Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an experimental catalytic mimic of glutathione oxidase.
BACKGROUND
* The viral protease inhibitor ritonavir is known to inhibit clearance of intravenous midazolam. * ALT-2074, a catalytic mimic of glutathione oxidase, inhibits human cytochrome P450 3A (CYP3A) isoforms in vitro.


CONCLUSIONS
* Short-term administration of low-dose ritonavir increases area under the plasma concentration curve following oral midazolam by a factor of 28. * Therefore ritonavir is an appropriate positive control inhibitor for clinical drug interaction studies involving CYP3A substrates. * Midazolam clearance is weakly inhibited by ALT-2074, consistent with its in vitro profile.


OBJECTIVE
We evaluated whether 'boosting' doses of ritonavir can serve as a positive control inhibitor for pharmacokinetic drug-drug interaction studies involving cytochrome P450 3A (CYP3A). The study also determined whether 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an investigational organoselenium compound that acts as a catalytic mimic of glutathione oxidase, inhibits CYP3A metabolism in vivo.


METHODS
Thirteen healthy volunteers received single 3-mg oral doses of midazolam on three occasions: in the control condition, during co-treatment with low-dose ritonavir (three oral doses of 100 mg over 24 h), and during co-treatment with ALT-2074 (three oral doses of 80 mg over 24 h).


RESULTS
Ritonavir increased mean (+/-SE) total area under the curve (AUC) for midazolam by a factor of 28.4 +/- 4.2 (P < 0.001), and reduced oral clearance to 4.2 +/- 0.5% of control (P < 0.001). In contrast, ALT-2074 increased midazolam AUC by 1.25 +/- 0.11 (P < 0.05), and reduced oral clearance to 88 +/- 8% of control.


CONCLUSIONS
Low-dose ritonavir produces extensive CYP3A inhibition exceeding that of ketoconazole (typically 10- to 15-fold midazolam AUC enhancement), and is a suitable positive control index inhibitor for drug-drug interaction studies. ALT-2074 inhibits CYP3A metabolism to a small degree that is of uncertain clinical importance.
Greenblatt
David J
DJ
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA. dj.greenblatt@tufts.edu
Peters
Diane E
DE
Oleson
Lauren E
LE
Harmatz
Jerold S
JS
MacNab
Malcolm W
MW
Berkowitz
Noah
N
Zinny
Miguel A
MA
Court
Michael H
MH
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam