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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Bioavailability | 65 to 80% |
| Protein binding | < 4% |
| Metabolism | To apricitabine triphosphate |
| Eliminationhalf-life | 6 to 7 hours (triphosphate) |
| Excretion | Renal |
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| Formula | C8H11N3O3S |
| Molar mass | 229.25 g·mol−1 |
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Apricitabine (INN, codenamedAVX754 andSPD754, sometimes abbreviated toATC) is an experimentalnucleoside reverse transcriptase inhibitor (NRTI) againstHIV. It is structurally related tolamivudine andemtricitabine, and, like these, is ananalogue ofcytidine.
It was first developed by BioChem Pharma (where it was called BCH10618). BioChem Pharma was then sold toShire Pharmaceuticals (where apricitabine was called SPD754). Shire then sold the rights to develop the drug to Avexa Pharmaceuticals, an Australian pharmaceutical company.[1] As of 2009[update], apricitabine has closed itsphase IIIclinical trial,[2] and has been grantedfast track status by theUnited States Food and Drug Administration.[3]
Avexa announced its decision to end work on apricitabine in May 2010, which Avexa spent more than A$100 million ($90 million) developing and was in the final of three stages of patient studies usually needed for U.S. regulatory approval. Grounds for the shutdown included the inability to find commercial partners for global licensing, concerns about legal protections of the drug in the US market, and difficulty confirming the effectiveness of the drug in patients where other retroviral drugs masked key indicators.[4]
In March 2011 it was announced by the company to theAustralian Stock Exchange that the FDA had agreed that a new, shorter, single Phase III trial design, including about 300 patients dosed for 2 weeks, was required before approval. A similar agreement with the EMA was announced in March 2012.[5]
In November 2011 the company sought to extend its patents over apricitabine and was in discussions for fast-track approval with European regulators. The company also indicated that clinical trials had shown better-than-expected results from simultaneous provision of the drug alongside two other marketed drugs when compared to those drugs withlamivudine, another NRTI.[6]
Avexa's latest update in 2013 reported that the drug was still in phase IIb trials and had not yet started phase III.[7]
As a monotherapy, 1200 mg apricitabine per day reduced theviral load by up to 1.65 logs (45 fold) in a small, 10-dayrandomized controlled trial.[8] An 800 mg dose twice a day is being used in later studies.
Apricitabine appears to be well tolerated. The most commonside effects associated with its use were headache (although there was nosignificant difference between participants who took apricitabine and those given aplacebo),nasal congestion, and muscle pain.[8] In a six-month trial, common adverse effects werenausea,diarrhea,elevated blood levels of triglycerides, andupper respiratory infection—similar to those of lamivudine; apricitabine was not associated with abnormallipase levels,bone marrow suppression, orliver andkidney toxicity.[9] No patients in either study had to stop taking apricitabine because of side effects.
In vitro, apricitabine is effective against NRTI-(lamivudine andzidovudine)-resistant virus strains, including M184V and multiplethymidine analogue mutations (TAMs).
In early studies, no mutations causing drug resistance were observed. Newer trials showed that apricitabine may induce K65R mutations, resulting in resistance againstdidanosine andtenofovir.[1]
In clinical studies, apricitabine has been good at reducing viral loads while apparently producing little selection pressure, resulting in the addition of no further mutations in treatment-experienced patients with common pre-existing mutations, including M184V or K65R or TAMs (M41L, M184V, and T215Y).[10]
