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Effect of Aprepitant on the Pharmacokinetics of Intravenous Midazolam

From Merck Research Laboratories, West Point, Pennsylvania (Dr Majumdar, Ms Yan, Ms Selverian, Dr Barlas, Mr Constanzer, Mr Dru, Dr McCrea, Ms Ahmed, Dr Petty), and the Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Frick, Dr Kraft, Dr Greenberg). Howard Greenberg is a member of the American College of Clinical Pharmacology (FCP).

Address for reprints: Jacqueline McCrea, PharmD, Merck & Co, PO Box 1000, UG4D-48, North Wales, PA 19545; e-mail: jackie_mccrea{at}merck.com.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazolam, was assessed for interaction with intravenous midazolam in 12 subjects randomized to intravenous midazolam 2 mg ± oral aprepitant 125 mg. The hypothesis was that midazolam AUC would not change by more than 2-fold (consistent with no more than weak inhibition) when midazolam + aprepitant was compared with midazolam alone. An AUC geometric mean ratio (midazolam + aprepitant/midazolam) with 90% confidence interval upper bound 2.0 (an increase in midazolam felt to be of modest clinical significance in the highly monitored perioperative period) was prespecified. Aprepitant increased intravenous midazolam AUC_0- 1.47-fold (90% confidence interval, 1.36-1.59), which fell within the prespecified criterion.

Key Words: Aprepitant • midazolam • CYP3A4 interaction • intravenous • pharmacokinetics

In vitro studies showed that aprepitant is a moderate inhibitor of cytochrome P450 3A4 (CYP3A4), with K_i values of 10 µM for the 1'- and 4-hydroxylation of midazolam and the N-demethylation of diltiazem.³ CYP3A4 is involved in the metabolic clearance of many drugs, and its activity may be induced or inhibited by various drugs. To evaluate CYP3A4 activity in humans, the drug midazolam has been used extensively as a probe. Oral midazolam undergoes extensive presystemic metabolism by both hepatic and intestinal CYP3A4 and is rapidly converted to 1'-hydroxymidazolam. Thus, the pharmacokinetics of oral midazolam can be used as a sensitive probe by which to detect changes in CYP3A4 activity caused by concomitant drugs. By determining the increase in midazolam AUC, following oral administration of midazolam, in the presence and absence of a suspected CYP3A4 inhibitor, a particular drug can be classified into a CYP3A4 inhibitor category: strong inhibitor (5-fold elevation in midazolam AUC), moderate inhibitor (>2- to <5-fold elevation in midazolam AUC), or weak inhibitor (2-fold elevation in midazolam AUC).⁴ During the development of aprepitant as an antiemetic agent for patients receiving chemotherapy, a study was conducted using oral midazolam as a probe of CYP3A4 activity. Coadministration of a single 125-mg dose of oral aprepitant caused a 2.3-fold increase in the area under the concentration-time curve (AUC) of orally administered midazolam, whereas a single 40-mg dose produced only a 1.2-fold increase in the AUC of oral midazolam (not a statistically significant effect).⁵ Thus, oral aprepitant in a 125-mg dose is categorized as a moderate inhibitor of CYP3A4, and it is possible that aprepitant could increase the plasma levels of other orally administered drugs that are metabolized by CYP3A4.

In addition to being a probe of CYP3A4 activity, midazolam is a drug given intravenously to produce sedation and reduce anxiety before surgery. Increased exposure to midazolam due to CYP3A4 inhibition could lead to prolonged sedation. In the surgical setting, patients may receive aprepitant with concomitant medications such as midazolam preoperatively. During the development program for the second indication (ie, postoperative nausea and vomiting), the current study was conducted to evaluate the effect of aprepitant 125 mg on the pharmacokinetics of midazolam under the conditions in which the 2 drugs would most likely be coadministered preoperatively. These conditions include oral administration of a single dose of aprepitant during the fasting state and intravenous (IV) administration of midazolam. The 125-mg dose of aprepitant was chosen based on the previous study in which aprepitant 40 mg produced only weak inhibition of oral midazolam (statistically insignificant 20% increase in midazolam AUC).⁵ Because the effect of a single 125-mg dose of oral aprepitant on oral midazolam is moderate CYP3A4 inhibition and because it was anticipated that the effect of this dose of aprepitant would be smaller on intravenously administered midazolam, it was reasonable to hypothesize that the effect of a single 125-mg dose of aprepitant would result in a 2-fold increase in the IV midazolam AUC (ie, weak inhibition of CYP3A4). In addition, the a priori geometric mean ratio limit of 2-fold increase in midazolam was thought to be of modest clinical significance in the highly monitored perioperative period.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
This study (aprepitant protocol 108) was conducted in healthy adults aged 18 to 45 years old who had not smoked for at least 6 months, were in general good health, and had height-appropriate weight. Women must have agreed to use contraception for the time period from at least 2 weeks before study start to the poststudy visit, and they must have had negative ß-hCG test results at prestudy and immediately before midazolam administration in each treatment period. Subjects were to refrain from consuming St John's wort and grapefruit/grapefruit juice starting from 2 weeks before study start and throughout the entire study. They were to refrain from drinking alcohol for 24 hours before the prestudy and poststudy visits, as well as for 24 hours before and 24 hours after study drug administration in each treatment period. Subjects were to avoid strenuous activity during the study and the follow-up period. All subjects provided written informed consent prior to the initiation of study procedures. The protocol was reviewed by the Institutional Review Board of Thomas Jefferson University (Philadelphia, Pa). The study was conducted at the Thomas Jefferson University Clinical Research Unit in accordance with applicable requirements regarding ethical committee review, as well as in accordance with principles derived from the Declaration of Helsinki.

Subjects were excluded if they had a significant medical or psychiatric history as determined by the investigators. Other exclusion criteria were drug/alcohol abuse, habitual and heavy caffeine consumption (>3 cups of coffee or equivalent/day), significant drug allergy, clinically significant adverse experiences related to the administration of midazolam or any other benzodiazepine, and clinically significant abnormalities on prestudy clinical or laboratory evaluations. Other exclusion criteria included regular use of prescription or nonprescription drugs, including herbal/organic/nutritional supplements or remedies that could not be discontinued at least 2 weeks before study start and for the duration of the study. This restriction applied particularly to drugs and foods known to affect CYP3A4 activity. No prescription or nonprescription drugs were to be taken within 14 days prior to the study. Other than the protocol-specified drugs under investigation, no drugs were to be taken during the study, except for investigator-prescribed acetaminophen for mild symptoms and drugs needed to treat serious adverse events.

Design
The trial was an open-label, single-center, randomized, 2-period, crossover study. The objective was to evaluate the effect of a single dose of oral aprepitant 125 mg on CYP3A4 activity as measured by the pharmacokinetics of IV midazolam. Subjects received midazolam either alone or with aprepitant in a randomized, crossover fashion. Midazolam was given as a single 2-mg dose administered intravenously over 2 minutes. Aprepitant was administered as a single 125-mg capsule 1 hour before midazolam administration. Each treatment was administered after an overnight fast. The sequence of treatments was randomly assigned, and treatment periods were separated by a 14-day washout period. A computer-generated allocation schedule was used to assign subject allocation numbers.

A complete physical examination, 12-lead electrocardiogram, vital signs, and laboratory safety tests were performed at prestudy (about 2 weeks before the first treatment period) and poststudy (about 10-14 days after the final administration of study drug or when the subject discontinued from the study). Additional vital sign measurements were taken before and 24 hours after midazolam administration.

Sample Collection and Evaluation
For evaluation of plasma midazolam levels, blood was collected into sodium heparin-containing tubes at 0 minutes (predose); 2 minutes (at the end of the midazolam infusion); 15, 30, and 45 minutes; and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after the start of the IV infusion. Samples were placed on ice and centrifuged immediately at 3500 rpm for 10 minutes at 4°C. The plasma fraction was transferred to cyrotubes that were stored at –20°C until shipped on dry ice to PPD Development (Richmond, Va) for midazolam assay. The analytical methods used were liquid-liquid extraction using methyl-t-butyl ether to isolate midazolam, followed by high-pressure liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) detection with a lower limit of quantification of 0.1 ng/mL. The assay was linear to 100 ng/mL. The internal standard was midazolam-d₄ maleate. The column was Aquasil C18, 2.1 x 100 mm, 5 µm (Thermo, Boston, Mass). The mobile phases were 80/20 acetonitrile/20 mM ammonium acetate and 0.1% formic acid in methanol. The mass transition was 326.2 to 291.4. For the quality control samples, the intra-assay precision, expressed as percentage coefficient of variation, ranged from 4.58% to 5.11%. The intra-assay accuracy ranged from –1.11% to 3.11% difference from theoretical. Plasma aprepitant levels were also determined in samples collected before aprepitant was administered and at 3 and 24 hours after midazolam was administered.⁶

