DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

occurs less frequently at codon 84. Secondary resistance
mutations occur at codons 10, 32, 46, 47, 54, 73,
and 90, which greatly increase resistance and crossresistance
(Arvieux and Tribut, 2005).
Absorption, Distribution, and Elimination. Fosamprenavir is
dephosphorylated rapidly to amprenavir in the intestinal mucosa.
The phosphorylated prodrug is ~2000 times more water soluble than
amprenavir. Meals have no significant effect on fosamprenavir pharmacokinetics
(Arvieux and Tribut, 2005). Amprenavir is 90% bound
to plasma proteins, mostly α 1
-acid glycoprotein. This binding is relatively
weak, and physiological concentrations of α 1
-acid glycoprotein
increase the in vitro IC 50
only 3- to 5-fold. Amprenavir clearance
is mainly by hepatic CYP3A4, and excretion is by the biliary route.
Amprenavir is a moderate inhibitor and inducer of CYP3A4.
Ritonavir increases amprenavir concentrations by inhibiting
CYP3A4, allowing lower fosamprenavir doses. The daily fosamprenavir
dose may be reduced from 1400 mg twice daily to 1400 mg
plus 200 mg ritonavir when given once daily, or 700 mg (one tablet)
plus 100 mg ritonavir twice daily.
Untoward Effects. The most common adverse effects associated
with fosamprenavir are GI and include diarrhea, nausea, and vomiting.
Hyperglycemia, fatigue, paresthesias, and headache also have
been reported. Fosamprenavir can produce skin eruptions; moderate
to severe rash is reported in up to 8% of recipients, and onset is
usually within 2 weeks of starting therapy (Arvieux and Tribut,
2005). Fosamprenavir has fewer effects on plasma lipid profiles than
lopinavir-based regimens.
Precautions and Interactions. Inducers of hepatic CYP3A4 activity
(e.g., rifampin and efavirenz) may lower plasma amprenavir concentrations.
Because amprenavir is both a CYP3A4 inhibitor and
inducer, pharmacokinetic drug interactions can occur and may be
unpredictable. For example, atorvastatin, ketoconazole, and rifabutin
concentrations increase significantly when fosamprenavir is given
without ritonavir, whereas methadone concentrations decrease.
Therapeutic Use. Clinical trials have demonstrated
long-term virologic benefit in treatment-naive and treatment-experienced
patients receiving fosamprenavir
(LEXIVA) with or without ritonavir, in combination with
nucleoside analogs (Arvieux and Tribut, 2005).
Twice-daily fosamprenavir/ritonavir produces virologic outcomes
equivalent to lopinavir/ritonavir in both treatment-naive and
treatment-experienced patients (Arvieux and Tribut, 2005). However,
once-daily fosamprenavir/ritonavir is inferior to lopinavir/ritonavir
in protease-inhibitor experienced patients, and the drug should only
be given twice daily in this patient population. Fosamprenavir is
approved for use in treatment-naive pediatric patients ≥2 years of age
and treatment-experienced patients ≥6 years of age, at a dose of
30 mg/kg twice daily or 18 mg/kg plus ritonavir 3 mg/kg twice daily.
Lopinavir
Chemistry and Antiviral Activity. Lopinavir is a peptidomimetic
HIV protease inhibitor that is structurally
similar to ritonavir (Figure 59–6) but is 3- to 10-fold
more potent against HIV-1 in vitro. Lopinavir is active
against both HIV-1 and HIV-2; its IC 50
for wild-type
HIV variants in the presence of 50% human serum
ranges from 65 to 290 nM. Lopinavir is available only
in co-formulation with low doses of ritonavir (KALE-
TRA), which is used to inhibit CYP3A4 metabolism and
increase concentrations of lopinavir (Oldfield and
Plosker, 2006).
Mechanisms of Action and Resistance. Treatment-naive
patients who fail a first regimen containing lopinavir
generally do not have HIV protease mutations but may
have genetic resistance to the other drugs in the regimen
(Oldfield and Plosker, 2006). For treatment-experienced
patients, accumulation of four or more HIV protease
inhibitor resistance mutations is associated with a
reduced likelihood of virus suppression after starting
lopinavir (Kuritzkes, 2004).
Mutations most likely to be associated with resistance include
I47A/V, V32I, and L76V. Additional mutations associated with
lopinavir failure in treatment-experienced patients include those at
HIV protease codons 10, 20, 24, 33, 46, 50, 53, 54, 63, 71, 73, 82,
84, and 90 (Oldfield and Plosker, 2006). There is no evidence that
exposure to the low doses of ritonavir in the lopinavir/ritonavir coformulation
selects for ritonavir-specific resistance mutations.
Absorption, Distribution, and Elimination. Lopinavir is absorbed
rapidly after oral administration. Food has a minimal effect on
bioavailability of lopinavir/ritonavir tablets, and the drug can be
taken with or without food. Although the tablets contain
lopinavir/ritonavir in a fixed 4:1 ratio, the observed plasma concentration
ratio for these two drugs following oral administration is
nearly 20:1, reflecting the sensitivity of lopinavir to the inhibitory
effect of ritonavir on CYP3A4. Lopinavir undergoes extensive
hepatic oxidative metabolism by CYP3A4. Approximately 90% of
total drug in plasma is the parent compound, and <3% of a dose is
eliminated unchanged in the urine. Both lopinavir and ritonavir are
highly bound to plasma proteins, mainly to α 1
-acid glycoprotein,
and have a low fractional penetration into CSF and semen.
When administered orally without ritonavir, lopinavir plasma
concentrations were exceedingly low mainly owing to first-pass
metabolism. Both the first-pass metabolism and systemic clearance
of lopinavir are very sensitive to inhibition by ritonavir.
A single 50-mg dose of ritonavir increased the lopinavir
AUC by 77-fold compared with 400 mg lopinavir alone; 100 mg
ritonavir increased the lopinavir AUC by 155-fold. Lopinavir trough
concentrations were increased 50- to 100-fold by co-administration
of low doses of ritonavir (Oldfield and Plosker, 2006). Multiple-dose
pharmacokinetic studies have not been conducted with lopinavir in
the absence of ritonavir. Adding 100 mg ritonavir twice daily to the
lopinavir/ritonavir co-formulation (a total of 200 mg twice daily of
ritonavir) has only a modest further effect on lopinavir concentrations,
increasing the mean steady-state AUC by 46%.
Untoward Effects. The most common adverse events reported with
the lopinavir/ritonavir co-formulation have been GI: loose stools,
1651
CHAPTER 59
ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION