The benzodiazepine derivative midazolam, a substrate for biotransformation by cytochrome P450 3A (CYP3A) enzymes [1–3], is extensively used in drug development and clinical pharmacology as an index compound to profile the activity of hepatic and enteric CYP3A [4–12]. Under baseline conditions, midazolam undergoes extensive presystemic extraction after oral dosage, with net systemic bioavailability in the range of 30% [13–18]. It is established that incomplete oral bioavailability of midazolam results from a combination of hepatic and enteric CYP3A activity. An enteric-specific CYP3A inhibitor, such as grapefruit juice, has no effect on total area under the plasma concentration curve (AUC) of intravenous midazolam [19, 20], but increases AUC for oral midazolam by a factor of up to twofold [17, 20–23]. In contrast, an inhibitor such as ketoconazole, acting on both hepatic and enteric CYP3A, increases AUC of both intravenous and oral midazolam, but the effect on oral midazolam AUC is substantially greater [14, 18, 24–27].
In the course of drug development, new chemical entities suspected of being CYP3A inhibitors may be evaluated in clinical drug–drug interaction (DDI) studies using midazolam as the in vivo CYP3A probe compound [4–12]. The scientific value of such studies is strengthened by inclusion of a ‘positive control’ arm, intended to depict the ‘worst case scenario’ DDI. Ketoconazole is a possible choice as a positive control CYP3A inhibitor. However, recent studies suggest that CYP3A inhibition by ritonavir, even at relatively low ‘boosting’ doses, may produce CYP3A inhibition exceeding that of ketoconazole [28–35].
The present study evaluated low-dose ritonavir as an inhibitor of oral midazolam clearance, in the course of a DDI study of a medication under development. The candidate drug was 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074; formerly BXT-51072), a low-molecular-weight, orally active, organoselenium catalytic mimic of the enzyme glutathione peroxidase that is being developed for the treatment of inflammatory disorders characterized by the involvement of reactive oxygen species [36–41]. One possible indication is the treatment of acute coronary syndromes.
Previous in vitro studies have shown ALT-2074 is an inhibitor of human CYP3A, with an IC50 value in the range of 2.0–2.6 µM. This concentration might be achieved within the gastrointestinal tract or in the systemic circulation after oral administration of ALT-2074, raising the possibility that ALT-2074 might produce drug interactions with other CYP3A substrate drugs in vivo.