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Drugs

Apricitabine

Other Names: ATC, AVX754, BCH10618, SPD754 Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: CH11 NOS
Registry Number: 160707-69-7 (CAS) Chemical Name: 4-amino-1-[(2R,4R)-2-(hydroxymethyl)-1,3-oxathiolan-4-yl]pyrimidin-2-one Chemical Class: Pyrimidine Nucleosides Organization: Avexa Limited Phase of Development: III (discontinued)

Chemical Image:

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apricitabine

apricitabine

Molecular Weight: 229.2589

(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)

NOTE: The development of apricitabine for HIV treatment has been discontinued.


The study of apricitabine as an NRTI HIV medicine was discontinued in 2016. The company developing the drug announced that this decision was based on lack of interest in apricitabine’s early access program and lack of funding.3


Pharmacology


Mechanism of Action: NRTI. Apricitabine (ATC), a deoxycytidine analogue, is a prodrug that is intracellularly phosphorylated to its active triphosphate form of ATC-TP. ATC-TP has an intracellular half-life of 6 to 7 hours. ATC-TP inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with natural substrates for binding to viral RT and by causing DNA chain termination after incorporation into viral DNA.4-6

Half-life (T½)
: In a study of single oral doses of apricitabine in healthy participants, the plasma elimination half-life of apricitabine was approximately 3 hours.7
 
Metabolism/Elimination: An in vitro study indicated that apricitabine is not metabolized by hepatocytes, and is neither an inhibitor nor an inducer of CYP enzymes. Apricitabine also does not undergo glucuronidation by UGT1A1. Following oral administration of apricitabine to healthy participants, 65% to 80% of the dose is excreted unchanged in the urine, indicating that apricitabine is primarily eliminated via renal excretion. A single inactive apricitabine metabolite (BCH-335), possibly a product of apricitabine metabolism in the gastrointestinal tract, has been identified. BCH-335 is renally excreted in a non-competitive manner with apricitabine.4,7,8 

Resistance: Apricitabine demonstrates in vitro activity against virus harboring mutations that are associated with resistance to other NRTIs, including viruses containing M184V, thymidine analogue mutations (TAMs), L74V, and single mutations at codon 69. In vitro, reduced susceptibility to apricitabine was seen with the K65R mutation (2.6- to 4.6-fold reduction), with multi-drug resistant virus containing the Q151M mutation (14- to 16-fold reduction), and with virus with certain triple mutations at codon 69 (≥ 4.35-fold reduction). Selection experiments have shown that resistance to apricitabine is slow to emerge. The M184V, V75I, and K65R RT mutations were selected in vitro, but demonstrated low level resistance to apricitabine.9 

In a 10-day, Phase II study of apricitabine monotherapy given at various doses up to 1600 mg/day in treatment-naive adults, apricitabine did not appear to select for any particular mutations.10  

The AVX-201 Phase IIb study (NCT00126880) investigated twice-daily apricitabine 600 mg or 800 mg in treatment-experienced individuals who had virus containing M184V (with and without TAMs) and who were failing their current lamivudine- or emtricitabine-containing ART. For the first 21 days, apricitabine was administered as functional monotherapy; thereafter, background regimens were optimized. Analysis at Week 24 found that the M184V mutation was maintained in the majority of apricitabine-treated participants in whom a genotype could be obtained, and there was no development of K65R, L74V, or other nucleoside analogue mutations. There were few changes in genotype in apricitabine-treated participants up to 48 weeks. There was no evidence of resistance development to apricitabine up to Week 48 and through completion of the AVX-201 extension study (NCT00367952) at Week 144.11-15 

Furthermore, the AVX-301 Phase IIb/III study (NCT00612898) evaluated twice-daily apricitabine 800 mg or 1200 mg, plus an optimized background regimen, in treatment-experienced participants with virus containing M184V/I and who were failing their current lamivudine- or emtricitabine-containing ART over 24 weeks. No evidence of apricitabine resistance arose during the treatment period. The M184V mutation was maintained in the few apricitabine-treated participants in whom genotypes were obtained at Week 24.16-18 
 


Clinical Trials


Study Identifiers: Not available
Sponsor: Not available
Phase: II
Study Purpose: The purpose of this study was to evaluate the safety and efficacy of various doses of apricitabine monotherapy in treatment-naive adults.
Study Population: Participants were HIV-infected, treatment-naive adults with HIV RNA between 5,000 and 100,000 copies/mL and CD4 counts ≥250 cells/mm3.
Dosing: Participants were randomized to 1 of 4 daily doses of apricitabine (400, 800, 1200, or
1600 mg/day) or to placebo, all of which were administered orally over 10 days. Participants who received apricitabine were administered 1 of the following 6 dosage regimens: 200 mg twice daily, 400 mg twice daily, 800 mg once daily, 600 mg twice daily, 1200 mg once daily, or 800 mg twice daily.10,19
Selected Study Results:

