Glaxo Wellcome announced about Oct 16 that they filed an application for accelerated approva (NDA) with the FDA for amprenavir, their new protease inhibitor. Several days later they announced filing with Canadian officials and an expectation of filing in Europe within coming weeks. GW said they submitted data from 20 clinical trials involving more than 1500 patients.
At the recent ICAAC meeting they presented 16 week data comparing amprenavir+AZT/3TC to AZT/3TC. Eighty-eight perecent had <400 copies/ml using an as-treated analysis and 82% had <400 copies/ml using an intent-to-treat analysis. 59-66% had <50 copies/ml using an as-observed analysis depending on the criteria. See ICAAC report on this web site for more details about this study. In September GW announced an expanded access program for patients. See the announcement on this web site for the 800 toll free # and an explanation of the program.
If all goes well approval from the FDA usually takes about 3-4 months which would place expected approval in Jan/Feb '99. Application for approval for both pediatric and adult use was submitted. In addition, an application for the liquid formulation of Amprenavir is expected to be submitted soon. Both adults and children should have the option of using the liquid. Adults having a choice between pills or liquid creates flexible dosing choices.
Amprenavir (APV) has several interesting characteristics. There are a number of interactions that have been identified. They are discussed in an article listed on this web site.
At the Geneva conference the following data were presented based on preliminary PK studies:
The PK interactions of APV with NFV & IDV are of particular note.
APV effect on SQV-- reduces AUC 18%, increases Cmax 21%, Cmin ?
APV effect on NFV-- increases AUC 15%, increases Cmax 12, increases Cmax 14%
APV effect on IDV- decreases AUC 38%, dec Cmax 22%, dec Cmin 27%
IDV effect on APV- increases Cmax, AUC & Cmin by 6%, 26%, and 18% respectively (multiple dosing study)
NFV effect on APV- increases Cmin 167%, dec Cmax by 21$, no effect on AUC
SQV effect on APV- dec Cmax & AUC by 40% & 36%, respectively, no effect on Cmin
In ACTG 398 and 400, EFV+IDV+APV are used in one combination with IDV being dosed bid. EFV reduces IDV blood levels necessitating an increase in IDV dosing to 1000 mg tid. A lead in PK study is being conducted for 398 & 400 but data will not be available for a few months.
APV is dosed 1200 mg twice daily with or without food. The PK profile is such that there is flexibility around dosing. You probably have a few hours flexibility around dosing. Unfortunately, you have to take 8 150 mg pills twice daily. The side effect profile so far appears relatively favorable with most commonly appearing side effects being nausea, diarrhea, headache, fatigue, vomiting, rash, parasthesia. A concern some have is distinguishing what may be causing a rash if it appears if using APV, abacavir and EFV.
48 week data on APV in double PI regimens will be availablr in November.