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DRUG INTERACTIONS |
From the Department of Clinical Pharmacology (Dr Liu, Dr Sharma) and Department of Biostatistics (Mr LaBadie), Pfizer Global Research and Development, Groton/New London, Connecticut; Department of Clinical Sciences, Pfizer, Inc, New York (Dr Foster); and Comprehensive NeuroScience, Inc, Ft Lauderdale, Florida (Dr Gutierrez).
Address for reprints: Ping Liu, PhD, Clinical Pharmacology, Pfizer Global Research and Development, 50 Pequot Avenue, MS6025-A3232, New London, CT 06320; e-mail: Ping.Liu{at}pfizer.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Voriconazole • efavirenz • pharmacokinetic
Voriconazole is a broad-spectrum triazole antifungal agent approved for the primary treatment of acute invasive aspergillosis and as a salvage therapy for serious fungal infections caused by Scedosporium apiospermum and Fusarium species as well as for candidemia in nonneutropenic patients. In common with other triazole antifungal agents, voriconazole inhibits fungal cytochrome P450 (CYP)–dependent 14-
-sterol demethylase, an essential enzyme in the synthesis of ergosterol.1-3 Results of in vitro and in vivo studies have shown that voriconazole is primarily metabolized by CYP2C19, CYP2C9, and, to a lesser extent, CYP3A, and it also inhibits the activity of CYP2C19, CYP2C9, and CYP3A possibly through the saturation of active sites.4-8 It has been demonstrated that the genetic polymorphism of CYP2C19 accounts for a considerable proportion of the inter-subject variability in voriconazole exposure.7-9 In this study, however, subjects were not genotyped for CYP2C19 because the study had a crossover design in which each subject was his own control. The prevalence of CYP2C19 poor metabolizers is low (3%-5%) in the study population (Hispanics, Caucasians, and Blacks).10,11 Each of the above enzymes contributes to the major metabolite of voriconazole, the N-oxide metabolite, which accounts for 72% of the circulating radiolabeled metabolites in plasma. Nevertheless, because this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole.
Efavirenz is primarily metabolized by CYP3A4 and CYP2B6 to hydroxylated metabolites with subsequent glucuronidation. In vitro studies have shown that efavirenz inhibits CYP2C9, CYP2C19, and CYP3A4 with inhibition constant (Ki) values (8.5-17 µM) in the range of observed efavirenz plasma concentrations.12,13 In vitro and in vivo studies also demonstrated that efavirenz induces CYP3A4 activity in a concentration-dependent and time-dependent manner.14,15 Clinical drug-drug interaction studies showed that efavirenz decreased the systemic exposure of several CYP3A4 substrates, such as amprenavir,16 indinavir,17 and methadone.18 Efavirenz induces P450 enzymes, also resulting in the induction of its own metabolism upon chronic administration.12
Because efavirenz is a mixed inhibitor/inducer of CYP3A4, and CYP3A4 participates in voriconazole metabolism, a drug interaction may be expected. The recommended therapeutic dosing regimen of oral voriconazole was evaluated: 400 mg twice-daily (bid) loading doses on day 1 followed by 200-mg bid maintenance doses. Although the recommended maximum efavirenz dosing regimen is 600 mg once daily (qd), the 400-mg qd regimen was selected for evaluation because of the anticipated side effects associated with the maximum therapeutic dose and the desire to maximize the exposure to efavirenz while minimizing the risk to healthy subjects.
The primary objective was to evaluate the effect of efavirenz on voriconazole pharmacokinetics at steady state in healthy male subjects and vice versa. The tolerability and safety of repeated doses of voriconazole coadministered with efavirenz were also evaluated.
Some of the data in this article have been presented as an abstract and poster presentation at the 2005 annual meeting of the American Society for Clinical Pharmacology and Therapeutics.19
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The study protocol was approved by the local institutional review boards (Independent Investigational Review Board, Plantation, Florida). Subjects were enrolled after providing written informed consent.
Study Population
Subjects enrolled were healthy nonsmoking male subjects aged 18 to 55 years old, with a body mass index between 18 and 30 kg/m2 and weight >50 kg. Health was evaluated using a detailed medical history, full physical examination including vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory test. Subjects were excluded if they had known hypersensitivity to azole antifungals, positive urine drug screens for drugs of abuse, or evidence of liver disease (eg, alanine transaminase, aspartate transaminase, alkaline phosphatase >3x upper limit of normal [ULN], total bilirubin >1.5x ULN). Subjects were prohibited from taking medications known to be inhibitors, inducers, or substrates of the CYP3A enzyme or that interact with voriconazole as described in the product label.20 Subjects were abstained from using prescription or nonprescription drugs (other than acetaminophen at doses of 
2 g/day), vitamins, and dietary supplements within 7 days or 5 half-lives (whichever was longer) prior to the first dose of study medication and throughout the study. Herbal supplements had to be discontinued at least 30 days before the first dose of study medication. No consumption of grapefruit or grapefruit-containing product was allowed within 7 days before the first dose of study medication and throughout the study. Subjects were abstained from alcohol and tobacco or nicotine-containing products for at least 14 days before the first dose and throughout the study.
