The new soft gelatin capsule formulation of (SGC) saquinavir received FDA full approval on Friday November 7, 1997. Invirase is the old formulation of saquinavir (HGC-hard gelatin capsule). Due to the limited bioavailability of HGC saquinavir, the antiviral effect and its durability had limitations. Fortovase is the new formulation and it provides 8-10 times the exposure of squinavir than was seen with the HGC saquinavir at its standard dose of 600 mg, three times per day. The new SGC saquinavir is prescribed at 1200 mg three times per day. Multiple dosing with Fortovase produced AUC (drug blood levels over a fixed period of time) about 10 times higher than with multiple dosing of Invirase (HGC saquinavir).

Roche has explained that Fortovase delivers more drug through the body than Invirase. The HGC took too long to dissolve and be absorbed so enzymes had a chance to degrade, it leaving less in the bloodstream. The new formula combines the drug with an oil like substance that is more rapidly digested and allows more drug to reach the bloodstream. The new formulation absorber faster because small or micron sized droplets of medium chain mono- and di-glycerides contain dissolved saquinavir. The oil is comprised of these small saquinavir containing droplets which allow for a wider dispersion of the drug, enabling it to be absorbed quickly before degradation from the enzymes.

Roche Labs is transitioning the old form of saquinavir off the market. Unless someone is using Invirase abs wishes to continue, it will only be available in the pharmacy for 6 more months. Invirase will be available after 6 months for individuals currently using it in combination with ritonavir or for those patients who, through consultation with their doctors, have decided to continue taking Invirase.

For nelfinavir, indinavir, ritonavir and ritonavir/saquinavir the efficacy and safety data extends to 1 year, 2 years, 2 years and 1 year, respectively. We don’t have data yet for Fortovase extending out as long . Also, the populations (drug naive or experienced; high or low CD4 and viral load, etc.) in which all these drugs are studied vary, complicating comparisons of the efficacy of the different protease inhibitors. But the preliminary data available on Fortovase is reported below in various studies, extending to 20 weeks and longer and suggests that Fortovase may be on a par with the other approved protease inhibitors in terms of efficancy as evaluated by CD4 increases, viral load decreases, and % <400 copies/ml (undetectable). The side effects and toxicity profile observed so far is reported below.

For example, in one study of treatment naive individuals, reported below in more detail, the baseline CD4 and viral load were 419 cells and 63,000 copies/ml. After 20 weeks on Fortovase+AZT/3TC, CD4s increased by 259 cells, viral load was reduced by 3.34 log (n=23) (as measured by the 20 copy test, which gives a higher reduction than if using the 400 copy test), and 80-90% of those still in the study were <400 copies/ml. Nineteen out of 42 had withdrawn for various reasons listed below.

Refrigeration. Your pharmacist will refrigerate saquinavir upon receipt. You can also store saquinavir in your fridge. If you don’t refrigerate it, or take it in and out of your fridge, you have a total of 3 months of unrefrigerated time. In other words, the new saquinavir can be kept out of refrigeration and at room temperature for a total of 3 months. Of course, if you subject the new saquinavir to higher temperatures than normal room tempurature, these instructions are subject to change. This might apply if you live in a hot climate such as Arizona and do not use air conditioning; or, if you live in NYC during the summer without air conditioning.

Ritonavir+Saquinavir. Both Roche and Abbott have explained that if you are currently taking the double protease combination of ritonavir+saquinavir it doesn’t matter if you use Invirase or Fortovase. The dose will be the same -- 400 mg every 12 hours. The drug blood levels of saquinavir hit a maximum peak with ritonavir. Ritonavir increases saquinavir blood levels 20-50 fold. Whether you use Invirsae or Fortovase saquinavir, blood levels cannot be higher. Abbott and Roche have also stated that side effects should not be any different. However, as mentioned earlier, Roche has agreed to continue availability of Invirase beyond 6 months for those currently using it. Therefore, when using 400 or 600 mg RTV+400 mg SQV every 12 hours, you can either continue using 400 mg Invirase or take 400 mg Fortovase.

Food Effect. Eating instructions for Fortovase do not appear to have changed from those for Invirase. Taking Fortovase with a full meal is recommended by Roche Labs, the manufacturer. In studies, eating greatly increased drug levels and absorption when, compared to taking Fortovase without eating or with a light meal. The mean 12 hour AUC (drug lvels in blood) was increased about 6.7 times when a single dose of 800 mg of Fortovase was given to a healthy volunteer with a full breakfast (48g protein, 60g carbohydrates, 57g fat; 1006 kcal) compared to the same dose taken under fasting conditions.

