A Textbook of Clinical Pharmacology and Therapeutics

356 HIVANDAIDS

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 lopinaviris excreted as
metabolites in the faeces, with only about 4% appearing in urine.
Ritonaviris also well absorbed (bioavailability 60%). It is 60%
plasma protein bound and metabolized by CYP3ACYP2D6.
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 metabo-
lism. 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,triazolamand

excessive hypotension with calcium channel blockers).

Protease inhibitors inhibit the metabolism of rifabutin

increasing the risk of rifabutintoxicity.

2.Enzyme inducers (e.g. rifamycins – rifampicin/rifabutin

ornevirapine) 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. lopinaviris available combined

with low-dose ritonavir;ritonavirinhibits CYP3A and

P-glycoprotein (MDR1) increasing the bioavailability of

lopinavir. The same principle applies if saquinavir/

low-doseritonaviroramprenavir/low-doseritonavirare

combined.

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 Tmax1–2 h, t1/2 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 Tmax2 h, t1/2is 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). Tmaxis 0.8–1.5 h, does inhibit it, especially CYP3A

with other PIs, hepatic t1/2is 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). Tmaxis inhibits it, especially CYP3A

redistribution, transaminitis 2–4 h, t1/2is 3.5–5 h, 98%

protein bound. Hepatic

metabolism

Tipranavir Gastro-intestinal disturbances, Well absorbed (40–60% Induces CYP450, especially

hyperglycaemia, hepatitis- bioavailable). t1/2is 5–6 h CYP3A

transaminitis cerebral

haemorrhage