Drug Administration and Sample Collection
Voriconazole (VFEND, Pfizer, New York) and matching placebo tablets were supplied to the CRU by Pfizer. Efavirenz (SUSTIVA, Bristol-Myers Squibb, Princeton, New Jersey) capsules were obtained by the CRU from commercial sources. While confined to the CRU, subjects were fasted for at least 4 hours before any safety laboratory evaluations and 8 hours before the morning dose of voriconazole, and they continued without food for at least 1 hour following dosing. For the evening dose of voriconazole, subjects were not allowed to consume food for at least 1 hour before and 1 hour after dosing. Efavirenz was administered in the evening to improve the tolerability of central nervous system side effects associated with this drug. Subjects received efavirenz alone with restrictions of no food for at least 1 hour before or up to 1 hour after evening dosing. During coadministration, efavirenz was administered at the same time as the evening dose of voriconazole or placebo. At time of dosing, the medications were administered either alone (days 1-3 for voriconazole and days 11-20 for efavirenz) or together (days 21-29) with 240 mL water under direct supervision of study personnel.
Blood samples (3 mL) to characterize voriconazole and its N-oxide metabolite pharmacokinetics were collected on days 3 and 29 at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose; blood samples were also collected prior to the evening dose of voriconazole on days 1 to 3, 21, and 26 to 29 for the measurement of trough concentrations (Cmin). Blood samples (3 mL) to characterize efavirenz pharmacokinetics were collected on days 19 and 29 at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours postdose; blood samples were also collected prior to the evening dose of efavirenz on days 11, 16 to 19, 21, and 26 to 29 for the measurement of Cmin. All blood samples were centrifuged at 1700 g for approximately 10 minutes at 4°C, and the plasma was obtained and stored at approximately –20°C within 1 hour of collection until analyzed.
Analytical Methods
PPD Development (Richmond, Virginia) analyzed plasma samples for voriconazole and its N-oxide metabolite using a previously validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.21 The plasma samples (0.100 mL) were extracted using a solid-phase extraction procedure followed by LC/MS/MS separation and detection. The dynamic range of the assay for voriconazole was 10 to 2500 ng/mL. The accuracy (percent difference from nominal) of the quality control (QC) samples used during sample analysis ranged from –6.18% to –3.50% with a precision (as measured by percent relative standard deviation) of 3.83% for voriconazole. The dynamic range of the assay for the N-oxide metabolite was 20 to 5000 ng/mL. The accuracy of the QCs used during sample analysis ranged from –5.31% to –2.75%, with a precision of 4.33% for the N-oxide metabolite. PPD Development also analyzed plasma samples for efavirenz using validated high-performance liquid chromatography with ultraviolet detection similar to previously published methods.22,23 The plasma samples (0.100 mL) were extracted using a liquid/liquid extraction procedure. Calibration curves were constructed by linear regression of the calibration data using a weight factor of 1/concentration. The dynamic range of the assay for efavirenz was 0.100 to 10.0 µg/mL. The accuracy of the QCs used during sample analysis ranged from –1.02% to –0.594%, with a precision 2.08%. All the samples were analyzed within an established long-term stability period (1 year).
Pharmacokinetic Analysis
Pharmacokinetic analysis was performed with WinNonlin v.3.2 (Pharsight, Mountain View, California) using standard noncompartmental methods. Maximum observed plasma concentrations (Cmax), time to reach Cmax (tmax), and trough concentrations (Cmin) for voriconazole, its N-oxide metabolite, and efavirenz were estimated directly from the concentration-time data. The area under the plasma concentration-time curve over the dosing interval (
) (voriconazole and its N-oxide metabolite: AUC0-12; efavirenz: AUC0-24) was estimated using linear/log trapezoidal approximation.
Safety Assessment
Assessments included repeated safety laboratory tests (hematology, chemistry, and urinalysis) and physical examinations on days 0, 4 (before discharge from CRU), 10, 15, 19, 25, and 29; multiple measures of vital signs (supine heart rate and blood pressure) and single 12-lead ECGs on days 0, 1, 3, 4, 11, 12, 15, 16, 19 to 22, 25, 26, 29, and 30; and continuous adverse event (AE) monitoring. These assessments were also measured at screening and follow-up visit. Only prior to voriconazole morning dosing on day 1 were triplicate ECG measurements collected, and the mean served as each subject's baseline value.
