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).
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.
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).
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.
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.
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).