Reduced Pupil Diameter in Volunteers on Stable Buprenorphine Maintenance Therapy with Telaprevir: a Drug-Drug Interaction Involving P-Glycoprotein at the Blood-Brain Barrier?

LETTER

Luo et al. investigated the effects of telaprevir on the pharmacokinetics (PK) of buprenorphine (BUP) and norbuprenorphine (NBUP) in volunteers on stable BUP/naloxone maintenance therapy (4). Regarding BUP, they reported a telaprevir-induced decrease in the maximum concentration (C_max) (∼20%) and the minimum concentration (C_min) (∼6%) despite no modifications in the time to the maximum concentration (T_max) and the area under the concentration-time curve from 0 to 24 h (AUC_{0-24 h}). Regarding NBUP, they described a telaprevir-induced decrease in C_max (∼15%), with increased T_max (+5 h) and decreased C_min (∼6%) and AUC_{0-24 h} (∼9%). These modifications were accompanied by a significant reduction in pupil diameter without serious events and withdrawal symptoms, supporting an unnecessary dose adjustment when coprescribing BUP/naloxone and telaprevir.

We agree that alterations in plasma PK were small, related to the overall variability in PK parameters, thus devoid of pertinent clinical consequences. The absence of alteration in NBUP-to-BUP ratios of C_max and AUC_{0-24 h} ruled out significant metabolic interactions between telaprevir and BUP, even if BUP is metabolized into NBUP by hepatic cytochrome P450 (CYP) 3A4 (3) and telaprevir is both a CYP3A substrate and inhibitor (2). The lack of a drug-drug interaction between BUP metabolism into NBUP and telaprevir is probably due to the route of BUP administration since sublingual absorption is not dependent on hepatic first-pass metabolism. However, although we agree that the interpretation of outpatient pupil diameter during the safety follow-up period could not be trusted since BUP is frequently misused by opioid abusers (6), we believe that the decrease in pupil diameter observed at the study site 4 h after the coadministration of telaprevir and BUP/naloxone in comparison to BUP/naloxone alone at 4 h postdose on day 1 was misinterpreted. This observation cannot be explained by the mild decrease in plasma BUP and NBUP concentrations when combining BUP/naloxone and telaprevir, which would have increased pupil diameters. However, the hypothesis of possible effects of better inpatient adherence with medications, resulting in more consistent plasma concentrations, was not supported by the data.

Another mechanism of interaction between both drugs likely explains this effect. NBUP, in contrast to BUP, is a substrate of human P-glycoprotein (7), a drug transporter involved in all PK steps, including efflux transport at the blood-brain barrier (BBB). We demonstrated that the BUP-related respiratory effects in mice were significantly increased in relation to reduced NBUP efflux at the BBB, with either P-glycoprotein pharmacological inhibition or gene disruption (1). Telaprevir, a P-glycoprotein inhibitor (2), may thus decrease NBUP efflux at the BBB in BUP/naloxone-treated patients. Such alteration in brain NBUP distribution cannot be detected by measuring plasma concentrations, whereas the absence of significant modifications in total exposure to BUP and NBUP (represented by AUC_{0-24 h}) ruled out any significant P-glycoprotein-mediated effects on BUP absorption or elimination.

We hypothesize that a decreased pupil diameter corresponded to the pharmacodynamic expression of the telaprevir-induced inhibition of P-glycoprotein-mediated NBUP transport at the BBB. This interaction, when using the recommended doses of BUP, has limited consequences, supporting the notion that telaprevir and BUP/naloxone can be safely coadministered. However, despite limited analgesic activity, NBUP acts as a full mu-opioid receptor agonist, displaying marked respiratory toxicity compared to BUP (5, 8). Consequently, if BUP is misused, such P-glycoprotein-mediated drug-drug interactions may result in sedation and respiratory depression. Physicians should be aware of possible increased toxicity if telaprevir-treated patients misuse BUP.