Fosamprenavir Lexiva, GW 433908

5 Jun

Fosamprenavir is a water-soluble, calcium phosphate ester pro- drug of amprenavir. It was approved by the FDA on October 20,2003. The water solubility permits a reduction in pill size and count when compared with the parent compound, amprenavir. Fig.  2.19  shows  the  structure, nomenclature, and  approved usage. By reducing the  pill  number and  size,  it is hoped  that patient  compliance will  improve (283).  Fosamprenavir com- bined with ritonavir is  not  inferior to  lopinavir/ritonavir (Kaletra) in  protease inhibitor-experienced patients  and achieved viral loads  below  the  limits of detection, even  in

Fig. 2.19 Trade names, structure, and  uses of Fosamprenavir.

patients with high  viral RNA levels  or low CD4+ counts (284). In treatment of naïve patients, fosamprenavir achieved better viral suppression than nelfinavir. Fosamprenavir appears to be suitable for first-line use  as there is no indication that it is cross-resistant with other PIs  (except amprenavir).  Fosam- prenavir is administered as  700-mg tablets. There are  three recommended dosages for  fosamprenavir: 1) 1400  mg  twice daily  for those not  using ritonavir; 2) 1400  mg once daily  plus ritonavir 200 mg daily; or 3) 700 mg daily  plus ritonavir 100 mg daily. For  protease inhibitor-experienced patients, the  recom- mendation is  700  mg  twice  daily  plus  100  mg  of ritonavir twice  daily. An additional 100  mg/day of ritonavir is recom- mended when efavirenz is administered with fosamprenavir/ ritonavir once daily. The drug is rapidly hydrolyzed by cellular phosphatases in  the  gut  epithelium during absorption. The absolute oral  bioavailability of amprenavir from  fosam- prenavir administration has   not  been  established. It has been  proposed, however, that the  development of water-soluble prodrugs of HIV-1  PIs  have the  potential to control the  con- version time to the  parent drug and  to improve gastrointes- tinal absorption (285). Treatment-naïve HIV patients taking fosamprenavir once  daily  may  have favorable increases in HDL  cholesterol levels  (286).

Adverse Events

Patients with known sulfonamide allergy or any  patient who has  demonstrated significant hypersensitivity to amprenavir should not use fosamprenavir. Most adverse events were  mod- erate to mild  during clinical studies and  included:

Nausea. Nausea occurs  in 61% of patients on amprenavir.

For  low  and  high  doses  of fosamprenavir, the  occur- rence was  31% and  55%, respectively.

Diarrhea. The frequency of diarrhea was nearly equal in both  low and  high  dose treatments.

Rash. Nineteen percent of fosamprenavir patients expe- rienced a rash. Most  rashes are  of moderate to mild  in- tensity. Fewer than  1%  developed severe  or  life threatening rash, including Stevens-Johnson syndrome. Medication should be discontinued in case  of severe or life-threatening rash or moderate rash with accompa- nying systemic reactions.

Special Considerations

Fosamprenavir is contraindicated or should not be coadminis- tered with a number of different types of drugs. Most  of these recommendations are  based upon  prior severe events, known biochemical composition, and  mechanisms of action of ampre- navir and  other related drugs.

Coadministration with amiodarone, systemic lido- caine, tricyclic antidepressants, and quinidine. Drug concentrations should be monitored if any  of these are  coadministered with fosamprenavir.

Coadministration with lovastatin or  simvastatin.

Fosamprenavir should not be used concomitantly with either lovastatin or simavastatin as the  increased con- centrations of statins may  increase the  risk of myopa- thy  or rhabomyolysis. Other drugs that are  dependent upon  the  CYP3A4  clearance pathway or may  be asso- ciated with increased plasma concentrations that cause severe events should be  avoided. These include the numerous ergot-based drugs, cisapride, pimozole, mi- dazolam, and  triazolam.

Coadministration with products containing St. John’s wort. St John’s wort  is expected to substantially reduce drug plasma levels. This,  in  turn, may  lead  to loss  of viral response to fosamprenavir and  contribute to viral resistance to amprenavir or other PIs.

Coadministration with rifampin. Rifampin may  re- duce  plasma concentrations of amprenavir by  90% when coadministered with fosamprenavir.

Fosamprenavir combined with ritonavir. Neither flecainide nor  propafenone may  be  coadministered if ritonavir is coadministered with fosamprenavir.

Coadministration with sildenafil. Coadministration of any  protease inhibitor with sildenafil will  increase sildenafil concentrations which may  cause hypoten- sion, visual changes, and  priapism.

Atazanavir (Reyataz, BMS-232632)

Atazanavir has  been  approved for use with two NRTIs to clin- ically  reduce HIV viral load. Atazanavir is a novel  azapeptide PI  that  specifically attacks and  acts  against the  HIV-1  pro- tease. It specifically inhibits the  P450  hepatic cytochrome enzymes and  interacts with several drugs. Figure 2.20 shows the  nomenclature, structure, and  usage of atazanavir. A bene- fit  has  been  shown to last at least 48 weeks with no adverse effect on total cholesterol, LDL cholesterol or triglyceride lev- els after 108 weeks. In  some  cases, the  lipid  profile improved over  the  first 48 weeks of treatment (287–289). Atazanavir is administered once-daily orally (290).

Adverse Effects.

Atazanavir was recently released and  there are  few reports of concerns or events from individual physicians.

Diarrhea. Diarrhea occurs  in 23–30%  of patients who take atazanavir as compared with 60% of patients who take nelfinavir.

Jaundice. Jaundice can occur in those who take atazanavir.

Lopinavir + Ritonavir [ABT-378/r] (Kaletra®)

On  September 18, 2000,  the  FDA  approved the  combination coformulation of two  PIs,  ritonavir and  lopinavir (Kaletraâ), also  know  as ABT-378/r, for the  treatment of HIV infection in adults and  children 6 months and  older  in combination with other antiretroviral  medications. The  antiviral activity of ABT-378/r is  mostly attributable  to  lopinavir, not  ritonavir. Figure. 2.21  shows   the   nomenclature, structure,  and approved usage for  lopinavir. ABT-378/r takes advantage of the ability of ritonavir to boost the levels  of other PIs, creating a  potent  anti-HIV combination. ABT-378/r is  to  be  used in conjunction with other antiretrovirals  for  the  treatment of HIV infection. ABT-378/r is available in capsules and  solution. A 400/100 mg/5 ml lopinavir/ritonavir solution should be given twice  daily. The  capsules contain 133.3/33.3 mg  lopinavir/ ritonavir, and  three capsules should be taken twice  a day.

Adverse Events

Multiple severe toxicities involving the kidney have been reported in  persons taking Kaletra, tenofovir, and  didanosine concur- rently (291).

The most  common adverse effects  are  gastrointestinal.

Diarrhea. Diarrhea is described as usually moderately severe in 10–20%  of patients.

Triglyceride and cholesterol  levels. Significant in- creases in triglyceride and  cholesterol levels  have been seen  in 12–14%  of patients receiving ABT-378/r.

Cutaneous side effects. Cutaneous side  effects   have yet  to be reported.

Special Considerations

Coadministration of  Kaletra and phenytoin. Phenytoin (dilantin) and  Kaletra levels  are  reduced by one  another. In PI-experienced patients, the  dosage of Kaletra may  need  to be increased (292).

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