Pharmacokinetic and Safety Evaluation of BILR 355, a Second-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers

Metabolic Switching of BILR 355 in the Presence of Ritonavir. I. Identifying an Unexpected Disproportionate Human Metabolite

“…BILR 355 has been shown to be a good substrate of CYP3A with a relatively low apparent K m of 0.79 M and a high turnover in HLMs. Extensive first-pass metabolism by intestinal and hepatic CYP3A was proposed as an explanation for the low systemic exposure and short half-life after oral administration to humans (Huang et al, 2008). A favorable PK profile, with increased systemic exposure, was achieved after concomitant administration of the CYP3A inhibitor RTV (Huang et al, 2008) as seen with other HIV drugs (Hull and Montaner, 2011).…”

“…Extensive first-pass metabolism by intestinal and hepatic CYP3A was proposed as an explanation for the low systemic exposure and short half-life after oral administration to humans (Huang et al, 2008). A favorable PK profile, with increased systemic exposure, was achieved after concomitant administration of the CYP3A inhibitor RTV (Huang et al, 2008) as seen with other HIV drugs (Hull and Montaner, 2011). An unexpected consequence of the inhibition of this primary clearance pathway was a metabolic switching, leading to the formation of a disproportionate human metabolite.…”

“…The average CL h /Q h from four HLM lots was 82%, indicating that BILR 355 may go through extensive phase I metabolism in vivo. The apparent K m values for BILR 355 metabolism ranged from 0.63 to 1.14 M with a mean value of 0.79 M. In the clinical phase Ia study with administration of single doses of BILR 355 from 12.5 to 100 mg, C max ranged from 14.8 ng/ml (0.03 M) to 937 ng/ml (2.12 M) (Huang et al, 2008), which bracketed the range of apparent K m values shown above. Therefore, it was not surprising to see the mean exposure (AUC 0 -ϱ ) increase superproportionally (71.8 -1310 ng ⅐ h/ml) and the mean apparent clearance (CL/F) decrease (246 -79.2 l/h) over this range of doses in the phase Ia study (Huang et al, 2008).…”

“…Thus, in an attempt to overcome the resulting low exposure in humans, BILR 355 was administered with ritonavir (RTV), a potent CYP3A inhibitor previously used to boost plasma concentrations and to increase the t 1/2 of HIV protease inhibitors (Hull and Montaner, 2011). With concomitant administration of RTV, the t 1/2 of BILR 355 increased to approximately 10 to 16 h and the maximum plasma concentration (C max ) increased 2-to 5-fold with the area under the plasma concentration-time curve from time 0 to infinity (AUC 0 -ϱ ) increasing 15-to 30-fold (Huang et al, 2008), a profile more consistent with once daily dosing.…”

“…The in vitro results showed that the EC 50 of BILR 355 was 0.26 ng/ml (0.59 nM) against wild-type HIV-1 and ranged from 1.5 to 13 ng/ml (3.4 -29 nM) against clinically common single and double NNRTI mutations (Bonneau et al, 2005). A clinical study revealed that BILR 355 was rapidly absorbed after a single oral dose in healthy volunteers with the mean time to maximum drug concentration (T max ) of 0.5 to 1.5 h. However, thereafter the concentrations of BILR 355 rapidly declined, resulting in a short terminal half-life (t 1/2 ) of approximately 2 to 4 h (Huang et al, 2008). Our in vitro data demonstrated signif-icant metabolism of BILR 355 by cytochrome P450 (P450) 3A.…”