Pharmacokinetic Methods
Pharmacokinetic parameters calculated for midazolam were AUC_0-, maximum plasma concentration (C_max), time to C_max (t_max), apparent terminal half-life (t_1/2), and plasma clearance (Cl_p). These parameters were analyzed by noncompartmental modeling using WinNonlin Version 4.1 (Pharsight, Mountain View, Calif). The AUC_0- and C_max were adjusted for actual doses (in milligrams) of midazolam that were administered, which were calculated by subtracting the weight (in grams) of the empty syringe after administration from the weight (in grams) of the filled syringe before administration, dividing the difference by the density of midazolam solution (assumed 1 g/mL), and then multiplying the result by the concentration of midazolam in the solution (1 mg/mL). The mean (SD) actual dose of midazolam was 1.95 (0.04) mg for administration of midazolam alone and 1.97 (0.03) mg for administration of midazolam plus aprepitant.

Statistical Methods
The study hypothesis was that pretreatment with a single oral dose of aprepitant 125 mg would not increase the geometric mean AUC_0- of IV midazolam by more than 2-fold. Specifically, the ratio of the geometric means of AUC_0- for midazolam (with aprepitant/without aprepitant) would be 2.0, based on the assumption that aprepitant would be a weak CYP3A4 inhibitor. Assuming the ratio of the geometric means was 1, a sample size of 12 (6 in each sequence) would yield a >99.9% probability ( = .05, 1-tailed) that the 90% confidence interval (CI) for the ratio of the geometric mean AUC_0- for midazolam (with aprepitant/without aprepitant) would be 2.0. The ratio could be as high as 1.7 and still have an 80% probability that the 90% CI would be 2.0. This calculation was based on a within-subject standard deviation of 0.1606 log (in ng·h/mL) in IV midazolam log AUC from a previous study (unpublished data).

To address the study hypothesis, an analysis of variance (ANOVA) model appropriate for a 2-period crossover design was used to analyze the midazolam AUC_0-. The individual midazolam AUC_0- values were natural log transformed prior to the analysis. The ANOVA model had terms for sequence, subject within sequence, period, and treatment. Carryover was assessed by testing the sequence effect at = .10. To compare the midazolam AUC_0- with and without aprepitant, the geometric mean ratio (with aprepitant/without aprepitant) with corresponding 90% CI (equivalent to a 1-sided 95% CI) was calculated based on the ANOVA model. A CI with an upper bound 2.0 would be interpreted as no more than a weak CYP3A4 inhibition according to Bjornsson et al.⁴ The plasma clearance of midazolam was analyzed in a fashion similar to that for AUC_0-. A similar inferential analysis of C_max was not considered appropriate for IV midazolam, and summary statistics were calculated instead. Summary statistics were also calculated for t_max and the apparent half-life. No multiplicity adjustments were needed because there was only 1 primary hypothesis.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Enrollment began on August 19, 2004, and the study was completed September 23, 2004. A total of 13 subjects aged 20 to 36 years old were randomized, and 12 subjects (3 men, 9 women) completed the study. One subject was discontinued due to poor venous access on day 1 of period 1, necessitating the replacement (13th) subject to be randomized. None of the subjects used concomitant medications during the study.

Figure 1 shows the mean plasma midazolam concentrations over time after the subjects received midazolam alone and with aprepitant. The geometric mean AUC_0- of midazolam was 75.0 ng·h/mL when midazolam was given alone and 110.3 ng·h/mL when it was given with aprepitant. The geometric mean ratio for AUC_0- (midazolam with aprepitant/midazolam alone) was 1.47 with a 90% CI of 1.36 to 1.59. The geometric mean plasma clearance of midazolam was 444.5 mL/min when midazolam was given alone and 302.1 mL/min when it was given with aprepitant. The geometric mean ratio for plasma clearance (midazolam with aprepitant/midazolam alone) was 0.68 with a 90% CI of 0.63 to 0.73. There were no significant sequence or period effects for AUC_0-. Table I displays additional pharmacokinetic data for IV midazolam given alone and with aprepitant.

View larger version (10K): [in this window] [in a new window]   Figure 1. Mean (± SE) plasma concentrations of midazolam when administered intravenously, alone and with a single 125-mg dose of oral aprepitant, in 12 healthy subjects.

