Alprazolam-ritonavir interaction: implications for product labeling.
BACKGROUND
Pharmacokinetic interactions involving antiretroviral therapies may critically influence the efficacy and toxicity of these drugs, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor ritonavir is of particular concern since it both inhibits and induces the activity of cytochrome P450 3A (CYP3A) isoforms.


METHODS
The inhibitory effect of ritonavir on the metabolism of alprazolam, a CYP3A-mediated reaction in humans, was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer subjects received 1.0 mg of alprazolam concurrent with low-dose ritonavir (four doses of 200 mg) or with placebo.


RESULTS
Ritonavir was a potent in vitro inhibitor of alprazolam hydroxylation. The 50% inhibitory concentration was 0.11 micromol/L (0.08 microg/mL); this is below the usual therapeutic plasma concentration range (generally exceeding 2 microg/mL). In the clinical study, ritonavir reduced alprazolam clearance to 41% of control values (P < .001), prolonged elimination half-life (mean values, 30 versus 13 hours; P < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment.


CONCLUSIONS
Consistent with in vitro results, administration of low doses of ritonavir for a short duration of time resulted in large impairment of alprazolam clearance and enhancement of clinical effects. Removal from product labeling of a warning against coadministration of ritonavir and alprazolam was based on a previous study only of extended exposure to ritonavir, in which CYP3A induction offset inhibition. Kinetic interactions involving antiretroviral therapies may be complex and time dependent. Product labeling should reflect this complexity.
Greenblatt
D J
DJ
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and New England Medical Center, Boston, MA 02111, USA. dj.greenblatt@tufts.edu
von Moltke
L L
LL
Harmatz
J S
JS
Durol
A L
AL
Daily
J P
JP
Graf
J A
JA
Mertzanis
P
P
Hoffman
J L
JL
Shader
R I
RI
D000328:Adult; D000525:Alprazolam / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D014151:Anti-Anxiety Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004311:Double-Blind Method; D004347:Drug Interactions; D004348:Drug Labeling; D005260:Female; D017320:HIV Protease Inhibitors / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects; D020033:Protein Isoforms / Q000187:drug effects; D019438:Ritonavir / Q000097:blood / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D000935:Antifungal Agents; D017320:HIV Protease Inhibitors; D020033:Protein Isoforms; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D019438:Ritonavir; D007654:Ketoconazole; D000525:Alprazolam