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DRUG METABOLISM

The Effect of Oral Pleconaril on Hepatic Cytochrome P450 3A Activity in Healthy Adults Using Intravenous Midazolam as a Probe

Joseph D. Ma, PharmD, Anne N. Nafziger, MD, MHS, Gerry Rhodes, PhD, Siyu Liu, MD, PhD, Anne M. Gartung, MS, FNP and Joseph S. Bertino, Jr, PharmD, FCP

From the Clinical Pharmacology Research Center, Research Institute (Dr Ma, Dr Nafziger, Ms Gartung, Dr Bertino), and the Department of Medicine (Dr Nafziger, Dr Bertino), Bassett Healthcare, Cooperstown, New York; and ViroPharma Incorporated, Exton, Pennsylvania (Dr Rhodes, Dr Liu).

Address for reprints: Joseph S. Bertino, Jr, PharmD, FCP, ORI Drug Development Center, Ordway Research Institute, Inc, 150 New Scotland Avenue, Albany, NY 12208.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single-dose, IV midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS-GMR) with 90% confidence intervals (90% CIs) for the measured midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased midazolam AUC0-{infty} 28% and increased systemic clearance 39%. LS-GMR (90% CI) were 0.718 (0.674-0.765) and 1.392 (1.307-1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in midazolam AUC0-{infty} and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.

Key Words: Pleconaril • cytochrome P450 • CYP3A

Members of the Picornaviridae family include rhinoviruses and enteroviruses.1 Various viruses are associated with the common cold, with rhinoviruses implicated in up to 80% of reported cases.1 Rhinoviruses also contribute to acute exacerbation of asthma and chronic obstructive pulmonary disease.2,3 Enteroviruses cause approximately 10 to 15 million infections annually and are the most common cause of viral meningitis.4 Other infections associated with enteroviruses include encephalitis, myocarditis, and hemorrhagic conjunctivitis.5,6

Pleconaril is a novel, oral antipicornaviral agent. Pleconaril inhibits viral function by integrating into the hydrophobic pocket of the virus capsid, thereby affecting capsid conformational stability.7 Viral attachment to the ICAM-1 cellular receptor is also attenuated with subsequent interruption of viral RNA uncoating and viral replication.8 In vitro experiments provide evidence of pleconaril antiviral activity, with a minimum inhibitory concentration of 50% of <0.21 and <0.03 µM for isolates of rhinoviruses and enteroviruses, respectively.9-11 Randomized, double-blind, placebo-controlled trials have reported that pleconaril lessened the duration and severity of the common cold and picornavirus-associated viral respiratory infections.3,12 The pharmacokinetics of single-dose pleconaril has been evaluated in adults, adolescents, and children and is reported elsewhere.13,14

Data regarding the hepatic metabolism of pleconaril are limited. Liver microsome studies in rats and dogs reported that pleconaril had minimal impact on total liver cytochrome P450 (CYP) content and did not induce CYP1A, 2B, 2E, 3A, or 4A activity.15 In vitro studies suggest that pleconaril is a weak CYP1A2 inhibitor (Ki ~6.5 µM).15 CYP1A2 activity was further assessed in healthy adults, in whom coadministration of pleconaril and theophylline, a CYP1A2 substrate,16 resulted in reduced theophylline clearance.17 In a C1F1 cell-based assay, pleconaril showed no CYP3A induction at 1 and 3 µM (34.1 and 341 ng/mL, respectively) but weak to moderate CYP3A induction at 10 µM (3410 ng/mL; data on file, ViroPharma Inc, Exton, Pa). However, the potential for pleconaril to affect in vivo hepatic CYP3A activity in humans has not been extensively evaluated. CYP3A is responsible for the metabolism of up to 50% of all medications and is an important enzyme involved in the potential cause of drug-drug interactions.18 Therefore, if pleconaril interacts with CYP3A, there may be important clinical consequences.

Evaluation of midazolam pharmacokinetics, specifically midazolam clearance (CL) and the area under the concentration-time curve (AUC), provides an accurate assessment of CYP3A activity.19 Although CYP3A isozymes are expressed in the intestine and liver, intravenous (IV) midazolam was used to specifically phenotype hepatic CYP3A activity.19 The purpose of this study was to evaluate the effect of oral pleconaril on hepatic CYP3A activity in healthy adults as assessed by IV midazolam.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
This study was approved by the Institutional Review Board of Bassett Healthcare, Cooperstown, New York, and written informed consent was obtained from each adult prior to study procedures. Screening procedures included a medical history, physical examination, electrocardiogram, and blood and urine laboratory tests. Healthy, nonsmoking adults were at least 18 years of age and not on any medications (including oral contraceptives) known to affect CYP3A activity. All subjects refrained from consuming caffeine-containing foods for 2 days and grapefruit and grapefruit juice for 7 days before the start of the study and for the entire study duration. Subjects with clinically significant findings by medical history, physical examination, laboratory testing, history of alcohol or drug abuse within the past 6 months, history of medication allergy (including skin rash), or intolerance to benzodiazepines were excluded.

Study Design
This was an open-label, single-sequence crossover study evaluating the potential pharmacokinetic interaction between single-dose IV midazolam and oral pleconaril administered 3 times daily for 16 doses. A single-sequence crossover study design was selected because of the elimination half-life of pleconaril (~180 hours).8 This design permits an evaluation of the effect of pleconaril on midazolam pharmacokinetics over a reasonable time period and without the need for an extended washout period.

At approximately 7:00 AM on day 1 and day 7, subjects were administered IV midazolam 0.025 mg/kg (Versed, 1 mg/mL; Roche Pharmaceuticals, Nutley, NJ) following a minimum 8-hour fast. On days 2 through 6, oral pleconaril 400 mg (Picovir, 200 mg tablet; ViroPharma Inc) was administered 3 times daily and within 5 minutes after completion of a meal or snack since pleconaril bioavailability is increased with food.20 On the morning of day 7, IV midazolam and the last (16th) dose of pleconaril were administered. Subjects were monitored with pulse oximetry and blood pressure measurements for at least 30 minutes after midazolam administration.

Blood Sample Collection
Blood samples for determination of plasma midazolam concentrations were collected at predose and at 5, 30, 60, 120, 180, 240, and 360 minutes after midazolam administration. Blood samples for determination of plasma pleconaril concentrations were collected on days 5, 6, and 7 before the morning pleconaril dose. All blood samples were collected by venipuncture or an intravenous catheter kept patent with 2.5 mL of 10 U/mL heparin in 0.9% sodium chloride. Within 1 hour after collection, blood samples were centrifuged at 2800 rpm for 15 minutes, with the isolated plasma stored at –70°C until analysis.

Midazolam Assay Analysis
Plasma midazolam was analyzed by a liquid chromatographic tandem mass spectrometry (LC/MS/MS) assay developed by Prevalere Life Sciences, Whitesboro, New York. Details of this procedure are described elsewhere.21 Plasma midazolam (1 mL) was isolated by solid-phase extraction with addition of alprazolam as the internal standard and addition of 30:70 acetonitrile:water to precipitate plasma proteins. Samples were eluted with 800 µL of methanol and evaporated to dryness. The dried residues were reconstituted in 100 µL of mobile phase (80:20 methanol:5 mM ammonium acetate) and injected onto the LC/MS/MS system. A water symmetry C18 analytic column was used and was coupled to a Sciex API III MS system (Perkin-Elmer Sciex Instruments, Rochester, NH) equipped with a Waters 616 pump and 600S controller (Waters Corporation, Milford, Mass). Approximate retention time for the midazolam isolates was 4 minutes. For midazolam detection with mass spectrometry, the transition m/z 326->291 was selected. The linear range of the assay was 0.5 to 100 ng/mL, with intra- and interday precision ≤7.9% at quality control samples of 0.75, 7.5, and 75.0 ng/mL.

Pleconaril Assay Analysis
Plasma pleconaril was analyzed by an LC/MS/MS assay developed by MDS Pharma Services (Montreal, Quebec, Canada). Plasma pleconaril (0.1 mL) was isolated by a liquid-liquid extraction with addition of internal standard (VP 64027, 750 ng/mL) and 5 mL of hexanes. After brief vortex mixing, samples were evaporated to dryness, reconstituted in 100 mL of mobile phase (85:15 acetonitrile:water), and injected onto the LC/MS/MS system. A BDZ-Hypersil C18 column was used and coupled to a Sciex API 3000 or API III MS system (Perkin-Elmer Sciex Instruments, Rochester, NH) and an Alliance 2690 autosampler (Waters Corporation, Milford, Mass). Approximate retention time for the pleconaril isolates was 3 minutes. For pleconaril detection with mass spectrometry, the transition m/z 382->298 was selected. The lower limit of detection was 5 ng/mL, while the upper limit of detection was 500 ng/mL. Intra- and interday percentage coefficients of variation were ≤10% at quality control samples of 5, 15, 150, and 350 ng/mL.

