Available
Products
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Ingredient UNII CAS InChI Key Piperaquine tetraphosphate IHB5WLO51Q 911061-10-4 OAKKJVUSSVZQRF-UHFFFAOYSA-N - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Eurartesim Piperaquine tetraphosphate (320 mg) + Artenimol (40 mg) Tablet, film coated Oral Alfasigma s.p.a. 2021-01-27 Not applicable EU 
Eurartesim Piperaquine tetraphosphate (320 mg) + Artenimol (40 mg) Tablet, film coated Oral Alfasigma s.p.a. 2021-01-27 Not applicable EU EURARTESIM Piperaquine tetraphosphate (160 320) + Artenimol (40 MG) Tablet, film coated Oral Alfasigma s.p.a. 2014-07-08 Not applicable Italy 
Eurartesim Piperaquine tetraphosphate (320 mg) + Artenimol (40 mg) Tablet, film coated Oral Alfasigma s.p.a. 2021-01-27 Not applicable EU EURARTESIM Piperaquine tetraphosphate (160 320) + Artenimol (40 MG) Tablet, film coated Oral Alfasigma s.p.a. 2014-07-08 Not applicable Italy
Categories
- ATC Codes
- P01BF07 — Artemisinin and piperaquine
- P01BF — Artemisinin and derivatives, combinations
- P01B — ANTIMALARIALS
- P01 — ANTIPROTOZOALS
- P — ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS
- P01BX — Other antimalarials
- P01B — ANTIMALARIALS
- P01 — ANTIPROTOZOALS
- P — ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS
- Drug Categories
- Anti-Infective Agents
- Antimalarials
- Antiparasitic Agents
- Antiparasitic Products, Insecticides and Repellents
- Antiprotozoals
- Cytochrome P-450 CYP2B6 Inhibitors
- Cytochrome P-450 CYP2B6 Inhibitors (weak)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2E1 Inducers
- Cytochrome P-450 CYP2E1 Inducers (strength unknown)
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (weak)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- 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
- Davis TM, Hung TY, Sim IK, Karunajeewa HA, Ilett KF: Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65(1):75-87. [Article]
- 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]
- 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]
- EMA: Eurartesim Assessment Report [Link]
- External Links
- 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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Active Not Recruiting Prevention Malaria 2 4 Active Not Recruiting Prevention Malaria in Pregnancy 1 4 Active Not Recruiting Prevention Malaria / Parasitic Diseases 1 4 Active Not Recruiting Treatment Malaria 1 4 Completed Not Available Uncomplicated Malaria 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral Tablet, soluble Oral - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0167 mg/mL ALOGPS logP 5.53 ALOGPS logP 5.27 Chemaxon logS -4.5 ALOGPS pKa (Strongest Basic) 8.47 Chemaxon Physiological Charge 3 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 38.74 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 153.42 m3·mol-1 Chemaxon Polarizability 59.56 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 216.75377 predictedDeepCCS 1.0 (2019) [M+H]+ 219.14932 predictedDeepCCS 1.0 (2019) [M+Na]+ 225.06184 predictedDeepCCS 1.0 (2019)
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- EMA: Eurartesim Assessment Report [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- 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]
- EMA: Eurartesim Assessment Report [Link]
- 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
- 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
- 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
- EMA: Eurartesim Assessment Report [Link]
Drug created at January 04, 2018 21:59 / Updated at April 16, 2021 04:48