Statistical Methods
Sample size determination. Assuming a dropout rate of approximately 30%, 34 subjects were randomized to ensure that 24 subjects (12 subjects per treatment group) would complete the study. This sample size provided an 80% probability of calculating the 90% confidence intervals (CIs) and levels of precision we can expect to obtain for various possible relative bioavailability estimates for AUC0-12 and Cmax of voriconazole in the presence of efavirenz.24 These calculations were based on the intrasubject coefficient of variation estimates for voriconazole AUC0-12 and Cmax of 0.108 and 0.178, respectively, from an internal study (data on file, Pfizer, Inc, 1999). For instance, if the estimated ratio of voriconazole AUC0-12 (day 29/day 3) was 0.9, the 90% CI would be no wider than (0.82, 0.99).
Pharmacokinetic parameters. AUC0- and Cmax for voriconazole, the N-oxide metabolite, and efavirenz are presented as arithmetic mean with standard deviation (SD), and tmax is presented as median and range. Natural log-transformed AUC0- and Cmax of voriconazole and efavirenz were analyzed using a mixed-effects analysis of variance (ANOVA) model with SAS MIXED procedure using SAS Version 8.2 (SAS Institute, Inc, Cary, North Carolina). Restricted maximum likelihood (REML) estimation was used. Treatment was specified as the fixed effect with a random effect for subjects within group. For voriconazole and the N-oxide metabolite, the point estimates of the adjusted mean treatment differences (day 29–day 3) and their respective 90% CIs around the differences were calculated. These estimated treatment differences and their respective confidence limits were antilog (exponent) transformed to the ratios of the adjusted geometric means (day 29/day 3) and their respective 90% CIs around the ratios. The adjusted geometric mean ratios (day 29/day 19) of AUC0- and Cmax for efavirenz and their respective 90% CIs around the ratios were calculated in the same manner. The lack of drug interaction could be established if the 90% CIs of the geometric ratios of AUC0- and Cmax are contained in the acceptance interval (80%, 125%).
Safety data. All the safety data were summarized descriptively. In addition, ECG data (Bazett-corrected QT [QTcB] and Fridericia-corrected QT [QTcF]) were qualitatively described and categorized relative to the change from the baseline value (mean of triplicate values prior to dosing on day 1). Because comparisons of possible QTc prolongation relationships between treatment regimens and placebo were exploratory in nature and presented for descriptive purposes only, no adjustments were made for multiple comparisons. A linear mixed-effects model for repeated ECGs was used to model the change from baseline data for all nominal time points obtained on days 3, 19, and 29 (full pharmacokinetic days), respectively, for each treatment regimen with SAS Version 8.2. This model had the treatment as the fixed effect and the baseline as a covariate. The within-treatment group differences between the voriconazole group and the placebo group were also compared. Appropriate linear contrasts were used to obtain point estimates of mean differences of interest, and 95% CIs of the mean differences were constructed.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Effect of Efavirenz on Steady-State Voriconazole Pharmacokinetics
The steady state of voriconazole was achieved on day 3 during bid dosing of voriconazole alone and within 7 days following coadministration with efavirenz, as indicated by similar Cmin values on days 2 and 3, as well as days 26 to 29 (data not shown).
The steady-state mean voriconazole concentrations decreased significantly when coadministered with 400 mg qd efavirenz (Figure 1, upper panel). As shown in Figure 2 (left panel), there was a significant decrease in individual steady-state exposure parameters (AUC0-12 and Cmax) of voriconazole during coadministration with 400 mg qd efavirenz. The decrease in voriconazole mean AUC0-12 and Cmax was 80% (range, 24%-89%) and 66% (range, 3%-86%), respectively, during coadministration with 400 mg qd efavirenz (Table II).
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Compared to the voriconazole exposure, the steady-state mean concentrations of the N-oxide metabolite were decreased to a much lesser extent when coadministered with efavirenz (Figure 1, lower panel). The mean steady-state AUC0-12 and Cmax of the N-oxide metabolite on day 29 were decreased by 39% and 19%, respectively, compared to those on day 3 (Table II). The mean N-oxide metabolite/parent AUC0-12 ratio following coadministration with 400 mg qd efavirenz was increased significantly compared to that when voriconazole was given alone (5.02 vs 1.94). The substantial increase in metabolite/parent ratio following coadministration with efavirenz indicates the enzymatic induction by efavirenz.
Effect of Voriconazole on Steady-State Efavirenz Pharmacokinetics
In both treatment groups, the steady state of efavirenz was achieved within 7 days during repeated dosing of efavirenz alone and coadministration with voriconazole, as indicated by similar Cmin on days 16 to 19 and days 26 to 29 (data not shown).
