Adv Ther (2017) 34:2371–2385
`DOI 10.1007/s12325-017-0621-9
`
`ORIGINAL RESEARCH
`
`Effects of Ketoconazole on the Pharmacokinetics
`of Mifepristone, a Competitive Glucocorticoid
`Receptor Antagonist, in Healthy Men
`
`Dat Nguyen . Sarah Mizne
`
`Received: August 11, 2017 / Published online: October 11, 2017
`Ó The Author(s) 2017. This article is an open access publication
`
`ABSTRACT
`
`Introduction: Mifepristone,
`competitive
`a
`glucocorticoid receptor antagonist approved for
`Cushing syndrome, and ketoconazole, an anti-
`fungal and steroidogenesis inhibitor, are both
`inhibitors of and substrates for cytochrome P450
`(CYP3A4). This study evaluated the pharma-
`cokinetic effects of concomitant ketoconazole, a
`strong CYP3A4 inhibitor, on mifepristone.
`Methods: In
`an
`open-label,
`two-period,
`single-center study, healthy adult men received
`mifepristone 600 mg orally daily for 12 days
`(period 1)
`followed by mifepristone 600 mg
`daily plus ketoconazole 200 mg orally twice
`daily for 5 days (period 2). Serial pharmacoki-
`netic blood samples were collected predose and
`over 24 h postdose on days 12 (period 1) and 17
`(period 2). A cross-study comparison (using data
`on file) further examined whether systemic
`exposure to mifepristone plus ketoconazole
`exceeded the exposure following mifepristone
`1200 mg orally administered for 7 days.
`
`Enhanced content To view enhanced content for this
`article go to http://www.medengine.com/Redeem/
`D5BCF0602C731D7F.
`
`D. Nguyen (&)
`Corcept Therapeutics, Menlo Park, CA, USA
`e-mail: dnguyen@corcept.com
`
`S. Mizne
`MedVal Scientific Information Services, LLC,
`Princeton, NJ, USA
`
`Results: Sixteen subjects were enrolled and 14
`completed the study. Concomitant adminis-
`tration with ketoconazole
`increased the
`systemic exposure to mifepristone, based on
`geometric least squares mean ratios, by 28%
`for Cmax and 38% for AUC0–24. This increase
`was 85% and 87% of the exposure observed
`following mifepristone’s highest label dose of
`1200 mg/day for Cmax and AUC0–24, respec-
`tively. Adverse events (AEs) were reported in
`56.3% (9/16) of subjects during administra-
`tion of mifepristone alone and in 57.1%
`(8/14) during combination with ketoconazole.
`No serious AEs were reported.
`Conclusion: Systemic exposure to mifepris-
`tone increased following multiple doses of
`mifepristone 600 mg daily plus ketoconazole
`200 mg twice daily. Little to no increase in
`AEs occurred. Dose adjustment of mifepris-
`tone may be needed when given with
`ketoconazole.
`Funding: Corcept Therapeutics.
`
`Keywords: Cushing syndrome; CYP3A4-
`inhibitor; Drug interaction; Endocrinology;
`Ketoconazole; Mifepristone; Pharmacokinetics
`
`INTRODUCTION
`
`Mifepristone (KorlymÒ, Menlo Park, California)
`is a competitive glucocorticoid receptor antag-
`onist that has demonstrated clinical efficacy
`
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`Adv Ther (2017) 34:2371–2385
`
`and safety in patients with Cushing syndrome
`(CS) and diabetes or glucose intolerance and
`who cannot undergo surgery or have failed
`surgery [1]. The pharmacokinetic profile of
`mifepristone is characterized as nonlinear with
`less than dose-proportional increases in serum
`concentration following increased single or
`multiple doses [2, 3]. Following oral adminis-
`tration, mifepristone is rapidly absorbed with
`time to peak plasma concentrations between 1
`and 2 h after single doses and 1 and 4 h after
`multiple doses [2, 4]. The half-life of mifepris-
`tone is * 85 h, with time to steady state
`achieved within 2 weeks [4].
