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Chloroquine

Other Names: Aralen, CQ, chloroquine phosphate Drug Class: Immune Modulators
Molecular Formula: C18 H26 Cl N3
Registry Number: 54-05-7 (CAS) Chemical Name: Quinoline, 7-chloro-4-((4-(diethylamino)-1-methylbutyl)amino)- Chemical Class: 4-aminoquinoline Phase of Development: Chloroquine is in Phase II development for HIV treatment.

Chemical Image:

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chloroquine

chloroquine

Molecular Weight: 319.8774

(Compound details obtained from ChemIDplus Advanced,1 Retrovirology article,2 PLoS Medicine article,3 and ClinicalTrials.gov4)

Pharmacology


Mechanism of Action: Immune modulator. Chloroquine, an alkylated 4-aminoquinoline and analog of hydroxychloroquine, is an FDA-approved drug indicated for the treatment of malaria and extraintestinal amebiasis. It has been studied for its ability to reduce HIV-related chronic immune activation, which is known to be associated with advancement of HIV disease, inadequate response to ART, and viral reservoir generation and persistence.2,5,6

Chloroquine has been described to suppress immune activation through multiple mechanisms, such as by inhibition of toll-like receptor signaling in plasmacytoid dendritic cells (pDCs) and inhibition of inflammatory cytokine secretion. Chloroquine has also been shown to inhibit HIV-1 replication by increasing endosomal pH and inhibiting post-translational modification of gp120. Additionally, it has been suggested that chloroquine could potentially help reduce viral reservoirs by making reactivated latently infected cells sensitive to apoptosis.2,6-8

Results from clinical trials evaluating the effects of chloroquine on HIV infection have been mixed. One study evaluating chloroquine in individuals with chronic HIV who were either ART-naive or off ART for at least 16 months demonstrated some beneficial immunomodulatory effects, such as (1) a significant reduction in frequency of CD8 cells co-expressing CD38 and HLA-DR, (2) a significant, although transient, reduction of Ki-67 expression in CD4 and CD8 cells, and (3) a significant, although transient, reduction in plasma lipopolysaccharide (LPS) concentration.6 However, 2 other studies (one involving participants who were either on or off ART and the other involving participants who were on ART but had low CD4 counts) found chloroquine provided only modest or no beneficial immunomodulatory effects.8,9

Half-life (T½): In healthy individuals, the plasma half-life of chloroquine is 72 to 120 hours. One study indicated that chloroquine declines in a biphasic manner, with the terminal phase half-life increasing with increasing doses, as follows: 3.1 hours after a single 250-mg oral dose, 42.9 hours after a single 500-mg oral dose, and 312 hours after a single 1-g oral dose.10

Metabolism/Elimination: Chloroquine is metabolized by dealkylation in the liver, primarily by CYP2C8 and CYP3A4 enzymes. Metabolites formed include the major metabolites desethylchloroquine (DCQ) and bisdethylchloroquine (BDCQ), as well as other unidentified metabolites. Both DCQ and BDCQ are pharmacologically active; the half-life of DCQ is longer than that of the parent compound.10,11

Chloroquine is excreted both renally and hepatically. The amount of chloroquine excreted in the urine as unchanged drug ranges from 10% to 60% (median 38%). The amount excreted in the urine as metabolized drug is 7% to 31% (median 18%). Eight percent to 10% is excreted in feces, 5% is sloughed off in skin, and 45% is stored in lean tissues.11


Select Clinical Trials


Study Identifiers: ACTG A5258; NCT00819390
Sponsor: AIDS Clinical Trials Group
Phase: II
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety and effectiveness of chloroquine in reducing HIV-associated immune activation.
Study Population:

  • Off-ART cohort: Participants were adults with HIV who were off ART for at least 6 months prior to study entry. Participants had HIV RNA ≥1000 copies/mL and CD4 counts ≥400 cells/mm3 within 30 days of study entry.
  • On-ART cohort: Participants were adults with HIV who were receiving ART for at least 24 months prior to study entry. Participants had HIV RNA <200 copies/mL and CD4 counts <350 cells/mm3 within 30 days of study entry.
Dosing: The ACTG A5258 trial evaluated 2 study populations (off-ART cohort and on-ART cohort) separately. Participants in each cohort were randomly assigned either to first receive chloroquine (250 mg given orally once daily) for 12 weeks and then cross over to receive placebo for 12 weeks or to first receive placebo and then cross over to receive chloroquine.4,9

Selected Study Results:


Study Identifiers: CTN 246; NCT02004314
Sponsor: CIHR Canadian HIV Trials Network
Phase: Not available
Status: This study has been completed.
Study Purpose: The purpose of this proof-of-concept study was to evaluate the effect of chloroquine on CD4 cell recovery and immune activation in participants who were on ART but had low CD4 counts.
Study Population: Participants were adults with HIV who were receiving a suppressive and stable ART regimen. Participants had HIV RNA <50 copies/mL for at least the previous 36 weeks and had CD4 counts ≤350 cells/mm3.
Dosing: Participants received chloroquine 250 mg orally once daily. There was an initial 8-week observation period on ART alone, then 24 weeks of chloroquine treatment in combination with ART, and finally 12 weeks of follow up on ART alone.8,12

Selected Study Results:


Study Identifiers: NCT00308620
Sponsor: University of Minnesota - Clinical and Translational Science Institute
Phase: I
Status: This study has been completed.
Study Purpose: The purpose of this pilot study was to evaluate the efficacy of chloroquine in reducing HIV viral load and immune activation.
Study Population: Participants were adults with HIV who were treatment-naive or who were treatment-experienced but off ART for at least 16 months. Participants had HIV RNA >3000 copies/mL and CD4 counts >250 cells/mm3.
Dosing: Participants were randomized to receive either chloroquine (250 mg or 500 mg) or placebo orally once daily for 8 weeks.6,13

Selected Study Results:


Other HIV-related studies involving chloroquine have been completed. One of the studies (NCT00972725) evaluated the safety and immunogenicity of an investigational therapeutic HIV vaccine (F4/AS01B) when given after a single dose of chloroquine in healthy adults. In this study, chloroquine was used to enhance the antigen-specific CD8 cell response induced by F4/AS01B.14,15


Adverse Events


ACTG A5258 (NCT00819390):
In this Phase II study, no chloroquine-related adverse events (AEs) were reported. Twelve weeks of chloroquine administration resulted in only modest immune suppression and was associated with an increase in plasma HIV RNA in participants in the off-ART cohort.4,9

CTN 246 (NCT02004314):
In this study, in which daily chloroquine was administered in combination with ART for 24 weeks, no Grade 3 or 4 AEs were reported. During the first week of treatment with chloroquine, 1 participant discontinued because of a Grade 2 gastrointestinal AE.8

Additional AEs known to be associated with chloroquine are described in the FDA-approved Full Prescribing Information for Chloroquine.5


Drug Interactions


Chloroquine is metabolized in the liver, primarily by CYP2C8 and CYP3A4 enzymes, and it can selectively inhibit CYP2D6 activity. Drugs that inhibit CYP3A4 (such as ritonavir) may increase plasma levels of chloroquine. Potential interactions may also exist between chloroquine and drugs that are substrates for CYP2D6.11,16,17

Interactions between chloroquine and lopinavir/ritonavir or saquinavir/ritonavir can occur, and close monitoring is recommended. Minor interactions may also occur between chloroquine and nelfinavir, nevirapine, or efavirenz.18

Proton pump inhibitors may antagonize the immunomodulating effects of chloroquine.11

Additional known interactions between chloroquine and coadministered drugs are described in the FDA-approved Full Prescribing Information for Chloroquine.5