Pharmacokinetic Analysis
Midazolam pharmacokinetics was determined by noncompartmental analysis using Kinetica version 2.0.1 (InnaPhase Corporation, Philadelphia, Pa). A log-linear trapezoidal method was used to calculate the AUC from time 0 to the last measurable concentration (AUC0-last). The AUC from time 0 to infinity (AUC0-{infty}) was calculated as the sum of AUC0-last plus the ratio of the last measurable concentration and the elimination rate constant (ke). Elimination half-life (t1/2) was estimated by linear regression, and systemic CL was calculated as Dose/AUC0-{infty}.

Statistical Analysis
Statistical analyses were performed using SAS version 6.12 (SAS Institute, Cary, NC). Midazolam pharmacokinetic data were log transformed prior to analyses. Analyses of variance were performed, which included subject and treatment effects as factors and least squares geometric mean ratios (LS-GMR). Ninety percent confidence intervals (90% CIs) for the difference between the treatment group (eg, midazolam alone vs midazolam plus pleconaril) LS-GMR were calculated for the parameters AUC0-last, AUC0-{infty}, CL, volume of distribution at steady state (Vss), and t1/2. The 90% CIs are expressed as a percentage relative to the LS-GMR of the midazolam-alone phase. No significant drug interaction (or lack of bioequivalence) was present if the 90% CIs were within the 0.8 to 1.25 interval.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Sixteen white subjects were enrolled, and 14 subjects (8 men) completed the study. One female subject withdrew from the study due to diarrhea, and 1 male subject developed a ruptured appendix after enrollment but before drug administration. Mild sedation was noted after midazolam administration. No clinically significant adverse events were observed as a result of pleconaril or midazolam administration. The mean ± standard deviation age was 36.1 ± 7.5 years, and weight was 75.9 ± 12.6 kg.

Plasma concentration versus time profiles of midazolam alone (day 1) and midazolam plus pleconaril (day 7) are shown in Figure 1. Starting at 30 minutes and extending through 360 minutes, plasma midazolam concentrations were lower during the midazolam plus pleconaril phase compared to the midazolam-alone phase. Plasma pleconaril concentrations (mean ± SD) steadily increased and were 838.56 ± 319.38, 880.59 ± 271.85, and 1127.68 ± 307.08 ng/mL on days 5, 6, and 7, respectively.



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  		Figure 1. Midazolam plasma concentration versus time profiles following IV midazolam 0.025 mg/kg alone and after administration of pleconaril 400 mg 3 times daily for 16 doses. Data for 14 adults are presented as mean ± standard deviation. Solid lines represent midazolam alone, and broken lines represent midazolam plus pleconaril.

 
Midazolam pharmacokinetic parameters are presented in Table I. The maximum plasma concentration and volume of distribution at steady state for the midazolam-alone phase were equivalent to the midazolam plus pleconaril phase. Geometric mean midazolam AUC0-{infty} decreased 28% and systemic CL increased 39% during the midazolam plus pleconaril phase. These changes correspond to LS-GMR (90% CI) of 0.718 (0.674-0.765) and 1.392 (1.307-1.483), respectively. Midazolam elimination half-life decreased to 105.5 minutes during the midazolam plus pleconaril phase (Table I).


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  		Table I Midazolam Pharmacokinetic Parameters for 14 Adults

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
We evaluated the effect of oral pleconaril on hepatic CYP3A activity as measured by IV midazolam. Numerous probe drugs have been used to evaluate CYP3A activity, with each probe drug possessing advantages and disadvantages to their use.22 Government regulatory agencies and drug development companies have endorsed midazolam as a preferred CYP3A probe drug for use in in vivo drug-drug interaction studies.23 The advantages of using midazolam include a strong correlation between in vivo midazolam CL and in vitro hepatic CYP3A content (r = 0.93, P < .01) and the short elimination half-life (1-4 hours) of IV midazolam, which allows for a convenient blood-sampling collection scheme.24,25 Although mild sedation, metabolism by both CYP3A4 and CYP3A5,26 and the influence of hepatic blood flow27 are potential disadvantages, IV midazolam was chosen as our probe drug to evaluate hepatic CYP3A activity.