Taking Fortovase with a light low fat meal is preferable to not eating but blood levels of the drug are increased further when taking it with a high fat meal. Preliminary results from an ongoing study indicated that blood levels of Fortovase are reduced by about 40% when the drug is taken following a low fat meal as opposed to high fat meal.

1. Study Reported at European AIDS Conference, October 1997. At Hamburg, Brian Conway reported preliminary data on a study of 18 individuals receiving SGC saquinavir, extended to 48 weeks for some individuals In this study the 18 participants were previously either in study NV15182 or NV15355. Participants in NV15355 were all therapy naive, while participants in NV15182 could be either nucleoside naive or experienced.

The purpose of this study was to follow these 18 individuals evaluating a longer term response to therapy by CD4 count and viral load by the standard test, plus a more sensitive measure.

Five out of 18 were treatment naive. The 13 individuals who had prior treatment experience had previously taken at least 2 nucleosides. Eleven out of 13 had taken at least 3 nucleosides; and 1 person had taken all 5 nucleosides. All were protease inhibitor and NNRTI naive.

Number who had taken drug:
            AZT     13
            ddI       8
            ddC      6
            d4T      5

Of the 18 persons, 14 received AZT/3TC/SGC SQV, 3 received d4T/3TC/SGC SQV, and 1 received AZT/Loviride/SGC SQV. Loviride is a NNRTI that has been recently withdrawn from clinical studies because it appeared to be too ineffective.

Viral Load Responses

Individuals With the Most Prior Therapy Experience (copies/ml)

Investigators did not report the actual regimen each individual was taking nor the actual drugs each individual had previously taken. In this study, 4/6 were taking AZT/3TC/SQV, and 2/6 were taking d4T/3TC/SQV. I think these results point out the need to use drugs neverused before when starting a new regimen.

Composite Viral Load Responses For All Study Participants (copies/ml) - Includes the middle group of individuals with less prior drug therapy (n-7), as well as those who are naive (5) and those with the most prior therapy (6)

Fourteen out of 18 had <10,000 copies/ml at week 24. Five out of 11 from the first two tables were <50 copies/ml at week 24, therefore 4/7 of the remainng individuals (with less prior drug therapy) were <50 copies/ml.

2. NV15355: SGC Saquinavir (Fortovase) vs HGC Saquinavir (Invirase)

This is a 16 week analysis of an ongoing, 48 week study of 171 treatment naive individuals comparing the new saquinavir to the old saquinavir for safety and efficacy. Participants were randomized to either Fortovase or Invirase and permitted their choice of 2 nucleosides to add to the triple drug regimen. The analysis was done by intent-to-treat, which means the data includes individuals who may have withdrawn from study medications due to any number of reasons. Viral load responses were evaluated using both the Roche Amplicor 400 copy test and the Roche Ultrasensitive 50 copy test.

Safety and Tolerability

Five persons (5.6%) taking SGC saquinavir and 2 persons (2.5%) taking HGC saquinavir reported severe adverse events, possibly related to study medications. Most were gastrointestinal related. It is important to remember the following data is based on only 16 weeks data. Side effects and toxicities can take longer to develop.

* Shift from grade 0 to grade 3, or from grade 1 to grade 4.

Premature Withdrawals

3. Sun Study: Fortovase+AZT/3TC

This is an open-label, non-comparative examination of the triple regimen of saquinavir SGC (soft-gel capsule, Fortovase}, plus AZT and 3TC. 42 treatment-naive individuals were enrolled with a mean baseline, HIV RNA and CD4 of 4.8 log (about 63,000 copies/ml, range 8,951-1,193,168) and 419 cells, respectively. The study is ongoing and the following data is preliminary.

The investigators reported that after 20 weeks:

• the reduction in viral load for 23 evaluable study participants was 3.34 log (range: -4.5 to 2.2 log). However, the investigators used a more sensitive viral load test (20 copies/ml) which can report (accuracy of results using 20 copy test can be inconsistent) viral load reductions down to a lower level than you’ll get from using the 400 copy test.
• 91% were <400 copies/ml (undetectable)
• 60% <20 copies/ml.
• 259 CD4 increase from baseline of 419 cells
• 19/42 particiants had withdrawn from the study by week 20 and were not included in the analysis. Two withdrew due to adverse events, 3 due to non-compliance, 4 due to refusal of treatment, 6 lost to follow-up, and one missed the week 16 visit.

Safety. Investigators characterized the triple combination as well-tolerated. The most frequent side effects related to study drug (>5%): nausea, vomiting, diarrhea, and headaches.

Lab abnormalities: One person had a grade III AST/ALT (liver function tests) at week 2 which resolved after discontinuing study treatment. One person had a grade IV AST/ALT at week 12 associated with acute hepatitis A. One person had a Grade III AST/Grade IV ALT at week 20 associated with acute hepatitis A. An approximate 20% incidence of diarrhea has been reported associated with saquinavir SGC in a different study.