 

Study Identifiers: (1) AVX-201; NCT00126880 and (2) AVX-201E; NCT00367952
Sponsor: Avexa
Phase: IIb
Study Purpose: The purpose of this study was to evaluate the safety and efficacy of 2 doses of apricitabine in treatment-experienced adults with HIV containing M184V.
Study Population:

  • Participants were HIV-infected, treatment-experienced adults with HIV containing the M184V reverse transcriptase mutation, with and without additional TAMs.
  • Participants had prior treatment experience with at least 2 classes of ARVs, were receiving a stable ART regimen that had 3 or more ARVs and contained either lamivudine or emtricitabine for at least 2 months, and were currently failing treatment.
  • Participants had HIV-1 RNA ≥2,000 copies/mL and CD4 counts ≥50 copies/mm3.

Dosing:
AVX-201

  • Day 0 to Day 21 (blinded): Participants stopped their existing lamivudine or emtricitabine treatment and were randomly assigned to apricitabine 600 mg, apricitabine 800 mg, or lamivudine 150 mg, all of which were taken twice daily and orally. (Matching placebos were also administered to each group.) No other changes were made to participants’ existing background ART.
  • Day 21 to Week 24 (blinded): Participants continued their assigned treatments. Background ART could be optimized.
  • Week 24 to Week 48 (open-label): Participants in all groups were offered open-label apricitabine 800 mg twice daily in addition to optimized background ART.

AVX-201E

  • Week 48 to Week 144 (open-label): Participants who completed AVX-201 could enroll in an extension study to continue receiving open-label apricitabine 800 mg twice daily in addition to optimized background ART.12-15,20,21 

Selected Study Results:

Study Identifiers: AVX-301; NCT00612898
Sponsor: Avexa
Phase: IIb/III
Study Purpose: The purpose of this study was to evaluate the safety and efficacy of apricitabine in treatment-experienced adults.
Study Population: Participants were HIV-infected, treatment-experienced adults with the M184V/I reverse transcriptase mutation. Participants were receiving an ART regimen containing either lamivudine or emtricitabine and were failing treatment, with HIV-1 RNA >2,000 copies/mL.
Dosing:
Participants were randomized to apricitabine 800 mg, apricitabine 1200 mg, or lamivudine 150 mg, all of which were taken twice daily and orally, plus optimized background ART over 48 weeks.

Note:

  • At Week 16, the 1200-mg apricitabine arm was discontinued because it showed no benefit over the 800-mg apricitabine dose.
  • AVX-301 was terminated early prior to study completion.16-18

Selected Study Results:

An open-label Phase III safety study (NCT00686270) was withdrawn prior to participant enrollment. This study was originally designed to evaluate the long-term safety of apricitabine in participants from the AVX-301 and AVX-302 studies. (AVX-302 was intended to evaluate the safety and efficacy of a single dose of apricitabine, as determined from the AVX-301 study; however, AVX-302 did not take place.)22


Adverse Events


In the Phase II study of apricitabine monotherapy in 63 treatment-naive adults, there were no serious adverse events (SAEs) or severe adverse events (AEs) reported. No participants discontinued the study because of an AE. Seventy-eight percent of apricitabine-treated participants and 69.2% of placebo-treated participants experienced an AE that was considered possibly or probably related to the study drug. Headache was the most common AE in the apricitabine groups, occurring in 42% of apricitabine-treated participants versus in 30.8% of placebo-treated participants. Nasal congestion was reported more frequently in apricitabine-treated participants than in placebo-treated participants. There were no Grade 3 or 4 laboratory abnormalities, and there were no clinically significant changes in vital signs or ECG tests.10,19

In the AVX-201 Phase IIb study (NCT00126880), Week 24 safety data from 51 participants showed that the most common AEs (occurring equally in the 3 study arms) were diarrhea, nausea, nasopharyngitis, hypertriglyceridemia, and upper respiratory tract infection. The following AEs occurred in 5 apricitabine-treated participants and were considered possibly related to apricitabine treatment: diarrhea, dizziness, nausea, pyrosis, anorexia, weight loss, and gastric intolerance. Although no participants permanently discontinued apricitabine because of a drug-related AE, 4 participants temporarily discontinued apricitabine because of an AE, with only 1 (mild nausea) considered possibly related to apricitabine. No Grade 3 or 4 laboratory abnormalities related to apricitabine occurred through Week 24.21 No apricitabine-related SAEs were reported through Week 48 of AVX-201 or up to Week 144 of the AVX-201E extension study (NCT00367952).12-15,20,21 