Midazolam pharmacokinetics was significantly altered after administration of pleconaril. The decreases in midazolam AUC0-{infty} and elimination half-life (Vss was unchanged) during the midazolam plus pleconaril phase suggest increased hepatic CYP3A activity. Drugs primarily metabolized by CYP3A28 may need dosage adjustments upon coadministration with pleconaril. Although the elimination half-life of pleconaril was not measured in this study, other investigators have reported the half-life to be approximately 180 hours.8 We observed a steady increase in plasma pleconaril concentrations over time, which is also suggestive of a prolonged elimination half-life. Consequently, not only the extent but also the duration of increased CYP3A activity are important.

Pleconaril has been reported to affect ethinyl estradiol pharmacokinetics.12 In another study, ethinyl estradiol AUC0-{infty} decreased 17% after administration of a pleconaril 800-mg loading dose, followed by 400 mg every 4 hours for 4 doses (data on file, ViroPharma Inc). Although this study did not phenotype CYP3A activity, there was suggestion of increased enzyme activity via CYP induction. The molecular mechanisms of CYP induction are not completely understood but result in alterations in gene transcription, with de novo CYP protein synthesis occurring over several days.29,30 Interestingly, the decrease in ethinyl estradiol AUC0-{infty} occurred after short-term pleconaril administration as opposed to multiple-dose administration.31 Whether heterotropic cooperativity via distinct active and allosteric binding sites, multiple CYP3A enzyme conformations, or differential substrate physicochemical characteristics are contributory factors is unknown.31 Additional evidence to suggest CYP3A cooperativity was from another study in which short-term pleconaril administration (800-mg loading dose, followed by 400 mg every 6 hours for 3 doses) in healthy adults decreased midazolam AUC0-{infty} 36% (data on file, ViroPharma Inc). Taken together, the increase in CYP3A activity by pleconaril may be due to CYP3A induction, heterotropic cooperativity, or both.

In this study, the effect of pleconaril on CYP3A activity was examined in healthy adults. Although pleconaril is not approved by the US Food and Drug Administration for treatment of the common cold, research for the treatment of viral infections (eg, enteroviral meningitis) is under way.8,32 Infection elicits production and release of various immunomodulators and inflammatory stimuli, including interleukin-10 (IL-10), interferon-{alpha}, and tumor necrosis factor–{alpha}.33,34 Numerous in vitro studies, animal models, and in vivo experiments suggest immunomodulators and inflammatory stimuli affect CYP expression and activity.35-38 With few exceptions, CYP activity is suppressed in response to inflammation and infection.39 In one study of 12 adults, the effects of IL-10 on CYP activity were evaluated.40 IL-10 decreased midazolam CL 12% compared to placebo (mean ± SD: 25.4 ± 5.7 vs 29.2 ± 6.5 L/h; P ≤ .05). These results suggest a downregulation of CYP3A activity during conditions in which IL-10 is prevalent (eg, infection). Consequently, the extent of increased CYP3A activity by pleconaril in healthy adults may not be the same as that in patients with viral-associated infections.

In summary, oral pleconaril 400 mg 3 times daily for 16 doses increased hepatic CYP3A activity. We speculate that the increase of hepatic CYP3A activity may be due to CYP3A induction, heterotropic cooperativity, or both. The drug-drug interaction between pleconaril and midazolam was observed in healthy subjects. The clinical significance of this interaction in patients with viral infections is unknown. Future studies are needed to determine if the extent of increased CYP3A activity by pleconaril is applicable to other drugs primarily metabolized by CYP3A. As CYP3A is expressed in the intestine, the potential effect of pleconaril on intestinal CYP3A activity also warrants further investigation.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
This study was approved by the Institutional Review Board of Bassett Healthcare, Cooperstown, New York. Presented in part at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 2002, San Diego, California. Financial support was provided by ViroPharma Incorporated.

Dr Rhodes was previously employed at ViroPharma, Exton, Pennsylvania, and is now at Gilead, South San Francisco, California; Dr Liu was previously employed at ViroPharma, Exton, Pennsylvania, and is now a consultant for ViroPharma.

DOI: 10.1177/0091270005283286


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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J. D. Ma, A. N. Nafziger, G. Rhodes, S. Liu, and J. S. Bertino Jr.
DURATION OF PLECONARIL EFFECT ON CYTOCHROME P450 3A ACTIVITY IN HEALTHY ADULTS USING THE ORAL BIOMARKER MIDAZOLAM
Drug Metab. Dispos., May 1, 2006; 34(5): 783 - 785.
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