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DRUG INTERACTIONS |
From Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey. Dr Kanamaluru is currently at Sanofi Aventis, Malvern, Pennsylvania.
Address for reprints: Jing-He Yan, PhD, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08542-4000.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Nelfinavir • ravuconazole • pharmacokinetics
HIV protease inhibitors (eg, saquinavir, indinavir, ritonavir, atazanavir, and nelfinavir) are metabolized by CYP3A4, and inhibition of CYP3A4 by azole antifungals may lead to increased exposure levels of these drugs. In a 6-day multiple-dose study in healthy volunteers, coadministration of ketoconazole (200 mg/d) and saquinavir (600 mg 3 times daily) caused a clinically significant area under the curve (AUC) increase of saquinavir (up by 130%).16-18 In a single-dose study, coadministration of 400 mg ketoconazole with 400 mg indinavir to healthy volunteers resulted in a 68% ±48% increase in indinavir AUC, and a reduction of indinavir dose by 25% is recommended when ketoconazole is administered concurrently.19 However, the interaction between HIV protease inhibitors and azole antifungals may not be all clinically significant. It has been reported that the 20% increase of the ritonavir AUC and the 11% increase of the atazanavir AUC by ketoconazole may not be clinically significant.20,21 Similarly, ketoconazole caused a clinically insignificant decrease in the clearance of nelfinavir in healthy volunteers given the nelfinavir safety profile.22 As reported, nelfinavir metabolism is mediated via multiple cytochrome P450 isozymes; inhibition of CYP3A4 by ketoconazole could be offset by shunting more metabolism to alternative pathways mediated by other isozymes, such as CYP2C19 and CYP2D6.23 A recent review categorized ritonavir, indinavir, and saquinavir interaction with fluconazole as probably clinically insignificant.24
The results from a simvastatin clinical interaction study confirmed the in vitro CYP3A4 inhibitory potential of ravuconazole.25 Although the AUC for simvastatin increased 2.1- and 4.0-fold after 1 and 14 days of dosing with ravuconazole, respectively, the AUC for simvastatin increased 
10-fold after concomitant dosing with itraconazole.26 Since simvastatin is a very sensitive substrate for CYP3A4 inhibition, the inhibitory effect of ravuconazole on drugs metabolized by CYP3A4 may or may not be clinically significant and will need to be further characterized. The primary objective of this study was to assess the effect of ravuconazole on the pharmacokinetics of nelfinavir. The secondary objective of this study was to assess the pharmacokinetics of ravuconazole before and at the steady state after once-daily oral dosing of 400 mg ravuconazole for 28 days. In addition, a safety evaluation was also performed throughout the study.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design
This was an open-label, nonrandomized study in healthy subjects conducted at the BMS Clinical Research Center and approved by the Institutional Review Board of the Robert Wood Johnson University Hospital at Hamilton, New Jersey. Volunteers were admitted to the study clinic on the day prior to study drug administration (day-1) for clinical and clinical laboratory evaluation. On day 1, subjects received a single oral dose of 750 mg nelfinavir. On day 2, subjects received a single oral dose of 750 mg nelfinavir and a single oral dose of 400 mg ravuconazole. On day 3, subjects were allowed to go home after a single oral dose of 400 mg ravuconazole and safety assessment. On days 4 to 28, subjects had once-daily oral doses of 400 mg ravuconazole with a daily call in to the clinical unit to confirm dosing except on days 8, 15, and 22, when subjects returned to the clinical unit for the daily dose of ravuconazole. In the evening of day 28, subjects reentered the clinical unit, and on day 29, subjects received a single oral dose of 750 mg nelfinavir and the last oral dose of 400 mg ravuconazole. Subjects were discharged from the clinical unit on day 30. Subjects returned for study-related procedures on days 36, 43, 50, and 57. Subjects were discharged from the study on day 57. Nelfinavir (Viracept®) 250-mg tablets were obtained by the investigator from commercial sources, and ravuconazole 200 mg tablets were provided by BMS. A light meal was administered as breakfast to the subjects prior to dosing of nelfinavir or nelfinavir coadministered with ravuconazole after a 10-hour overnight fast on days 1, 2, and 29. Each dose was ingested with 240 mL of water within 5 minutes of meal consumption. Serial blood samples for the determination of plasma nelfinavir concentrations were collected on days 1, 2, and 29 at predose and at 30 minutes and 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose, while serial blood samples for ravuconazole concentrations were collected on days 2 and 29 at predose and at 30 minutes and 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose. In addition, blood samples were collected for ravuconazole at predose on days 8, 15, and 22 and at the time of follow-up visits on days 36, 43, 50, and 57.
