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Anesth Analg 2002;95:667-673
© 2002 International Anesthesia Research Society

PAIN MEDICINE

The Influence of Parecoxib, a Parenteral Cyclooxygenase-2 Specific Inhibitor, on the Pharmacokinetics and Clinical Effects of Midazolam

Andra Ibrahim, MD*, Aziz Karim, PhD{ddagger}, Jennifer Feldman, BA*, and Evan Kharasch, MD PhD*{dagger}

Departments of *Anesthesiology and {dagger}Medicinal Chemistry, University of Washington, Seattle, Washington; and {ddagger}Pharmacia, Inc., Skokie, Illinois

Address correspondence and reprint requests to Evan D. Kharasch, MD, PhD, Department of Anesthesiology, University of Washington, Box 356540, 1959 NE Pacific, RR-442, Seattle, WA 98195. Address e-mail to kharasch{at}u.washington.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Parecoxib, a parenteral cyclooxygenase-2 inhibitor, is undergoing clinical development as an analgesic/antiinflammatory drug for perioperative use. Parecoxib, an inactive prodrug, is hydrolyzed in vivo to valdecoxib, a substrate for hepatic cytochrome P450 (CYP) 3A4. Thus, potential exists for interactions with other CYP3A4 substrates. In this investigation, we determined the influence of parecoxib on the pharmacokinetics and clinical effects of midazolam, a CYP3A4 substrate, in volunteers. This was a randomized, balanced crossover, placebo-controlled, double-blinded clinical investigation. Twelve healthy subjects aged 23–41 yr were studied after providing IRB-approved informed consent. Midazolam 0.07 mg/kg IV infusion was administered 1 h after placebo (control) or parecoxib 40 mg IV. Venous midazolam concentrations were determined by using liquid chromatography-mass spectrometry/mass spectrometry assay. Pharmacokinetic variables were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical end-points, cognitive function (memory; digit symbol substitution tests), subjective self-assessment of recovery (visual analog scales), and bispectral index. Midazolam plasma concentrations were similar between placebo and parecoxib-treated subjects. No differences were found in midazolam pharmacokinetics (maximal observed plasma concentration, clearance, elimination half-life, volume of distribution) or pharmacodynamics (clinical end-points, digit symbol substitution tests, memory, visual analog scales, bispectral index). Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam infusion. Parecoxib did not affect CYP3A4 activity as assessed using midazolam clearance as the in vivo probe.

IMPLICATIONS: Parecoxib, a parenteral cyclooxygenase-2 inhibitor intended for perioperative use as an analgesic/antiinflammatory drug, is a substrate for hepatic cytochrome P450 3A4. The potential for a drug interaction with midazolam, an in vivo CYP3A4 probe, was tested in healthy volunteers. Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Parecoxib is a highly selective nonsteroidal cyclooxygenase-2 (COX-2) inhibitor undergoing clinical development, with intended perioperative use as an analgesic/antiinflammatory drug (1,2). Parecoxib is a parenterally administered inactive prodrug, which undergoes rapid hydrolysis in vivo to the pharmacologically active COX-2 inhibitor, valdecoxib (2). Parecoxib has analgesic properties similar to ketorolac after oral surgery, hysterectomy, and orthopedic surgery (3–5). However, parecoxib has a significantly decreased incidence of untoward side effects. For example, the incidence of gastroduodenal ulcers with parecoxib was significantly less than with ketorolac and no different than placebo (1,6). Furthermore, arachidonate-induced platelet aggregation is not inhibited with parecoxib, in contrast to ketorolac (7). Fractional sodium excretion was decreased in subjects receiving parecoxib; however, the decrease was not as large as that observed in subjects receiving ketorolac.

Valdecoxib is a substrate for hepatic cytochrome P450 3A4 (CYP3A4), and CYP3A4 is greatly susceptible to drug interactions (8–12). Consequently, a potential exists for parecoxib (valdecoxib) interactions with other CYP3A4 substrates. Midazolam is a CYP3A4 substrate (13), and the systemic clearance, magnitude, and duration of effect of IV midazolam are highly susceptible to CYP3A4 drug interactions (8–10).

