Saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir is 97% protein-bound, and serum half-life is approximately 2 hours. Saquinavir has a large volume of distribution, but penetration into the cerebrospinal fluid is negligible. Excretion is primarily in the feces. Gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia) may occur. When administered in combination with low-dose ritonavir, there appears to be less dyslipidemia or gastrointestinal toxicity than with some of the other boosted PI regimens. Since prolongation of the QT interval and torsades de pointes have rarely been reported, saquinavir should not be used in patients with congenital long QT syndrome, AV block, refractory hypokalemia or hypomagnesemia, or in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval. The concurrent use of saquinavir and ritonavir may confer an increased risk of QT or PR prolongation.
Saquinavir is subject to extensive first-pass metabolism by CYP3A4 and functions as a CYP3A4 inhibitor as well as a substrate; thus, there are many potential drug-drug interactions (Tables 49–3 and 49–4). Increased saquinavir levels when co-administered with omeprazole necessitate close monitoring for toxicities. Digoxin levels should be monitored. Liver tests should be monitored if saquinavir is co-administered with delavirdine or rifampin. Concurrent darunavir or tipranavir is contraindicated.
Tipranavir is a newer PI indicated for use in treatment-experienced patients who harbor strains resistant to other PI agents. It is used in combination with ritonavir to achieve effective serum levels.
Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system and is contraindicated in patients with hepatic insufficiency. Tipranavir contains a sulfonamide moiety and should not be administered to patients with known sulfa allergy.
The most common adverse effects of tipranavir are diarrhea, nausea, vomiting, and abdominal pain. An urticarial or maculopapular rash occurs in 10–14%, and may be more common with co-administered ethinyl estradiol. Liver toxicity, including life-threatening hepatic decompensation, has been observed and may be more common than with other PIs, particularly in patients with chronic HBV or HCV infection. Because of an increased risk for intracranial hemorrhage in patients receiving tipranavir/ritonavir, the drug should be avoided in patients with head trauma or bleeding diathesis. Other potential adverse effects include depression, elevation in serum amylase, increased serum lipids, and decreased white blood cell count.
Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition. Tipranavir also induces the P-glycoprotein transporter and thus may alter the disposition of many other drugs (Tables 49–3 and 49–4). Concurrent use with atazanavir, elvitegravir/cobicistat, etravirine, fosamprenavir, lopinavir/ritonavir and saquinavir should be avoided. Supplemental vitamin E is contraindicated in patients receiving the oral solution.