Each subject was monitored for safety and tolerability throughout the study by physical examination, vital sign assessments, ECG measurements, wellness assessment, and clinical laboratory tests. The study concluded with a general safety follow-up examination prior to discharge on day 57. Adverse events were categorized by the investigator in terms of severity and relationship to the study drugs.
Sample Analysis
Within 30 minutes of collection, blood samples were centrifuged, and the plasma was transferred to screw-cap polypropylene tubes and stored at –20°C until assayed. Stability of the plasma sample under the storage condition was tested for both compounds, and both compounds were found to be stable in plasma during storage at –20°C for the entire storage period (1 month) and following 3 freeze-thaw cycles. Plasma samples from the study were assayed for nelfinavir and ravuconazole simultaneously by a validated high-performance liquid chromatography (HPLC)/ultraviolet method. Briefly, the assay involved a double extraction procedure, followed by injection of the extracted samples onto a YMC ODS AQ C18 HPLC column (4.6 x 150 mm, 5 µ). The mobile phase A was 50 mM ammonium formate buffer (pH 2.7), and the mobile phase B was acetonitrile. The following gradient was used with the flow rate of 0.9 mL/min: 0 to 2.5 minutes at 50% A followed by linear gradient from 50% A to 15% A in 6.5 minutes and 9.0 to 9.5 minutes linear gradient from 15% A to 0% A followed by 100% B isocratic from 9.5 to 12.5 minutes. Detection was by dual wavelengths of 220 (0-5.5 minutes) and 290 nm (5.6-12 minutes) for nelfinavir and ravuconazole, respectively. The standard curves, which ranged from 100 to 4000 ng/mL for nelfinavir and from 25 to 2000 ng/mL for ravuconazole, were fitted to a 1/x weighted linear regression model. The acceptance criteria established for analytical runs were (1) the predicted concentrations of at least three fourths of the standards shall be within ±15% of their individual nominal concentration values; (2) at least 1 replicate of the lowest concentration in the standard curve shall be within ±20% of the nominal concentration for that level to be qualified as the lower limit of quantitation (LLQ), otherwise the next level is subject to the same test and the LLQ raised accordingly; and (3) the predicted concentrations of at least two thirds of the quality control (QC) samples shall be within ±15% of their individual nominal concentration values. In addition, at least 1 QC sample at each concentration level must be within ±15% of its individual nominal concentration value. In the study, the standard curves had r2 values 0.995 and 0.999 for nelfinavir and ravuconazole, respectively. Mean predicted concentrations of the QCs were within ±3.5% and ±8.2% of their nominal values for nelfinavir and ravuconazole, respectively; between-run and within-run precision of the plasma nelfinavir QC samples were no greater than 11.3% and 8.6% coefficient of variation (CV), respectively, while those of ravuconazole were no greater than 4.7% and 7.5% CV, respectively. These standard curves and the QC data indicated that the assay method for both nelfinavir and ravuconazole was precise and accurate.
Pharmacokinetic Analysis
The plasma concentration-time data for nelfinavir and ravuconazole were analyzed by noncompartmental methods27,28 using the MENU/PKMENU application and the Statistical Analysis System (SAS, version 6.12; SAS Institute Inc, Cary, NC) software package.29 The peak plasma concentration, Cmax, and the time to reach the peak concentration, Tmax, were obtained directly from experimental observations. The slope (
) of the terminal phase of the plasma concentration-time profile was determined by the method of least squares (log-linear regression of at least 3 data points), using no weighting factor. The apparent terminal half-life, T-HALF, was estimated as ln2/. The area under the plasma concentration-time curve in 1 dosing interval, AUC(
) for ravuconazole or AUC(0-24) for nelfinavir, was determined by summing the areas from time 0 to the time of the last measured concentration (at 24 hours postdose), calculated by using trapezoidal and log-trapezoidal (nelfinavir) or trapezoidal-only (ravuconazole) methods. The accumulation index (AI) for ravuconazole was calculated by dividing the AUC() on day 29 by the AUC() on day 2.