The potential for a drug interaction between parecoxib and midazolam was studied for three reasons. First, midazolam is routinely used perioperatively as a sedative and/or anesthetic, thus, unexpected interference with midazolam clearance would unacceptably prolong midazolam clinical effects. Second, midazolam is a well-characterized and validated noninvasive probe for CYP3A4 activity, and is used to probe for CYP3A4 drug interactions (14). Third, prudence and safety considerations warrant evaluation of a potential interaction between parecoxib and midazolam. Therefore, the effects of parecoxib on the pharmacokinetics (systemic clearance) and pharmacodynamics (hypnotic effects, recovery profile) of midazolam were determined.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Thirteen healthy subjects (6 men, 7 women) within 30% of normal body weight, were studied after providing IRB-approved written informed consent. The average age, height, and weight was 31 ± 5 yr, 172 ± 9 cm, and 75 ± 13 kg, respectively. Individuals were excluded if they were pregnant, taking benzodiazepines, barbiturates, opioids, nonsteroidal antiinflammatory drugs, or drugs known to cause induction or inhibition of hepatic enzymes. All subjects fasted for a minimum of 6 h before the initiation of study. To detect a 35% difference in mean clearance between parecoxib and placebo with 80% power at a significance level of 0.05, a sample size of 12 subjects was needed (15,16).

This design was a randomized, balanced crossover, placebo-controlled, double-blinded clinical investigation. Each subject served as his or her own control and underwent physical and laboratory examination (hematology, biochemistry, urinalysis, hepatitis B surface antigen test, drug toxicology tests) both before the initiation and after the completion of the study.

Each subject received IV midazolam 0.07 mg/kg administered by an infusion pump over 5 min on 2 occasions: 1 h after placebo (normal saline) and 1 h after parecoxib 40 mg IV. The dose of parecoxib administered was the intended clinical dose. The sequence was randomized and the 2 sessions were separated by 7–14 days. For each drug administration, 2 20-g peripheral IV catheters were inserted in a vein for drug administration and blood sampling (separate arms). Supplemental oxygen and monitoring (electrocardiogram, blood pressure, pulse oximetry) were provided for all subjects. A trained independent observer, who was blinded to the purpose of the investigation and the identity of the drug pretreatment, was present throughout the study period to record hemodynamic and other effect data, and administer the psychomotor tests. The end of the midazolam infusion was designated as time 0. Venous blood samples were obtained at baseline, 2, 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, 540, and 600 min after midazolam administration. Samples were centrifuged, plasma was removed, and samples were stored at -20°C until analysis.

Plasma midazolam and 1-hydroxymidazolam concentrations were determined using a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assay. In brief, the internal standard triazolam was added to plasma samples, then processed by liquid-liquid extraction. The evaporated and reconstituted samples were injected into a SCIEX API3000 LC/MS/MS equipped with a short high-pressure liquid chromatography column. Analytes were detected with multiple reaction monitoring. Quantification was performed using peak area ratios and standard curves (with 1/x2 linear least squares regression) prepared from calibration standards. Separate curves were used for the two analytes. The lower limits of quantitation were 1.0 ng/mL for midazolam and 0.1 ng/mL for 1-hydroxymidazolam.

Plasma concentrations of parecoxib, valdexocib, and 1-hydroxyvaldecoxib were determined by high-pressure liquid chromatography with tandem mass spectrometry using a validated assay conducted according to Good Laboratory Practice. After adding the 13C6 respective internal standards, plasma was extracted by using a C8 solid phase extraction column. Analytes (>98% recovery) were separated by reversed-phase liquid chromatography on a C18 column, detected by multiple reaction monitoring, and quantified by using standard curves of peak area ratios (using respective internal standards). Assay ranges were 0.5–200 ng/mL for valdecoxib and 1-hydroxyvaldecoxib and 5–2000 ng/mL for parecoxib. Coefficients of variation for valdecoxib, 1-hydroxyvaldecoxib, and parecoxib were 10%, 9%, and 3% (interday) and 14%, 9%, and 12% (intraday) at the limit of quantitation.

Times at which subjects reached predefined clinical end-points (relative to the end of the midazolam infusion) were recorded by the blinded observer: loss of response to voice command, loss of eyelash reflex, eye opening, and return of response to voice command. Speed of awakening and return of preoperative baseline cognitive function were assessed by using the digit symbol substitution test (DSST) (17,18) and a memory test. These tests were given at baseline (before parecoxib/placebo), before midazolam infusion, and 10, 30, 60, 120, and 240 min after the end of midazolam administration. The DSST score represents the number of correct substitutions completed in 90 s. For the memory test, each subject listened, through headphones, to a prerecorded tape consisting of 16 nouns balanced on word frequency and normative free recall (19–21) and were asked to immediately recall as many words as possible. A different tape recording with a different list of nouns was presented each time the memory test was administered. The memory test was scored by the number of correct words recalled.

Subjective self-assessment of sedation, nausea, and anxiety was quantified by using the visual analog scale (VAS). Attributes assessed (and scored from 0 to 100) included level of alertness/sedation (almost asleep to wide awake), energy level (no energy to full of energy), confusion (confused to clear headed), clumsiness (extremely clumsy to well coordinated), anxiety (calm/relaxed to extremely nervous), and nausea (no nausea to worst nausea). These three tests (VAS, memory, DSST) were given at baseline (before parecoxib/placebo), before midazolam infusion, and 10, 30, 60, 120, and 240 min after the end of midazolam administration.

The electroencephalogram signal was acquired by using the bispectral index (BIS) sensorTM (Aspect Medial Systems, Natick, MA) electrodes applied to the forehead and temple using a frontal-temporal montage and the BIS monitor(software version 3.0, model A1050; Aspect Medical Systems). BIS values (with 30-s smoothing) were recorded every 5 s by using an IBM-compatible computer connected by serial cable. Data were recorded by using Hyperterm (Windows 95; Microsoft, Redmond, WA) and values were displayed by using Excel 97 (Microsoft). The BIS monitor was applied before parecoxib/placebo administration. BIS scores at intervals corresponding to blood sampling times during emergence were compared with baselines before and after parecoxib/placebo administration for recovery of anesthetic effect.

Midazolam plasma concentration-time data for each participant were analyzed by noncompartmental analysis using a 5-min IV infusion model for determination of pharmacokinetic variables using SAS, release 6.12 (SAS Institute Inc., Cary, NC). Terminal elimination half-life (T1/2) was estimated by using linear regression of the log concentration versus time curve, systemic clearance was calculated as dose/area under the plasma time-concentration time curve (AUC), and steady-state volume of distribution (VDss) was calculated as dose · AUMC/AUC (2). Variables were compared between groups by using Student’s paired t-test.

For midazolam and 1-hydroxymidazolam pharmacokinetic variables, an analysis of variance (ANOVA) was performed on the AUC, maximal observed plasma concentration (Cmax), time to maximal plasma concentration, T1/2, terminal elimination rate constant, plasma clearance (CL), and VDss. AUCs, Cmax, CL, and VDss were natural log-transformed before the ANOVA. In the ANOVA model, sources of variation included were sequence (1 or 2), subjects nested within sequence, period (1 or 2), and treatment (placebo versus parecoxib). Effects by subject were random whereas all other effects were fixed. Sequence effect was tested by subject nested within sequence as between-subject error term in the denominator of the F-statistic. All other effects were tested by within-subject mean square error from the ANOVA model. Within the ANOVA, a pairwise comparison was performed to assess whether pretreatment with parecoxib before midazolam had any effect on pharmacokinetics of midazolam or 1-hydroxymidazolam. By using the standard error estimate on the difference obtained from the ANOVA, 90% and 95% confidence intervals for the difference between the 2 treatments were calculated. The differences and lower and upper limits of the 90% and 95% confidence intervals were exponentiated to obtain the ratios of mean and confidence intervals in the original scale.

Wilcoxon’s signed rank test was performed for clinical end-points (times to: loss of response to voice command, loss of eyelash reflex, eye opening, and return of response to voice command). ANOVA was performed on BIS area under the percent decrement versus time curves, maximal observed percent decrement (Emax), time to Emax, and time to return to baseline. Percent decrement at time t is defined as 100 · (baseline score - score at time t)/baseline score. Two-way repeated-measures ANOVA was performed on VAS, DSST, and memory tests using treatment groups and measurement times as factors, and their interactions. Student-Newman-Keuls method for multiple comparison was used. Pharmacodynamic data were analyzed according to an inhibitory sigmoid Emax effect model by using WinNonlin 3.0 (Pharsight Corp., Mountain View, CA). BIS versus venous plasma midazolam data were fit to the following equation: E = Emax - ( Emax - E0) · C{gamma}/(C{gamma} + EC50{gamma}). Results were reported as mean ± SD. All statistical tests were performed at {alpha} = 0.05 level.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Thirteen subjects were enrolled into the study. One woman took ibuprofen for flu symptoms 2 days after receiving midazolam and placebo (a protocol violation) and voluntarily withdrew from the study. Twelve subjects (six men, six women) completed the study. All subjects were included in the descriptive statistics for the pharmacokinetic and pharmacodynamic variables (n = 12 for parecoxib, n = 13 for placebo). All available data from subjects who completed both treatment periods were included in the pharmacokinetic and pharmacodynamic statistical analyses (n = 12).

Midazolam and 1-hydroxymidazolam plasma concentrations in the control and parecoxib-treated subjects were superimposable (Fig. 1). There was no significant difference between parecoxib and controls in any midazolam pharmacokinetic variable (Table 1). Ratios of the midazolam geometric least squares means for plasma AUC, Cmax, and CL values ranged from 0.934 to 1.071, and 90% confidence intervals for the AUC, Cmax, and CL ratios were contained within the bioequivalence limits of (0.80, 1.25), indicating that the two treatments were bioequivalent (data not shown). No significant difference was found in midazolam clearance (Fig. 2A) or 1-hydroxymid-azolam/midazolam AUC ratio between parecoxib pretreatment and placebo (Fig. 2B). Parecoxib and metabolite concentrations are presented in Figure 3.



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  		Figure 1. Midazolam (circles) and 1-hydroxymidazolam (triangles) plasma concentrations after parecoxib (solid symbols and line) compared with placebo (open symbols and dotted line) pretreatments. Time 0 designates the end of the midazolam infusion (0.07 mg/kg over 5 min). Mdz = midazolam, 1-OH-mdz = 1-hydroxymidazolam.

 

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  		Table 1. Table 1. Midazolam and 1-Hydroxymidazolam Pharmacokinetic Variables
 


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  		Figure 2. The effect of parecoxib on midazolam clearance (A) and the area under the plasma time-concentration time curve (AUC) ratio of 1-hydroxymidazolam/midazolam (B). Each pair of points represents data from an individual subject. Also shown are mean ± SD.

 


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  		Figure 3. Plasma concentrations of parecoxib and its metabolites, valdecoxib and 1-hydroxyvaldecoxib. Time 0 designates the administration of parecoxib bolus. 1-OH-valdecoxib = 1-hydroxyvaldecoxib.

 
Parecoxib had no effect on any pharmacodynamic measure; BIS, DSST, memory, and VAS scores were similar before and after parecoxib. Parecoxib had no influence on the clinical effects of midazolam and did not alter clinical end-points (loss of response to voice, loss of eyelash reflex, eye opening, return of response) compared with placebo (Table 2). BIS scores after midazolam administration were similar after placebo and parecoxib pretreatments (Fig. 4). The percent decrement in BIS score at each time point was determined for each subject and mean effect variables were calculated. No significant differences were noted between treatments for any BIS variable (area under the percent decrement versus time curves, Emax, and time to Emax based on the percent decrement versus time curve).


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  		Table 2. Table 2. Midazolam Clinical Effects
 


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  		Figure 4. Bispectral index (BIS) scores after midazolam infusion in parecoxib (solid symbols and line) compared with placebo (open symbols and dotted line) pretreatments. Time 0 designates the end of the midazolam infusion.

 
DSST scores were not different between parecoxib and placebo at any time point. Ten minutes after the end of midazolam infusion, mean DSST scores decreased to 31 and 25 in the parecoxib and placebo groups, respectively. After both treatments, mean DSST scores returned to baseline by 2.5 h after midazolam administration. Memory scores were not different between treatment groups at any time point. Ten minutes after the end of midazolam infusion, mean scores decreased to two in both groups. Memory test scores returned to baseline at 1.6 h after parecoxib and 2 h after placebo. No significant differences were noted for any of the VAS pharmacodynamic variables (anxiety, clumsiness, confusion, energy level, sedation) between groups at any time point (data not shown). The influence of parecoxib on midazolam pharmacodynamics was determined by comparing BIS-midazolam concentration relationships after parecoxib versus placebo ( Fig. 5). Data were fit to an inhibitory sigmoid Emax model. The midazolam 50% effective concentration (EC50) for BIS effects (±SE of the estimate) was 74 ± 61 and 52 ± 41 ng/mL, respectively, for parecoxib and placebo (P = not significant). Although an Emax model was used, the dose of midazolam was not large enough to achieve a true Emax; hence, there is inaccuracy in our variable estimates (EC50, Emax). Nevertheless, the primary comparison was between groups, for which there was no difference in variable estimates.



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  		Figure 5. Bispectral index (BIS)-midazolam concentration-effect relationships. Solid and open circles represent parecoxib and placebo pretreatments, respectively. Nonlinear regression using an inhibitory sigmoid maximal observed percent decrement (Emax) model yielded Emax, 50% effective concentration, E0, and {gamma} (±SE of the estimate) of 97 ± 2, 74 ± 61 ng/mL, 70 ± 10 and 1.0 ± 0.52 for placebo and 97 ± 2, 52 ± 41 ng/mL, 72 ± 9 and 0.97 ± 0.55 for parecoxib, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this investigation, we tested the hypothesis that parecoxib, an inactive prodrug designed to enable parenteral administration of the active highly selective COX-2 inhibitor, valdecoxib, is involved in significant drug interactions with midazolam. Because midazolam and parecoxib are both designed for pre- and perioperative administration, examining the potential for drug interactions has significant clinical relevance. Valdecoxib is a CYP3A4 substrate, and CYP3A4 is susceptible to drug interactions (11,12). Midazolam is also a CYP3A4 substrate (13), and the systemic clearance, magnitude, and duration of effect of IV midazolam are highly susceptible to CYP3A4 drug interactions. For example, compared with placebo-treated subjects, those pretreated with the CYP3A4 inhibitor, ketoconazole, who were administered midazolam had peak plasma concentrations fourfold larger, were significantly more drowsy, and had worse cognitive function (measured by VAS, DSST) for six hours after receiving midazolam (9). Furthermore, when midazolam was administered to subjects also receiving troleandomycin (a CYP3A4 inhibitor), systemic clearance of midazolam was decreased by 75% and T1/2 increased threefold (10). Thus, unexpected interference with midazolam clearance could unacceptably prolong midazolam clinical effects. Midazolam is a validated noninvasive in vivo probe for CYP3A4 activity (14).

Parecoxib is rapidly bioactivated to valdecoxib by amide hydrolysis of the sulfonamide propionate substituent (2,22). Peak valdecoxib concentrations occur approximately 20 minutes after parecoxib injection. Valdecoxib can also be administered orally (23). Parecoxib hydrolysis in humans is mainly mediated by hepatic microsomal carboxylesterases, but parecoxib is stable in human plasma, suggesting that nonenzymatic hydrolysis and plasma esterases or amidases are not involved in amide hydrolysis to valdecoxib. Valdecoxib is extensively metabolized in humans, with only 2% excreted unchanged in urine (22). The main route of valdecoxib phase I metabolism is hydroxylation of the methyl group on the isoxazole ring primarily by CYP3A4 to form 1-hydroxyvaldecoxib, which is pharmacologically active (22). Plasma 1-hydroxyvaldexocib concentrations are approximately one-tenth those of valdecoxib.

The results of this investigation showed that there was no significant effect of parecoxib on pharmacokinetics, clinical effects, or pharmacodynamics of midazolam. Plasma midazolam disposition was similar between placebo and parecoxib-treated subjects and no significant differences between groups were seen in Cmax, systemic CL, T1/2, or VDss. There was no clinically significant interaction as evidenced by clinical end-points, BIS scores, DSST, memory, or VAS scores. Finally, there was no evidence of a pharmacodynamic interaction, because parecoxib had no influence on the BIS-midazolam concentration relationship when compared with placebo. Thus, there was no interaction between parecoxib and midazolam. Using midazolam as an in vivo probe, parecoxib/valdecoxib had no effect on hepatic CYP3A4 activity.

There are a few limitations to this investigation. Midazolam is not a perfect CYP3A4 probe. It is possible that a CYP3A4 substrate exists that would be more sensitive to CYP3A4 inhibition than midazolam; thus, a parecoxib drug interaction may occur although midazolam was unaffected. Furthermore, only 70% of total midazolam clearance is accounted for by hepatic 1'-hydroxylation. Variability in the remaining 30% can influence midazolam clearance without reflecting true CYP3A activity (14). Moreover, as an intermediate extraction drug, midazolam’s clearance is also influenced by hepatic blood flow, not just by metabolism (24). Other potential limitations include the use of venous rather than arterial plasma midazolam concentrations, although there would still be a significant delay between arterial and effect-site (brain) midazolam concentration. Measured venous concentrations were nearly identical in both groups; thus, it is unlikely that arterial measurements would have shown a different result. Furthermore, our investigation did not intend to develop either a full arterial pharmacokinetic-pharmacodynamic model for midazolam or to capture the hysteresis curve. Hence, we did not perform arterial sampling. Rather, our goal was to compare midazolam concentration-effect relationships after placebo versus parecoxib, which is a model-independent comparison. Moreover, Tuk et al. (25) analyzed arterial and venous concentration-effect relationships in rats receiving a midazolam infusion and found that significant hysteresis was observed in the arterial but not the venous concentration-effect relationships. This was suggested to occur because the delay from the arterial to the effect site was masked by the delay from the arterial to the venous sampling site; thus, minimal hysteresis was observed in the venous concentration-effect relationship of midazolam. Significant arteriovenous concentration differences did not result in biased pharmacodynamic estimates because the effect relevant elimination rate constant of midazolam is relatively small compared with its equilibration rate constant (25). Measuring depth of sedation with BIS during the induction of anesthesia and rapidly changing midazolam concentrations has not been validated. BIS records data every 5 seconds but smoothes data over 30 seconds. Thus, BIS is not capable of measuring the second-to-second changes that occur during the induction of anesthesia and is not used to define the precise onset of loss of consciousness or onset of anesthesia. However, because recovery from bolus midazolam takes minutes (rather than seconds), BIS may be a better measure of recovery rate. The use of smoothing will also introduce a delay in the plasma concentration-effect relationship; however, this delay is present equally in both groups and probably did not affect the end result.

In summary, these results show that single-bolus parecoxib, in doses expected to be used perioperatively, does not alter the disposition of midazolam infusion. Single-bolus parecoxib does not alter the magnitude or the time course of bolus midazolam clinical effects. Using midazolam as an in vivo probe, parecoxib/valdecoxib had no effect on hepatic CYP3A4 activity.


   Acknowledgments
 
Supported by Pharmacia, Inc. and by National Institutes of Health Grants K24DA00417 and M01RR00037 to the University of Washington General Clinical Research Center.

The authors thank Aspect Medical Systems for the use of their bispectral index monitor, cable, software, and assistance with this investigation.


   Footnotes
 
EK has received speaking honoraria from, and consulted for, Pharmacia, Inc.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 13, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press