References


  1. United States National Library of Medicine. ChemIDplus Advanced: chloroquine. https://chem.nlm.nih.gov/chemidplus/rn/54-05-7. Accessed September 10, 2018.
  2. Savarino A, Shytaj IL. Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS. Retrovirology. 2015;12:51.
  3. Delves M, Plouffe D, Scheurer C, et al. The activities of current antimalarial drugs on the life cycle stages of plasmodium: a comparative study with human and rodent parasites. PLoS Med. 2012;9(2):e1001169.
  4. AIDS Clinical Trials Group. A Phase II, double blind, randomized, exploratory study of chloroquine for reducing HIV-associated immune activation. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 8, 2009. NLM Identifier: NCT00819390. https://clinicaltrials.gov/ct2/show/NCT00819390. Accessed September 10, 2018.
  5. West-ward Pharmaceutical Corp. Chloroquine: full prescribing information. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9b585ad5-ae86-4403-b83f-8d8363d43da5. Published July 2010. Accessed September 10, 2018.
  6. Murray SM, Down CM, Boulware DR, et al. Reduction of immune activation with chloroquine therapy during chronic HIV infection. J Virol. 2010;84(22):12082-12086.
  7. Paton N, Goodall R, Dunn D, et al. Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy a randomized controlled trial. JAMA J Am Med Assoc. 2012;308(4):353-361.
  8. Routy J-P, Angel JB, Patel M, et al. Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV-infected patients receiving antiretroviral therapy. HIV Med. 16(1):48-56.
  9. Jacobson JM, Bosinger SE, Kang M, et al. The effect of chloroquine on immune activation and interferon signatures associated with HIV-1. AIDS Res Hum Retroviruses. 2016;32(7):636-647.
  10. United States National Library of Medicine. PubChem. Chloroquine. https://pubchem.ncbi.nlm.nih.gov/compound/2719. Accessed September 10, 2018.
  11. Browning DJ. Pharmacology of Chloroquine and Hydroxychloroquine. In: Hydroxychloroquine and Chloroquine Retinopathy. New York: Springer Science+Business Media; 2014. http://www.springer.com/cda/content/document/cda_downloaddocument/9781493905966-c1.pdf?SGWID=0-0-45-1462618-p176657671. Accessed August 8, 2017.
  12. CIHR Canadian HIV Trials Network. Chloroquine as a modulator of T cell immune activation to improve CD4 recovery in HIV-infected participants receiving antiretroviral therapy: a proof-of-concept study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 27, 2013. NLM Identifier: NCT02004314. https://clinicaltrials.gov/ct2/show/NCT02004314. Accessed September 10, 2018.
  13. University of Minnesota - Clinical and Translational Science Institute. A randomized, pilot study of the anti-viral and anti-inflammatory effects of chloroquine in early HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 27, 2006. NLM Identifier: NCT00308620. https://clinicaltrials.gov/ct2/show/NCT00308620. Accessed September 10, 2018.
  14. Leroux-Roels G, Bourguignon P, Willekens J, et al. Immunogenicity and safety of a booster dose of an investigational adjuvanted polyprotein HIV-1 vaccine in healthy adults and effect of administration of chloroquine. Clin Vaccine Immunol. 2014;21(3):302-311.
  15. GlaxoSmithKline. A study to evaluate the safety and immunogenicity of a booster dose of GSK biologicals’ HIV candidate vaccine (732461) after administration of chloroquine in healthy adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 3, 2009. NLM Identifier: NCT00972725. https://clinicaltrials.gov/ct2/show/NCT00972725. Accessed September 10, 2018.
  16. Adedoyin A, Frye RF, Mauro K, Branch RA. Chloroquine modulation of specific metabolizing enzymes activities: investigation with selective five drug cocktail. Br J Clin Pharmacol. 1998;46(3):215-219.
  17. Centers for Disease Control and Prevention (CDC) website. Interactions among travel vaccines & drugs. https://wwwnc.cdc.gov/travel/yellowbook/2018/the-pre-travel-consultation/interactions-among-travel-vaccines-and-drugs. Accessed September 10, 2018.
  18. Dooley K, Flexner C, Andrade A. Drug interactions involving combination antiretroviral therapy and other anti-infective agents: repercussions for resource-limited countries. J Infect Dis. 2008;198(7):948-961.


Last Reviewed: September 10, 2018