Statistical Analysis
The SAS statistical software package, version 6.12 (SAS Institute Inc), was used for all statistical analyses.29 Cmax and AUC(0-24) of nelfinavir were analyzed using an analysis of variance. The factors in the analysis were subject and day. A priori, the variables Cmax and AUC(0-24) were log transformed, and the resulting point and interval estimates of means and mean differences were exponentiated to express the results as geometric means and ratios of geometric means on the original scale of measurement. Lack of interaction was to be concluded if the 90% confidence intervals (CIs) of the ratios of Cmax and AUC(0-24) for the day 2 and day 29 means to the day 1 means were contained entirely within the prescribed limits of 0.67 and 1.50. This CI for the geometric mean ratios was chosen based on data published for nelfinavir that indicated a 35% increase in nelfinavir plasma AUC and a 25% increase in its Cmax after coadministration with ketoconazole were clinically insignificant given the nelfinavir safety profile,22 and no dose adjustment was recommended.30 CIs entirely outside the prescribed limit would indicate an interaction. CIs partly inside and partly outside the prescribed limit would be declared indeterminate. The test treatments were day 2 and day 29. The reference treatment was day 1. No adjustments were made for multiple comparisons. A priori, a sample size of 12 subjects was determined to provide at least 90% power to conclude absence of effect of ravuconazole on nelfinavir pharmacokinetics, assuming there is no effect. Fourteen subjects were enrolled to allow for dropouts. Descriptive statistics were computed for Cmax, AUC, AI (ravuconazole only), Tmax, and T-HALF for both nelfinavir and ravuconazole.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics of Nelfinavir
Simple summary statistics of nelfinavir pharmacokinetic parameters are presented by day in Table II. The results of the statistical analysis of Cmax and AUC(0-24) values are shown in Table III. The mean plasma concentration time profiles of nelfinavir on days 1, 2, and 29 are depicted in Figure 1.
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For day 2 and day 29, 90% CIs of both Cmax and AUC(0-24) of nelfinavir fell within the range (90% CI, 0.67-1.50) prescribed for the study for the lack of interaction. For Cmax and AUC(0-24), the geometric means of nelfinavir given with ravuconazole on day 2 were 30.7% and 31.9% higher, respectively, than those of the nelfinavir given alone on day 1. After continuous treatment with ravuconazole, the geometric means for Cmax and AUC(0-24) of nelfinavir given with ravuconazole on day 29 were 7.9% and 16.2% lower, respectively, than those of nelfinavir given alone on day 1. The median Tmax was 4 hours on day 1 and 3 hours on both days 2 and 29. The mean T-HALFs were 3.86, 4.38, and 3.79 hours on days 1, 2, and 29, respectively, which is consistent with previous findings of 3.0 to 5.0 hours.22,30
Pharmacokinetics of Ravuconazole
Simple summary statistics of ravuconazole PK parameters are presented by day in Table IV. Means and standard deviations of Cmin values of ravuconazole are depicted in Figure 2. The mean plasma concentration-time profiles of ravuconazole on days 2 and 29 are depicted in Figure 3.
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The mean values of Cmax and AUC() of ravuconazole were 1052 and 9133 ng/mL and 13 872 and 153 561 ng·h/mL on days 2 and 29, respectively. The T-HALF on day 29 was determined to be 192 hours in keeping with previous findings.15 The median Tmax was 4 hours on both days 2 and 29. Examination of trough plasma concentrations indicates that day 29 was at or nearly at steady state. The mean accumulation ratio was found to be 12.2 following once-daily doses for 28 days, which is consistent with a long T-HALF of ravuconazole.
Safety
There were no serious adverse events (AEs) or deaths in this study. Twenty-one (21) AEs were reported in 9 of 14 (64%) subjects. The most commonly reported AE was headache (5 events). Other AEs included diarrhea (3 events), pharyngitis (3 events), pain in the abdomen (2 events), myasthenia (1 event), herpes simplex (1 event), erythema (1 event), sweating (1 event), pain in the eye (1 event), rhinitis (1 event), pain (1 event), and accidental injury (1 event). All AEs in this study were of mild to moderate intensity and judged by the investigator as either possibly related or unrelated to the study drug. No subject discontinued the study due to an AE. All AEs were resolved without intervention prior to study discharge. No clinical significant abnormalities in laboratory results, ECG parameters, physical examinations, or vital signs were noted in the study. Hence, nelfinavir 750 mg and ravuconazole 400 mg were safe and well-tolerated when administered concomitantly with the regimen in the study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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) of simvastatin were 4-fold higher compared to simvastatin dosed alone, although the increase in the exposure is less than the increase in AUC of simvastatin when coadministered with itraconazole (10-fold higher).25,26
The results from the current study indicate that both Cmax and AUC(0-24) of nelfinavir satisfied the lack of interaction criteria (90% CI, 0.67-1.50) prescribed for the study. Compared to values on day 1, the geometric means for Cmax of nelfinavir were 30.7% higher and 7.9% lower on days 2 and 29, respectively, while the geometric means for AUC(0-24) of nelfinavir were 31.9% higher and 16.2% lower on days 2 and 29, respectively. Although the criteria for lack of the pharmacokinetic interaction were met, these results suggest a trend for ravuconazole to affect the disposition of nelfinavir. Based on the observations, ravuconazole may exhibit inhibitory effects following a single dose, resulting in increased nelfinavir exposure, while ravuconazole may exhibit inductive effects following multiple dose administration, resulting in decreased nelfinavir exposure. As mentioned in the introduction, ravuconazole showed induction potential on CYP2B and CYP3A isozymes following multiple oral doses of ravuconazole in rats and dogs by increasing the hepatic cytochrome P450 content for these isozymes (BMS data on file).
In contrast to the current study, there was no indication of ravuconazole possessing clinical CYP3A4 induction properties in the simvastatin study25 nor in the initial multiple ascending dose (MAD) study in which urinary 6-ß-hydroxycortisol:cortisol ratios were examined as a measure of CYP3A4 induction.15 One possible explanation for this observation is the difference in ravuconazole dosing duration, 14 days in the simvastatin study and in the MAD study compared to 28 days in the current study. It is possible that the longer treatment duration of ravuconazole is needed to observe its induction properties. In this study, the increase in nelfinavir exposure (31% for Cmax, 32% for AUC) due to the CYP3A4 inhibitory effect of ravuconazole was comparable to what was found in the nelfinavir and ketoconazole interaction study (nelfinavir Cmax and AUC increased by 25% and 35%, respectively), in which the increase in nelfinavir exposure was deemed clinically insignificant given the nelfinavir safety profile22 and no dose adjustment is warranted,30 while the decrease in nelfinavir exposure due to a possible CYP3A4 inductive effect of ravuconazole was modest (8% for Cmax and 16% AUC), which is unlikely to have a clinically significant impact on the anti-HIV efficacy of nelfinavir.34,35 Collectively, the study data indicate that coadministration of ravuconazole did not result in a clinically significant change in the plasma levels of nelfinavir.
Although additional information may be provided if both ravuconazole and nelfinavir were coadministered as multiple doses and the nelfinavir dose was 1250 mg as opposed to the 750 mg dose used (the more commonly prescribed dose regimen today is 1250 mg twice daily instead of 750 mg thrice daily), it is concluded that these potential modifications would not change the overall conclusion of the study. The pharmacokinetic properties of nelfinavir were evaluated in both healthy volunteers and HIV-infected patients, and no substantial differences were observed between the 2 populations.30 Based on these findings, it is anticipated that, similar to the healthy volunteers, coadministration of ravuconazole will not result in a clinically significant change in the plasma levels of nelfinavir in HIV-infected patients.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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