`Mifepristone is metabolized primarily via
`cytochrome P450 (CYP) isoform 3A4, yielding
`three
`active metabolites
`RU
`42633
`(mono-demethylated), RU 42848 (di-demethy-
`lated), and RU 42698 (hydroxylated) (Fig. 1)
`[5, 6]. The metabolites are each less potent than
`mifepristone at the glucocorticoid receptor; the
`affinities of RU 42633, RU 42848, and RU 42698
`to the glucocorticoid receptor are 61%, 45%,
`and 48%, respectively, compared with 100% for
`mifepristone [7]. Mifepristone has also been
`shown under in vitro conditions to inhibit as
`well as induce CYP3A4 [8, 9]. In addition to CS,
`mifepristone has also been studied in other
`patient populations, including those with psy-
`chotic depression [10–12], and it is currently
`being evaluated as a concomitant treatment in
`certain forms of breast and prostate cancers
`(ClinicalTrials.gov NCT02014337, NCT02788981,
`NCT02012296) [13–15]. Because mifepristone is
`a substrate of CYP3A4,
`it
`is important
`to
`examine the effects of a strong CYP3A4 inhi-
`bitor on its pharmacokinetic parameters. Typi-
`cally an area under the curve (AUC) increase of
`at least 5-fold in the presence of a strong inhi-
`bitor indicates a sensitive substrate of CYP3A4
`[16]. Data on the pharmacokinetic effects of
`concomitant administration with a strong
`CYP3A4 inhibitor on mifepristone are, however,
`lacking.
`Ketoconazole (NizoralÒ, Titusville, New Jer-
`sey) is a substrate for and well-known strong
`inhibitor of CYP3A4 [17], and it is listed by the
`Food and Drug Administration (FDA) as an
`interacting drug to investigate potential drug–-
`drug interactions between CYP3A4 substrates
`
`[16]. Although approved as an antifungal,
`ketoconazole is sometimes used off-label as a
`steroidogenesis inhibitor in the treatment of CS
`[18, 19]. Thus, the assessment of the pharma-
`cokinetic effects of concomitant ketoconazole
`on mifepristone are of particular interest to
`clinicians treating patients with CS.
`This study, conducted in healthy adult men,
`evaluated the effects of steady-state ketocona-
`zole on the pharmacokinetics of steady-state
`mifepristone. The effects of mifepristone on the
`pharmacokinetics of ketoconazole were also
`examined. In addition, because mifepristone
`use is associated with increases in cortisol and
`adrenocorticotropic hormone (ACTH) levels [1],
`we examined the
`effects of
`concomitant
`administration of mifepristone and ketocona-
`zole on these parameters in comparison with
`mifepristone alone. Safety and tolerability of
`the coadministered agents were also reported.
`
`METHODS
`
`Subjects
`
`included healthy men
`Eligible participants
`18–45 years of age with a body mass index (BMI)
`of 19–32 kg/m2 who weighed at least 60 kg and
`had no clinically significant abnormal findings
`on physical examination, electrocardiogram
`(ECG), blood pressure, heart rate, medical his-
`tory, or clinical laboratory assessments. Subjects
`must have had a corrected QT interval no
`greater
`than 450 ms on ECG at screening,
`morning serum cortisol within normal limits,
`and normal serum potassium. Participants with
`partners of childbearing potential must have
`been using two forms of medically accepted
`methods of contraception throughout the study
`and for at least 3 months (90 days) after the last
`dose of study medication; subjects with preg-
`nant partners were excluded. Subjects with any
`alkaline phosphatase, total bilirubin, or direct
`bilirubin outside normal range or an alanine
`aminotransferase or aspartate aminotransferase
`value greater than 1.2 times the upper limit
`were also excluded. Additional exclusion crite-
`ria
`included consumption of
`alcohol or
`
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`Adv Ther (2017) 34:2371–2385
`
`2373
`
`OH
`
`CH3
`
`OH
`
`CH2OH
`
`N
`
`O
`
`Mifepristone
`
`RU 42698
`
`OH
`
`CH3
`
`RU 42633
`
`OH
`
`CH3
`
`N
`
`O
`
`NH
`
`O
`
`H2N
`
`O
`
`RU 42848
`
`Fig. 1 Mifepristone and its three major metabolites
`
`caffeine-containing products 72 h prior to study
`baseline or use of concomitant medications or
`nicotine-containing products.
`All procedures followed were in accordance
`with the ethical standards of the responsible
`committee on human experimentation (institu-
`tional and national) and with the Helsinki Dec-
`laration of 1964, as revised in 2013. Informed
`consent was obtained from all patients for being
`included in the study. The protocol was
`approved by an independent
`investigational
`review board (IntegReview, Austin, Texas). This
`manuscript was prepared according to the
`International Society for Medical Publication
`
`‘‘Good Publication Practice for
`Professionals’
`Communicating Company-Sponsored Medical
`Research: the GPP3 Guidelines’’ and the Inter-
`national Committee of Medical Journal Editors’
`‘‘Uniform Requirements for Manuscripts Sub-
`mitted to Biomedical Journals.’’
