Clinical Pharmacology and Therapeutics

356 HIV AND AIDS
Table 46.3: Properties of commonly available HIV-1 protease inhibitors
Protease inhibitors Side effects Pharmacokinetics Additional comments
Amprenavir Gastro-intestinal upsets, skin Well absorbed T max 1–2 h, t 1/2 Inhibits CYP3A
(fosamprenavir) rashes, fat redistribution 7–10 h. Hepatic metabolism
CYP3A
Atazanavir Hyperbilirubinaemia, gastro- Well absorbed with food. Does not induce CYP450, but
intestinal upsets T max 2 h, t 1/2 is 6–8 h, 80–90% does inhibit CYP3A drug
hyperglycaemia, fat protein bound. Hepatic interactions
redistribution
metabolism. No autoinduction
of metabolism
Indinavir Renal stones (5–15%), gastro- Well absorbed (65% Does not induce CYP450, but
intestinal upsets fewer than bioavailable). T max is 0.8–1.5 h, does inhibit it, especially CYP3A
with other PIs, hepatic
t 1/2 is 2 h. 60–65% protein
dysfunction, hyperglycaemia, bound. Hepatic metabolism
fat redistribution
Saquinavir Gastro-intestinal upsets, Poorly absorbed (13% Does not induce CYP450, but
(soft gel) hepatitis hyperglycaemia, fat bioavailable). Hepatic inhibits it, at the concentrations
redistribution metabolism achieved clinically (CYP3A)
Nelfinavir Gastro-intestinal upsets 20%, Well absorbed (20–80% Does induce CYP450 and
hyperglycaemia, fat bioavailable). T max is inhibits it, especially CYP3A
redistribution, transaminitis 2–4 h, t 1/2 is 3.5–5 h, 98%
protein bound. Hepatic
metabolism
Tipranavir Gastro-intestinal disturbances, Well absorbed (40–60% Induces CYP450, especially
hyperglycaemia, hepatitis- bioavailable). t 1/2 is 5–6 h CYP3A
transaminitis cerebral
haemorrhage
Pharmacokinetics
Lopinavir is well absorbed with food and 98–99% protein
bound (albumin and alpha-1-acid glycoprotein). It undergoes
oxidative metabolism by the CYP3A isozyme, with a half-life of
five to six hours. The majority of lopinavir is excreted as
metabolites in the faeces, with only about 4% appearing in urine.
Ritonavir is also well absorbed (bioavailability 60%). It is 60%
plasma protein bound and metabolized by CYP3A CYP2D6.
It has a half life of between three and five hours. Ritonavir
inhibits the metabolism of certain CYP3A substrates (and certain
drugs metabolized by CYP2D6) and induces its own metabolism.
Therefore drug–drug interactions are complex.
Drug interactions
These are numerous and clinically important; the following
list is not comprehensive:
1. Most protease inhibitors are inhibitors of hepatic CYP3A.
This leads to reduced clearance and increased toxicity of
a number of drugs often causing severe adverse effects
(e.g. increased sedation with midazolam, triazolam and
excessive hypotension with calcium channel blockers).
Protease inhibitors inhibit the metabolism of rifabutin
increasing the risk of rifabutin toxicity.
2. Enzyme inducers (e.g. rifamycins – rifampicin/rifabutin
or nevirapine) enhance the metabolism of protease
inhibitors, making them less effective, producing
subtherapeutic plasma concentrations and increasing the
likelihood of HIV resistance.
3. Several protease inhibitors reduce gastro-intestinal
metabolism (by CYP3A) and luminal transport (via
P-gp/MDR1) of co-administered protease inhibitors,
thereby increasing plasma concentrations. Combining two
agents from this group is called ‘boosted protease
inhibitor’ therapy, e.g. lopinavir is available combined
with low-dose ritonavir; ritonavir inhibits CYP3A and
P-glycoprotein (MDR1) increasing the bioavailability of
lopinavir. The same principle applies if saquinavir/
low-dose ritonavir or amprenavir/low-dose ritonavir are
combined.