Page 895 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 49 Antiviral Agents 881

nephrolithiasis with this combination compared with indinavir RITONAVIR
alone; thus, a high fluid intake (1.5–2 L/d) is advised. Indinavir
should not be co-administered with astemizole, cerivastatin, efavi- Ritonavir has a high bioavailability (~75%) that increases with
renz, ergotamine, etravirine, lovastatin, pimozide, rifampin, simv- food. It is 98% protein-bound and has a serum half-life of
astatin, terfenadine, or triazolam. Levels of amlodipine, levodopa, 3–5 hours. Metabolism to an active metabolite occurs via the
and trazodone may be increased with concurrent administration CYP3A and CYP2D6 isoforms; excretion is primarily in the feces.
of indinavir. Ritonavir as a pharmacologic “booster” is one of the recommended
antiretroviral agents for use in pregnant women (Table 49–5).
LOPINAVIR Adverse effects of full-dose ritonavir include asthenia, gastroin-
testinal disturbances, and hepatitis; these are greatly reduced with
the lower doses used for boosting. Dose escalation over 1–2 weeks
Lopinavir is available only in combination with low-dose rito- decreases these side effects. Other potential adverse effects include
navir as a pharmacologic “booster” via inhibition of its CYP3A- altered taste, paresthesias (circumoral or peripheral), elevated
mediated metabolism, resulting in increased exposure and a serum aminotransferase and lipid levels, headache, elevations in
reduced pill burden. serum creatine kinase, and pancreatitis. Inhibition of renal tubular
Lopinavir is highly protein bound (98–99%), and its half-life is
5–6 hours. It is extensively metabolized by CYP3A, which is inhib- secretion of creatinine causes a reversible elevation in serum creati-
nine, but glomerular filtration rate is not affected.
ited by ritonavir. Lopinavir/ritonavir is one of the recommended Ritonavir is a potent inhibitor of CYP3A4, resulting in many
antiretroviral agents for use in pregnant women (Table 49–5). potential drug interactions (Tables 49–3 and 49–4). However,
The most common adverse effects of lopinavir are diarrhea,
nausea, vomiting, increased serum lipids, and increased serum this characteristic has been used to great advantage when ritonavir
is administered in low doses (100–200 mg twice daily) in com-
aminotransferases (more common in patients with HBV or HCV bination with any of the other PI agents, to permit lower or less
co-infection). Prolongation of the PR and/or QT interval may frequent dosing (or both) with greater tolerability as well as the
occur. In some studies but not in others, lopinavir/ritonavir has potential for greater efficacy against resistant virus. Therapeutic
been associated with a higher risk of myocardial infarction. Pan- levels of digoxin and theophylline should be monitored when
creatitis has rarely been reported. Ritonavir-boosted lopinavir may co-administered with ritonavir. The concurrent use of saquinavir
be more commonly associated with gastrointestinal adverse events and ritonavir is contraindicated due to an increased risk of QT
than other PIs. prolongation (with torsades de pointes arrhythmia) and PR inter-
Potential drug-drug interactions are extensive (Tables 49–3
and 49–4). Levels of lamotrigine and methadone may be reduced val prolongation. Concurrent simeprevir is also contraindicated.
with co-administration, and levels of bosentan may be increased.
Concurrent use of darunavir, elvitegravir/cobicistat, fosamprena- SAQUINAVIR
vir, and tipranavir is contraindicated. Since the oral solution of
lopinavir/ritonavir contains alcohol, concurrent disulfiram and In its original formulation as a hard gel capsule, oral saquinavir
metronidazole are contraindicated. The oral solution also contains was poorly bioavailable (~4% after food). However, reformulation
propylene glycol, contraindicating the co-administration of other of saquinavir for once-daily dosing in combination with low-dose
drugs containing propylene glycol.
ritonavir has both improved antiviral efficacy and decreased gas-
trointestinal adverse effects. A previous formulation of saquinavir
NELFINAVIR in soft gel capsules is no longer available.
Saquinavir should be taken within 2 hours after a fatty meal for
Nelfinavir has high absorption in the fed state (70–80%), under- enhanced absorption. Saquinavir is 97% protein-bound, and serum
goes metabolism by CYP3A, and is excreted primarily in the feces. half-life is approximately 2 hours. Saquinavir has a large volume of
The plasma half-life in humans is 3.5–5 hours, and the drug is distribution, but penetration into the cerebrospinal fluid is negligible.
more than 98% protein-bound. Excretion is primarily in the feces. Gastrointestinal discomfort (nau-
The most common adverse effects associated with nelfinavir sea, diarrhea, abdominal discomfort, dyspepsia) may occur. When
(10–30%) are diarrhea and flatulence. Diarrhea responds to administered in combination with low-dose ritonavir, there appears
anti-diarrheal medications but may be dose-limiting. Nelfinavir to be less dyslipidemia or gastrointestinal toxicity than with some of
is an inhibitor of the CYP3A system, and multiple drug interac- the other boosted PI regimens. Since prolongation of the QT interval
tions may occur (Tables 49–3 and 49–4). An increased dosage and torsades de pointes have rarely been reported, saquinavir should
of nelfinavir is recommended when co-administered with rifabu- not be used in patients with congenital long QT syndrome, AV block,
tin (with a decreased dose of rifabutin), whereas a decrease in refractory hypokalemia or hypomagnesemia, or in combination with
saquinavir dose is suggested with concurrent nelfinavir. Do not drugs that both increase saquinavir plasma concentrations and pro-
co-administer with astemizole, cerivastatin, cisapride, ergotamine, long the QT interval. The concurrent use of saquinavir and ritonavir
lovastatin, omeprazole, pimozide, quinidine, rifampin, simvas- may confer an increased risk of QT or PR prolongation.
tatin, or terfenadine. The oral powder contains phenylalanine, Saquinavir is subject to extensive first-pass metabolism by
which can be harmful to patients with phenylketonuria. CYP3A4 and functions as a CYP3A4 inhibitor as well as a