title: Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers.
abstract: BACKGROUND
  Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam, a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions can be expected in patients who are concurrently receiving inhibitors and substrates of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam). Because of the potential for drug interactions, it is important to determine the effects of posaconazole on the pharmacokinetic properties of midazolam.
  
  
  OBJECTIVE
  The aim of this study was to compare the effects of oral administration of posaconazole versus ketoconazole on the pharmacokinetic properties of orally and intravenously administered midazolam.
  
  
  METHODS
  This Phase I, randomized, open-label, crossover study was conducted at Swiss Pharma Contract Ltd., Allschwil, Switzerland. Healthy volunteers were randomly assigned to 1 of 2 treatment arms. Arm 1 received posaconazole 200 mg BID for 7 days, posaconazole 400 mg BID for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg once daily for 7 days. Arm 2 received posaconazole and ketoconazole in the reverse order, with a 28-day washout between treatments. An oral/IV midazolam sequence (oral midazolam 2 mg and IV midazolam 0.4 mg) was administered on days -2/-1, 6/7, 13/14 (arm 1), 36/17 (arm 2), 43/44, and 50/51 in both treatment arms. Blood samples were collected up to 24 hours after midazolam administration. Pharmacokinetic parameters, including C(max), C(min) (before azole administration), terminal-phase t(1/2) (t(1/2z)), and AUC to final measurable sampling time (AUC(tf)), were calculated using noncompartmental methods, and drug interactions were evaluated using analysis of variance. Adverse events were collected using physical examination, including vital sign measurements; clinical laboratory analysis; electrocardiography; and direct questioning at predefined time points throughout the study to assess tolerability.
  
  
  RESULTS
  A total of 12 subjects were enrolled (11 men, 1 woman; all white; mean age, 42.8 years [range, 28-53 years]; mean weight, 80.6 kg; and mean body mass index, 25.6 kg/m(2)). All of the subjects completed the study. Based on point estimates of logarithm-transformed data, posaconazole 200 and 400 mg BID were associated with significant increases in midazolam C(max) (up to 1.3- and 2.4-fold) and AUC(tf) values (up to 4.6- and 6.2-fold), respectively. Ketoconazole 400 mg once daily was associated with significantly increased midazolam C(max) and AUC(tf) (up to 2.8- and 8.2-fold, respectively). When midazolam was concurrently administered with either azole, t(1/2z) was prolonged. Seven of 12 (58%) subjects reported > or =1 adverse event during the study (5 with posaconazole alone and 4 with posaconazole + midazolam). The most common adverse events were diarrhea (3 subjects [25%] with posaconazole alone, 2 [17%] with ketoconazole alone, and 1 [8%] with posaconazole + midazolam) and flatulence (1 [8%] with posaconazole alone and 1 [8%] with midazolam alone).
  
  
  CONCLUSIONS
  The results from this study in a small, all-white population of healthy volunteers suggest that posaconazole was a potent inhibitor of CYP3A4, but to a lesser extent than was ketoconazole. Monitoring patients for adverse events, the need for dose adjustments, or both during coadministration with posaconazole may be warranted in patients being treated with benzodiazepines that are predominantly metabolized through CYP3A4 (eg, midazolam).
authors.affiliation: Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. gopal.krishna@spcorp.com
authors.forename: Gopal
authors.initials: G
authors.lastname: Krishna
authors.forename: Allen
authors.initials: A
authors.lastname: Moton
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Ishani
authors.initials: I
authors.lastname: Savant
authors.forename: Monika
authors.initials: M
authors.lastname: Martinho
authors.forename: Michael
authors.initials: M
authors.lastname: Seiberling
authors.forename: James
authors.initials: J
authors.lastname: McLeod
mesh_terms: D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D014230:Triazoles; C101425:posaconazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D007654:Ketoconazole