The steady-state mean efavirenz concentrations were increased moderately following coadministration with 200 mg bid voriconazole compared to those of efavirenz alone (Figure 3, upper panel). In the placebo group, the steady-state mean efavirenz concentration-time profiles were similar on day 19 and day 29 following repeated dosing of efavirenz (Figure 3, lower panel).
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Safety
As stated earlier, 2 subjects discontinued due to treatment-related AEs. One subject had elevated CK levels that started on study day 19 (efavirenz alone) and progressively increased until the subject was hospitalized on day 23 (efavirenz active + placebo). This subject was diagnosed with rhabdomyolysis (serious AE). Study drug was permanently discontinued, and the subject was treated with intravenous therapy and sodium bicarbonate. The rhabdomyolysis resolved on day 27, and the elevated CK resolved on day 32. The other subject was discontinued due to a second-degree A-V heart block diagnosed on day 11 (efavirenz alone), and this event was mild and resolved in 8 hours.
A total of 151 treatment-emergent AEs were observed in 32 subjects during this study. Most (96%) events of the treatment-emergent AEs in this study were mild in intensity, and most (70%) were treatment related. The moderate AEs included 1 event of headache (efavirenz [placebo]), 2 incidences of dizziness (efavirenz [placebo]), and 1 event of myopathy (efavirenz + placebo). All these AEs resolved without intervention in less than 24 hours with the exception of the myopathy (as a result of discontinuation). As shown in Table IV, the most common AE in both treatment groups was dizziness. Other frequently reported AEs included headache and insomnia. The total number of AEs for the dosing period of efavirenz alone was similar in both groups. When voriconazole was combined with efavirenz, the total number of AEs was similar to that of efavirenz alone.
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There were no clinically significant trends in postdose vital signs or clinical laboratory assessments with the exception of the subject who had the CK change. There was an increased difference in QTcB for the change from baseline at 0, 1, and 4 hours postdose (no difference at 12 hours) when comparing the voriconazole + efavirenz treatment regimen to placebo on day 29. There did not appear to be any further differences in the remaining comparisons of QTcB or any of the QTcF for the change from baseline over time when comparing the other remaining treatment regimens to placebo. It should be noted that this study was not designed or powered to be a QTc study; no adjustments were made for multiplicity, and findings are for descriptive purposes only.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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It is known that the N-oxide metabolite of voriconazole is mainly excreted in urine in humans, and it also undergoes further serial oxidation, reduction, and glucuronidation. The terminal disposition phase of the N-oxide metabolite following coadministration with efavirenz was much steeper compared to that of voriconazole alone (Figure 1, lower panel). It suggests that enzymes involved in the metabolism of the N-oxide metabolite may also be induced by efavirenz.
A moderate increase (43%) in the steady-state mean efavirenz total exposure (AUC0-24) was observed following coadministration with 200 mg bid voriconazole. This may be due to the inhibition of CYP3A4 activity by voriconazole as efavirenz is metabolized mainly through CYP3A4 and CYP2B6. The placebo group confirmed that the 10-day 400-mg qd efavirenz dose was sufficient to maximize the enzymatic induction and reach the steady state. Similar time courses of efavirenz were also applied in previous studies to induce the enzymatic activities.15,18 This is consistent with other studies, in which maximal enzymatic induction typically occurred after 10 to 14 days of administration of an inducing agent such as rifampin and phenobarbital.25-27
In vitro and in vivo studies have demonstrated that the induction of CYP3A4 activity by efavirenz is concentration dependent (dose dependent),14,15 and this also might be true for the induction of CYP2C19 and CYP2C9 activities by repeated dosing of efavirenz. Therefore, the approved 600-mg dose of efavirenz is likely to interact with voriconazole to the same degree (if not greater) compared to the 400-mg dose evaluated in this study.
In summary, repeated therapeutic doses of efavirenz (400 mg qd) substantially decreased steady-state mean AUC0-12 and Cmax of voriconazole by 80% and 66%, respectively. Repeated therapeutic doses of voriconazole (200 mg bid) moderately increased steady-state mean AUC0-24 and Cmax of efavirenz by 43% and 37%, respectively. When voriconazole was coadministered with efavirenz, the incidence of adverse events was similar to that of efavirenz alone. However, due to the clinically significant effect of efavirenz on voriconazole pharmacokinetics, coadministration of 200 mg bid voriconazole with 400 mg (or higher) qd efavirenz is contraindicated.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: All the authors are employees of Pfizer except Dr Gutierrez, who was the principal clinical investigator for this study. This study was sponsored by Pfizer, Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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