The AVX-301 Phase IIb/III study (NCT00612898) was terminated early and results therefore lack statistical significance, but safety results at Week 24 showed that apricitabine appeared to have a safety profile similar to that of lamivudine. No apricitabine-related SAEs occurred through 24 weeks. Drug-related AEs occurred in 25.3% of participants in the 800-mg apricitabine group, 36.1% of participants in the 1200-mg apricitabine group, and 33.8% of participants in the lamivudine group.16,17 
 


Drug Interactions


In vitro, apricitabine is not metabolized by hepatocytes, and is neither an inhibitor nor an inducer of CYP enzymes. Apricitabine also does not undergo glucuronidation by UGT1A1. Apricitabine is therefore unlikely to interact with other drugs that undergo hepatic metabolism via these pathways.

Apricitabine is primarily eliminated via renal excretion by glomerular filtration and cationic active tubular secretion and may interact with drugs that compete for renal tubular secretion.7,23

Because of inhibition of intracellular phosphorylation of apricitabine to ATC-TP, apricitabine should not be coadministered with lamivudine, emtricitabine, or other deoxycytidine analogues.24

When a single 800-mg apricitabine dose was administered with ritonavir-boosted tipranavir at steady state in healthy participants, apricitabine exposure was moderately increased, but not to a clinically significant degree. No dose adjustment of apricitabine is required when coadministered with ritonavir-boosted tipranavir.25 

Following single and multiple doses of apricitabine administered with trimethoprim-sulfamethoxazole (up to 960 mg 4 times daily) in healthy participants, exposure to apricitabine and its metabolite (BCH-335) was moderately increased; however, the extent of the interaction did not appear to be affected by the dose of trimethoprim-sulfamethoxazole. Dose adjustment of apricitabine does not appear to be required when coadministered with trimethoprim-sulfamethoxazole.26
 


