Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction

Abstract

Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.

Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management

“…A 5-day oral pretreatment with voriconazole (400 mg twice daily on the first day and 200 mg twice daily thereafter) increased the mean AUC (0–infinity) of buprenorphine 1.80-fold ( P <0.001), C max 1.37-fold ( P <0.013), and half-life ( t ½ ) 1.37-fold ( P <0.001). Posaconazole appeared to have a weaker DDI with buprenorphine compared to voriconazole because its treatment (400 mg twice daily for 5 days) increased the AUC 0–∞ of buprenorphine 1.25-fold ( P <0.001) 39. The underlying DDI mechanism may be probably via inhibition of CYP3A4-mediated N -dealkylation of buprenorphine.…”

“…Evidence derived from RCTs included in this review were as follows: (1) morphine has a significant DDI with gabapentin rather than gabapentin enacarbil;21,22 (2) itraconazole rather than terbinafine has minimal effects on tramadol pharmacokinetics;50 (3) escitalopram rather than paroxetine less likely affects the pharmacokinetic and pharmacodynamic effect of tramadol;57,61 (4) buprenorphine rather than methadone has minimal effect on zidovudine disposition;23,24 (5) buprenorphine transdermal system rather than sublingual buprenorphine seems unlikely to be affected by coadministration of CYP3A4 inhibitors;39,40 and (6) tramadol rather than extended-release formulation of hydrocodone bitartrate and oxycodone interact with paroxetine 57–60…”

Voriconazole greatly increases the exposure to oral buprenorphine

“…In view of our previous studies [12,32], it was calculated that ten subjects would be needed to detect a 30% difference in the area under the plasma concentration-time curve (AUC 0-∞ ) of buprenorphine at a power of 80% and level of significance of P < 0.05. To also consider potential dropouts, we recruited 12 healthy non-smoking volunteers (4 females and 8 men; age range 18 to 29 years; body mass index from 20.5 to 27.8 kg/ m 2 ).…”

“…The bioavailability is higher, about 15-30%, when buprenorphine is administered sublingually [7,8]. The mean time to maximum plasma concentration following sublingual administration varies from 1 to 3 h [9][10][11][12]. After an oral and sublingual buprenorphine administration, extensive first-pass metabolism and large interindividual variability increase the susceptibility to drug interactions.…”

<i>C</i>-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics

“…For example, since buprenorphine is metabolized by CYP3A4, a CYP isozyme involved in metabolism of a wide variety of medicines, buprenorphine occasionally received the effects of a drug-drug interaction with some medicines such as anti-human immunodeficiency virus (HIV) drugs (protease inhibitors), 15) benzodiazepines, 16) and azole antifungals. 17,18) Additionally, buprenorphine is hardly administered orally because it extensively suffers from a first pass effect. 19,20) Indeed, buprenorphine is developed as suppository or injectable, sublingual, transdermal formulation.…”