Saquinavir oral bioavailability

Fig. 18.7. Oral bioavailability of saquinavir with and without CFJ [42], Saquinavir (600 mg three capsules of Invirase, 200 mg each tablet) was administered to eight healthy male subjects (average body weight 76 kg) before and after consumption of two glasses (200 mL each) of CFJ at 15 and 45 min before drug administration. QMPRPIus was used to estimate human effective permeability (0.93 X 10-4 cm s 1), pure aqueous water...

Saquinavir, despite its distinct peptidomimetic character is a very potent inhibitor of HIV PR with an inhibition constant of 0.9 nMand an antiviral IC50 in vitro of 0.020 iM[ 10]. Although it suffers from a low oral bioavailability (5-10% in humans), it became an important starting point for the design of second generation, less-or nonpeptidic inhibitors. Saquinavir became the first HIV PR inhibitor approved by the FDA for treatment of AIDS. 

The high aqueous solubility and largely nonpeptidic character of indinavir may be responsible for the good oral bioavailability, respectable pharmacokinetic profile, and high antiviral activity observed with this compound. Similar to saquinavir and ritonavir, indinavir has been recently approved by the FDA for treatment of AIDS. 

Norvir (ritonavir, ABT-538) by Abbott (Kalamazoo/MI, USA) in phase II demonstrated a 100-fold reduction of viral count, more than Crixivan and AZT. The threefold enhancement of CD4-T cell count after 12 weeks is also an improvement over AZT. However, even ABT-538 develops resistances, albeit more slowly than Crixivan. Hepatic side effects limit doses to 600 mg twice daily. Ritonavir has high oral bioavailability, about 78% in rats, good solubility (5.3 g IT1 (pH 7.4) to 6.9 g L-1 (pH 4.0)), and a plasma half-life of 1.2 h (Kempf, 1995). The molecule is difficult to produce in phase II, the overall yield in production was 2% ( ) in addition, the product was cherry-red. The combination of ritonavir and saquinavir has also been reported to dramatically increase saquinavir plasma concentrations (by as much as 50-fold). Ritonavir is believed to act by inhibiting cytochrome P450 (CYP 3A4), the enzyme responsible for saquinavir first-pass metabolism. 

These two prehepatic systems have been shown to contribute to the limited oral bioavailability of many lipophilic drugs including cyclosporine [8], terfenadine [9], saquinavir [10], midazolam [11], tacrolimus [12], atorvastatin [13], and others. 

Grapefruit juice has also been shown to inhibit CYP3A4 and P-gp in the small intestine, and hence, can elevate the oral bioavailability of lipophilic drugs [98,99]. Concomitant intake of grapefruit juice with the lipophilic cholesterol-lowering medication simvastatin caused a 16-fold increase in the AUC of simvastatin [100]. The oral bioavailability of the lipophilic HIV protease inhibitor saquinavir was doubled following concomitant administration with grapefruit juice [101]. 

Other close structural analogues of saquinavir (17) incorporating the hydroxyethylamine isostere have been developed to provide potent inhibitors of HIV-1 protease. For example, palinavir (21) (Table III) inhibits the enzyme with a Kj of 0.03 nM and blocks viral replication with an EC50 of 7 nM This antiviral potency was not substantially affected by the addition of oci-acid glycoprotein at physiological concentrations however, 21 did show reduced activity against HIV-1 variants with active site mutations, including valine-32 to isoleucine and isoleucine-84 to valine (Lamarre et al., 1997). Pharmacokinetics in rats have been reported for palinavir. The compound exhibited an oral bioavailability of 20 to 30%, with a plasma half-life of 30 to 50 minutes. 

Similarly, five days of saquinavir administration (1200 mg, t.i.d.) inhibited the metabolic clearance of intravenous and oral midazolam (106). The oral bioavailability of midazolam increased from 41% to 90%. The hepatic availability fraction was estimated to have increased from 0.64 to 0.84 and the intestinal availability fraction increased from 0.64 to about 1.0. Thus, saquinavir treatment resulted in a near complete inhibition of first-pass intestinal extraction and a lesser inhibition of hepatic extraction of midazolam. 