4. Cheese Study: SGC Saquinavir vs Indinavir

In Hamburg, JCC Borleffs of University Hospital Utrecht, and others reported preliminary findings from this 48 week study comparing Forotase+AZT/3TC to Crixivan+AZT/3TC. Study participants were protease inhibitor and 3TC naive. They were permitted to be AZT naive or with <12 months AZT experience. Two receiving Fortovase and one receiving Crixivan had <12 months AZT experience. Participants were required to have >500 CD4 and <10,000 HIV RNA at study entry. Those with ³ Grade 3 lab abnormalities were excluded.

After 16 weeks, participants were permitted to enter a rollover study for viral load failure.

By week 8, all participants regardless of which treatment they received, had their viral load reduced to below detection by the Amplicor viral load test. The cutoff was reported to be 2.6 log.

CD4 and Viral Load Changes

Discontinuation (by 24 wks) and Safety

Authors included : CV Fletcher, University of Minnesota; MW Kline, Baylor College of Medicine, Houston; NE Buss and F Duff, Roche Labs

Therapeutic options for children are more limited than for adults. The pathogenesis or course of disease, for children is different than for adults. Children born with HIV do not have a developed immune system to fight HIV. An adult has a developed and intact immune system when HIV is contracted. Therefore, the disease can progress quickly in children. It may be more crucial for children to initiate therapy earlier in the course of disease progression than adults. Although not yet widely accepted, some experts counsel that a potent therapy capable of maximal suppression of viral load should be considered as soon as possible after confirmation of HIV infection.

Fourteen children from 3-13 yrs old who were able to swallow adult capsules started treatment with SGC SQV (initial dose, 33 mg/kg tid) and 2 nucleosides of choice. Because children’s organ system’s are not fully developed and constantly evolving, the pharmacokinetics (blood levels) of a drug become more of a concern than for adults. Selecting adequate dosing for children is more complicated and difficult. Dosing of any HIV drug may need to be more individually assessed than for adults.

The study is assessing tolerability, efficacy, and pharmacokinetics. Participants will be followed for a minimum of 24 weeks with "intensive pharmacokinetic (PK) sampling at week 0 (single dose profile), week 4 (steady state), and as necessary thereafter. Sparse PK sampling is scheduled at every study visit after week 4.

Twelve out of 14 children had prior nucleoside experience with a mean duration of 4 years. The nucleoside combinations selected for this study were d4T/3TC (11), d4T/ddI (2), or AZT/3TC (1).

Safety and tolerability. No serious adverse events have been reported. One child with pre-existing thrombocytopenia had a marked decrease in platelet count in study week 4. There was no interruption or discontinuation of therapy.

The mean baseline CD4 and viral load were 446 cells and 4.6 log (about 39,000 copies/ml. Because disease progression is different in children compared to adults, the CD4 and viral levels have a different significance. Investigators reported by week 4, CD4 increased by 95 cells, and mean viral load declined by 2.1 log. At weeks 4 and 8, 5/12 and 7/7 children were <400 copies/ml. By visual observation of the line graphs it appeared that viral load at week 8 for 6/8 children was steady or declining further compared to the week 4 reduction. One child’s viral load reduction was about 1 log at week 4 and the same at week 8. One child who had been on study meds for 12 weeks had sustained about a 2.2 log reduction at week 12.

The authors concluded the PK characteristics are consistent with expectations. And the drugs were generally well tolerated.

Double Protease Combination Studies Using SGC Saquinavir. There are two such studies both of which are reported in the double protease section.

Pharmacokinetics (drug interactions) of Saquinavir with Selected Other Drugs - for interaction information with more drugs than listed here, refer to the Fortovase Package Insert available at any pharmacy selling saquinavir).

Effect of Saquinavir on PK of Other Drugs

Invirase (old formulation of SQV was used in delavirdine and nevirapine experiments; Fortovase (new SQV formulation) was used in nelfinavir and ritonavir experiments.

Effect of Other Drugs on Saquinavir Pharmacokinetics

For several experiments in the above table you will notice a single dose of a drug was used. For example, for the Fortovase-Indinavir experiment, single doses of Fortovase were used. When using a single dose the results may not necessarily be reliable. Using a single dose is not the same as reaching a steady state of a drug’s blood levels, which can take a week’s time. The results of Agouron’s single dose PK study of nelfinavir-indinavir did not hold true when Merck conducted steady state PK studies of the two drugs.

* Giving a single dose of nelfinavir 750 mg on the 4th day of multiple Fortovase dosing (1200 mg tid) resulted in nelfinavir AUC 1.2 times those seen with nelfinavir alone. Cmax remained unchanged.