For the plasma aprepitant concentrations, the geometric mean concentrations were 1656 ng/mL at 3 hours after midazolam administration and 636 ng/mL at 24 hours after midazolam administration.

Tolerability
All 13 subjects were included in the safety summary. Both treatments were generally well tolerated. Two subjects had clinical adverse experiences. One of these subjects, during treatment with midazolam plus aprepitant, had lightheadedness, fatigue, and disorientation, which were judged by the investigator to be probably related to study drug. The other subject, during treatment with midazolam plus aprepitant, had headache, which was judged to be not drug related. There were no serious clinical adverse experiences, and no subjects were discontinued due to adverse experiences. There were no laboratory adverse experiences. Physical examinations and electrocardiograms did not reveal any clinically meaningful differences between treatments.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Coadministration of 125 mg of oral aprepitant has been previously reported to elevate the plasma AUC of orally administered midazolam 2.3-fold on day 1 via a CYP3A4 interaction.⁵ Aprepitant is, thus, a moderate inhibitor of orally administered CYP3A4 substrates according to the classification scheme proposed by Bjornsson et al,⁴ in which oral midazolam is used as a probe substrate to determine the effect of a drug on CYP3A4 substrate drugs. According to this classification, a drug that increases the plasma AUC of orally administered midazolam is a strong CYP3A4 inhibitor (5-fold increase in midazolam AUC), a moderate CYP3A4 inhibitor (>2- to 4.9-fold increase in midazolam AUC), a weak CYP3A4 inhibitor (2-fold increase in midazolam AUC), or not a CYP3A4 inhibitor.

In the preoperative setting, the antiemetic drug aprepitant could potentially be coadministered with IV midazolam. The present study was conducted to determine whether an interaction could occur between oral aprepitant and IV midazolam. The results showed that coadministration of a single 125-mg dose of oral aprepitant with a single dose of IV midazolam increased the midazolam AUC 1.47-fold. The upper bound of the 90% CI was 1.59, which falls below the prespecified upper bound of 2.0. Although the classification scheme proposed by Bjornsson et al⁴ applies to orally administered CYP3A4 substrates, generalizing the classification scheme to IV midazolam administration would suggest that aprepitant 125 mg has a weak inhibitory effect on hepatic CYP3A4 activity, the site of IV midazolam metabolism. It would also suggest that aprepitant has less of an inhibitory effect on CYP3A4 substrates when they are administered intravenously than when they are administered orally, consistent with the product label of aprepitant.⁷

In the current study, plasma aprepitant concentrations were measured at 3 and 24 hours postmidazolam (ie, 4 and 25 hours postaprepitant). The concentrations of aprepitant at 24 hours postmidazolam were comparable to or slightly higher than historical values,⁸ and thus the weak inhibitory effect of aprepitant on IV midazolam pharmacokinetics would not be due to insufficient aprepitant exposure.

The mechanistic basis for the differential inhibitory effects of aprepitant on IV and oral midazolam metabolism is likely due to lack of inhibition of presystemic (intestinal and hepatic) metabolism of midazolam, when given intravenously, by CYP3A4. A comparison (Table II) of the oral midazolam data with and without aprepitant 125 mg that were reported earlier⁵ and the IV midazolam data with and without aprepitant 125 mg reported in the current study shows that aprepitant 125 mg increased the bioavailability of oral midazolam by 54%, which in turn consisted of a 26% increase in intestinal availability and a 22% increase in hepatic availability. (The availability estimates must be interpreted carefully because the IV and oral data are from 2 different studies, and the liver blood flow and the blood clearance to plasma clearance ratio were assigned values for all subjects.) Thus, the contributions from intestinal and hepatic presystemic inhibition of the metabolism of midazolam by aprepitant were about equal. It is also noted that the approximately 2.27-fold increase in the oral midazolam AUC when midazolam is coadministered with 125 mg of oral aprepitant consists of an approximately equal presystemic inhibition effect (1.54-fold) and systemic inhibition effect (1.47-fold). The 40-mg oral dose of aprepitant increased the AUC of oral midazolam by 1.2-fold.⁵ Based on the effects of the 125-mg dose of oral aprepitant, which showed about equal presystemic and systemic inhibition, a 40-mg oral dose of aprepitant, the dose recommended for postoperative nausea and vomiting,⁷ would have an even smaller than 1.2-fold effect on IV midazolam (ie, due to the lack of presystemic inhibition).