SAQUINAVIR (INVIRASE HARD CAPSULES) GRAPEFRUIT JUICE Possibly t efficacy Possibly t bioavailability 1 presystemic metabolism. Constituents of grapefruit irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited No dose adjustment is advised. Oral bioavailability is very low and is enhanced beneficially with grapefruit juice or grapefruit. Soft gel capsules have greater bioavailability so may interact to a lesser degree... 

An interesting example of polymorphic structure differentiation is that of human immunodeficiency virus (HIV) protease inhibitors. The HIV protease inhibitors pose a serious problem in their bioavailability. Invirase showed only modest market performance, and it was soon superseded by drugs, such as ritonavir (Norvir) and indinavir sulfate (Crixivan ) that had better bioavailability. Three years after initial approval, saquinavir was reintroduced in a formulation with sixfold higher oral bioavailability relative to the original product. Ritonavir was originally launched as a semisolid dosage form, in which the waxy matrix contained the dispersed drug in order to achieve acceptable oral bioavailabiUty. Two years after its introduction, ritonavir... 

The two Pis used most in the last 5 to 6 years, nearly always in combination regimens with two NRTIs, are indinavir and ritonavir. Saquinavir, one of the least toxic, has very low (and variable) oral bioavailability that predisposes to resistance development. 

In recent years there has been an increased interest in the utility of lipid-based delivery systems to enhance oral bioavailability (4). It is generally known that membrane permeability is directly correlated to a drug s water-lipid partition coefficient however, the systemic availability of highly lipophilic drugs is impeded by their low aqueous solubility. In an effort to improve this solubility-limited bio-availabiliy,formulators have turned to the use of lipid excipients to solubilize the compounds before oral administration. Several formulations are currently on the market, for example, Sandimmun/Neoral (cyclosporin microemulsion), Norvir (ritonavir), and Fortovase (saquinavir)... 

In initial clinical trials, hard-gelatin capsules of saquinavir mesylate at the approved dose (600 mg three times daily) produced only modest virologic effect most likely because of poor oral bioavailability. Greater activity was achieved by increasing the dose fourfold, to 1200 mg six times daily. When combined with ritonavir and nucleoside analogs, saquinavir produces viral load reductions comparable with those of other HTV protease inhibitor regimens. 

Saquinavir, one of the least toxic, has very low (and variable) oral bioavailability that predisposes to resistance development. 

It is well known, that the co-administration of poorly water soluble drugs with a meal rich in fat can enhance the oral bioavailability of poorly water soluble drugs and lipid based delivery systems mostly based on complex lipid mixtures are intensively studied to enhance the bioavailability of poorly water soluble drugs. ° ° A couple of lipid based formulations are already on the market, e.g. for cyclosporine (Neoral ), retonavir (Norvir ), saquinavir (Fortovase ) and amprenavir (Agenerase ). Formulations of solid lipid nanoparticles may present a further alternative for oral delivery of poorly water soluble drugs as well as for proteins and peptides with low oral bioavailability due to degradation in the intestinal fluids. ... 

Examples of commercialized SMEDDS formulations include cyclosporine (Neoral), ritonavir (Norvir), and saquinavir (Fortovase) [106,107]. Only few SEDDS and SMEDDS formulations have been conunercialized because of limitations in the usage level of excipients, e.g., surfactants and cosolvents, and the unpredictable improvement of oral bioavailability due to possibility of drug precipitation upon aqueous dilution in vivo. Predictive ability and quick methods for assessment of such problems could be very useful to the formulator in selecting lead formulations. 

In its original formulation as a hard gel capsule (saguinavir-H Invirase), oral saquinavir is pooriy bioavailable (only about 4% after food). However, reformulation of saquinavir-H for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased gastrointestinal adverse effects. 

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