References


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  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on December 14, 2016.
  3. Avexa Limited. Annual Report 2016. Available at: http://www.asx.com.au/asxpdf/20161028/pdf/43cf167shmyq98.pdf. Last accessed on December 14, 2016.
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  6. Herman BD and Sluis-Cremer N. Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors. In: Gallelli L, ed. Pharmacology. In Tech, DOI: 10.5772/32969; 2012: p 63-80. Available at: http://www.intechopen.com/books/pharmacology/molecular-pharmacology-of-nucleoside-and-nucleotide-hiv-1-reverse-transcriptase-inhibitors. Last accessed on December 14, 2016.
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  8. Nakatani-Freshwater T, Babayeva M, Dontabhaktuni A, Taft DR. Effects of Trimethoprim on the Clearance of Apricitabine, a Deoxycytidine Analog Reverse Transcriptase Inhibitor, and Lamivudine in the Isolated Perfused Rat Kidney. J Pharmacol Exp Ther. 2006 Nov; 319(2):941-7. Available at: http://jpet.aspetjournals.org/content/319/2/941.long. Last accessed on December 14, 2016.
  9. Cahn P, Wainberg MA. Resistance profile of the new nucleoside reverse transcriptase inhibitor apricitabine. J Antimicrob Chemother. 2010 Feb; 65(2):213-7. Available at: http://jac.oxfordjournals.org/content/65/2/213.full.pdf+html. Last accessed on December 14, 2016.
  10. Cahn P, Cassetti I, Wood, R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS. 2006 June; 20(9): 1261-1268. National AIDS Treatment Advocacy Project (NATAP): HIV Articles; Efficacy and tolerability of 10-day monotherapy with SPD574 (apricitabine) in antiretroviral-naive, HIV-infected patients. Available at: http://www.natap.org/2006/HIV/081106_07.htm. Last accessed on December 14, 2016.
  11. Cox S, Southby J, Moore S. Genotypic Analysis of Patients Enrolled in Study AVX-201 and Treated with Apricitabine for 24 Weeks. Poster presented at: XVII International HIV Drug Resistance Workshop; June 10-14, 2008; Sitges, Spain. Available at: http://www.avexa.com.au/sites/default/files/news/AVX-201%20Poster%20for%20HIV%20Drug%20Resistance%20Workshop%202008.pdf. Last accessed on November 30, 2015.
  12. Cahn P, Altclas J, Martins M, et al. O414 48-week data from Study AVX-201 – a randomised phase IIb study of apricitabine in treatment-experienced patients with M184V and NRTI resistance. J Int AIDS Soc. 2008 Nov; 11: O41. Available at: http://library.iasociety.org/JIASArticleView.aspx?jiasid=51. Last accessed on December 14, 2016.
  13. Avexa Limited: Press Release, dated February 15, 2010. Avexa Reports Positive Phase IIb 144 Week Data for HIV Drug Apricitabine (ATC). Available at: http://www.asx.com.au/asxpdf/20100215/pdf/31npkr2f12ypq0.pdf. Last accessed on December 14, 2016.
  14. Avexa. A Phase II, Randomised, Double-blind, Dose-ranging Study of AVX754 Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V Mutation in Reverse Transcriptase. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 3, 2005. NLM Identifier: NCT00126880. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00126880. Last accessed on December 14, 2016.
  15. Avexa. An Open Label Long Term Safety Extension Study of Apricitabine in Treatment-experienced HIV-1 Infected Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 22, 2006. NLM Identifier: NCT00367952. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00367952. Last accessed on December 14, 2016.
  16. Avexa. ATC: Phase 3 data from the AVX-301 study. Slides presented at: 24th International Conference on Antiviral Research (ICAR); May 8-11, 2011; Sofia, Bulgaria. Available at: http://www.avexa.com.au/sites/default/files/news/ICAR%20Sofia%20Clin%20Symp%20May%202011.pdf. Last accessed on November 30, 2015.
  17. Avexa Limited: Press Release, dated March 23, 2010. Avexa Announces Detailed ATC Phase III Results at 24 Weeks. Available at: http://www.asx.com.au/asxpdf/20100323/pdf/31pdv7h6w3hm57.pdf. Last accessed on December 14, 2016.
  18. Avexa. A Phase 2b/3, Randomized, Double Blind, Dose Confirming Study of the Safety, Efficacy and Tolerability of Apricitabine Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V/I Mutation in Reverse Transcriptase. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 30, 2008. NLM Identifier: NCT00612898. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00612898. Last accessed on December 14, 2016.
  19. Cahn P, van Leeuwen R, Sawyer J, Shiveley L. Tolerability and Anti-HIV-1 Activity of SPD754 as 10 days’ Monotherapy in Treatment-Naïve Patients. Poster presented at: 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 14-17, 2003; Chicago, IL. Poster/Abstract A-3093. Available at: http://www.avexa.com.au/sites/default/files/news/Cahn%20A-3093%2043rd%20ICAAC%202003.pdf. Last accessed on November 30, 2015.
  20. Cahn P, Altclas J, Martins M, et al. Antiviral activity of apricitabine in treatment-experienced HIV-1-infected patients with M184V who are failing combination therapy. HIV Med. 2011 Jul; 12(6):334-42. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2010.00887.x/pdf. Last accessed on December 14, 2016.
  21. Cahn P, Altclas J, Martins M, et al. 24 Week Data from Study AVX-201: A Prospective, Randomised, Double-Blind, Dose-Ranging Phase 2b Study of Apricitabine in Treatment-Experienced Patients with M184V and NRTI Resistance. Poster presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Poster 793. Available at: http://www.avexa.com.au/sites/default/files/news/CROI%20poster%20formatted%2024Jan2008.pdf. Last accessed on November 30, 2015.
  22. Avexa. A Phase 3, Open Label 96-week Extension Study of the Safety of Apricitabine in Treatment-experienced HIV-1 Infected Patients Who Have Completed Protocol AVX-301 or AVX-302 or Who Have Met the Criteria for Open-label Access to ATC Because of Virological Failure/Lack of Response. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 27, 2008. NLM Identifier: NCT00686270. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00686270. Last accessed on December 14, 2016.
  23. Sawyer J, Cox S. In vitro pharmacology of Apricitabine, a new NRTI for HIV. Abstract presented at: 16th International AIDS Conference (AIDS 2006); August 13-18, 2006; Toronto, Canada. Abstract CDB0446. Available at: http://library.iasociety.org/AbstractView.aspx?confID=2006&abstractId=16955. Last accessed on December 14, 2016.
  24. Holdich T, Shiveley LA, Sawyer J. Effect of Lamivudine on the Plasma and Intracellular Pharmacokinetics of Apricitabine, a Novel Nucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers. Antimicrob Agents Chemother. 2007 Aug; 51(8): 2943-7. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1932547/pdf/1013-06.pdf. Last accessed on December 14, 2016.
  25. Cox S, Southby J, Linet O, Tackwell K, Borin M, Perry K. Comparison of the pharmacokinetics of apricitabine in the presence and absence of ritonavir-boosted tipranavir: a phase I, open-label, controlled, single-centre study. Clin Drug Investig. 2009; 29(11): 721-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19813775. Last accessed on December 14, 2016.
  26. Shiveley L, Struthers-Semple C, Cox S, Sawyer J. Pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in healthy volunteers treated with trimethoprim-sulphamethoxazole. J Clin Pharm Ther. 2008 Feb; 33(1): 45-54. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18211616. Last accessed on December 14, 2016.
 


Last Reviewed: December 14, 2016