Clinical experience with the combination of aprepitant and IV midazolam in patients has been obtained in a double-blind study that randomized 805 patients to treatment with a single dose of oral aprepitant 40 mg, oral aprepitant 125 mg, or IV ondansetron 4 mg (active comparator) for the prevention of postoperative nausea and vomiting.^10,11 Patients were scheduled for surgery with an anesthetic regimen that included premedication with a benzodiazepine such as IV midazolam 1 to 3 mg and a narcotic such as fentanyl, both of which are CYP3A4 substrates. Safety assessments included awakening time and duration of recovery from anesthesia (including evaluation of respiratory status and sedation), which would be expected to be prolonged if aprepitant had a clinically significant interaction with midazolam or fentanyl. Of the 766 patients who received study drug, approximately 90% also received IV midazolam (data on file). Awakening time and duration of recovery were similar among the 3 treatment groups. There were no reported serious adverse events of excessive sedation and no adverse events of respiratory depression that were considered to be drug related by the investigator. Aprepitant did not appear to differ from ondansetron in terms of potential influence on the pharmacodynamics of IV midazolam or fentanyl.

In conclusion, coadministration of a single 125-mg dose of oral aprepitant with a single dose of IV midazolam in healthy subjects increased the midazolam AUC 1.47-fold (90% CI, 1.36-1.59). The clinical significance of these findings cannot be determined from the current study in healthy subjects. Safety data from a large-scale clinical study did not provide evidence for a clinical drug interaction. However, depending on clinical situations (eg, elderly patients) and the degree of monitoring available, dosing adjustments for IV midazolam may be necessary when it is coadministered with aprepitant for the chemotherapy-induced nausea and vomiting indication (aprepitant 125 mg on day 1 followed by aprepitant 80 mg on days 2 and 3).⁷

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors thank Rita Chiou for her assistance with the midazolam assay.

Financial disclosure: This study was funded by Merck Research Laboratories. K. X. Yan, D. V. Selverian, M. Constanzer, J. Dru, and J. B. McCrea are employees, and A. K. Majumdar, S. Barlas, K. J. Petty, and T. Ahmed were employees of Merck & Co, Inc, the manufacturer of aprepitant. H. E. Greenberg, G. S. Frick, and W. K. Kraft are or were employees of Thomas Jefferson University, which received funding from Merck to perform the study. G. S. Frick was enrolled in the National Institutes of Health (NIH)–supported institutional K30 Training Program in Human Investigation (K30 HL004522) and was supported by NIH institutional award T32 GM08562 for Postdoctoral Training in Clinical Pharmacology.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

1. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin. The Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21: 4112-4119.[Abstract/Free Full Text]

2. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97: 3090-3098.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Sanchez RI, Wang RW, Newton DJ, et al. Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the Substance P receptor antagonist aprepitant. Drug Metab Dispos. 2004;32: 1287-1292.[Abstract/Free Full Text]

4. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. J Clin Pharmacol. 2003;43: 443-469.[Abstract/Free Full Text]

5. Majumdar AK, McCrea JB, Panebianco DL, et al. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther. 2003;74: 150-156.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Constanzer ML, Chavez-Eng CM, Dru J, Kline WF, Matuszewski BK. Determination of a novel substance P inhibitor in human plasma by high-performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometric detection using single and triple quadrupole detectors. J Chromatogr B. 2004;807: 243-250.[CrossRef]

7. EMEND capsules (aprepitant) [product label]. West Point, Pa: Merck; 2006.

8. Nygren P, Hande K, Petty KJ, et al. Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol. 2005;55: 609-616.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Xie R, Tan LH, Polasek EC, et al. CYP3A and P-glycoprotein activity induction with St. John's wort in healthy volunteers from 6 ethnic populations. J Clin Pharm. 2005;45: 352-356.[CrossRef]

10. Gan TJ, Apfel C, Kovac A, Philip B, Lawson F. The NK1 receptor antagonist aprepitant for prevention of postoperative nausea and vomiting [abstract]. Anesthesiology. 2005;103: A769.

11. Gan TJ, Apfel CC, Kovac A, et al. A randomized, double-blind comparison of the NK₁ antagonist, aprepitant versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg. In press.
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This Article Abstract Full Text (PDF) All Versions of this Article: 0091270007300807v1 47/6/744    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Majumdar, A. K. Articles by Greenberg, H. E. Search for Related Content PubMed PubMed Citation Articles by Majumdar, A. K. Articles by Greenberg, H. E. Social Bookmarking                   What's this?