`
`Study Design
`
`This was a phase 1, open-label, two-period study
`conducted at a single US center to evaluate the
`pharmacokinetic effects in healthy men of
`multiple doses of ketoconazole 200 mg twice
`
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`2374
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`Adv Ther (2017) 34:2371–2385
`
`daily orally on concomitantly orally adminis-
`tered multiple doses of mifepristone 600 mg
`once daily and vice versa. A cross-study com-
`parison using data on file was also conducted to
`determine whether the effect of ketoconazole
`on the systemic exposure to coadministered
`mifepristone exceeded that of the maximum
`recommended dose of mifepristone (1200 mg)
`[4].
`The 600-mg mifepristone dose was selected
`for analysis based on internal data suggesting
`that
`the
`increased mifepristone
`exposure
`resulting from concomitant administration
`with ketoconazole 400 mg total daily would be
`generally comparable to the exposure following
`1200 mg of mifepristone. The 200-mg twice-
`daily ketoconazole dose was consistent with the
`highest clinical dosing recommendations in its
`product labeling [20]. The twice-daily dosing
`regimen was also used to enhance the inhibi-
`tory effect of ketoconazole when given with a
`substrate with a long half-life, as is the case for
`mifepristone [21].
`absorption of
`the
`Food can enhance
`mifepristone and ketoconazole [4, 22]; there-
`fore, all medications were administered within
`30 min of a typical breakfast consisting of 34%
`fat. Subjects were admitted to the clinic on
`day - 2. On day - 1, subjects received a single
`dose of ketoconazole 200 mg, followed by a
`48-h pharmacokinetic sampling period that was
`completed on day 1 prior
`to mifepristone
`administration (Fig. 2).
`Subjects were dis-
`charged from the clinic following the 12-h
`sample and returned for the 24-, 36-, and 48-h
`sample. During period 1, mifepristone 600 mg
`was administered alone on days 1–12. During
`period 2, which followed on days 13–17, keto-
`conazole 200 mg twice daily was administered
`
`concomitantly with mifepristone 600 mg once
`daily. The morning dose of ketoconazole was
`administered
`approximately
`5 min before
`mifepristone. Subjects were readmitted to the
`clinic on the evening of day 11 and remained
`onsite through day 19. Subjects returned to the
`clinic for pharmacokinetic sampling on days 20,
`22, 25, and 28 and a termination visit was
`conducted on day 32.
`
`Sampling Procedures
`
`Plasma trough concentrations of mifepristone
`and its three active metabolites were measured
`from blood samples collected 30 min predose on
`days 1–11 and days 13–16; on washout days 18,
`20, 22, 25, and 28; and on termination visit
`day 32. Serial blood samples were collected pre-
`dose and at 0.5, 1, 2, 4, 8, 12, and 24 h on days 12
`and 17.
`Plasma concentrations of ketoconazole were
`measured in blood samples collected within
`30 min predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12,
`24, 36, and 48 h on day - 1 and within 30 min
`predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on
`day 17. Plasma trough concentrations of keto-
`conazole were also measured 30 min predose
`from blood samples taken on days 13–16 to
`ensure steady-state concentrations were reached.
`In the reference study of mifepristone 1200 mg,
`plasma concentrations of mifepristone and its
`metabolites were measured in blood samples
`collected predose and at 0.5, 1, 2, 4, 8, 12, and
`24 h after dosing on days 1 and 7.
`Samples were collected in heparinized vacu-
`tainer tubes and centrifuged at 2500 rpm for
`15 min at 4–6 °C. Harvested plasma samples
`were stored at approximately - 20 °C or lower
`and shipped under dry ice for analysis.
`
`Fig. 2 Dosing schedule. BID twice daily, QD once daily
`
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`Adv Ther (2017) 34:2371–2385
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`2375
`
`Fasting blood samples for the analysis of
`serum cortisol and plasma ACTH were collected
`between 07:00 and 09:00 during screening and
`on days 1 and 6 of period 1, days 13–17 of
`period 2, and termination day 32. Samples were
`collected prior to dosing during the study
`periods.
`
`Bioanalytical Procedures
`
`its
`Plasma concentrations of mifepristone,
`metabolites, and ketoconazole were assessed by
`MicroConstants (San Diego, California) using
`validated high-performance liquid chromatog-
`raphy (HPLC) methods with mass spectrometric
`(MS) detection. The assay lower limit of quan-
`tification was 10 ng/mL for mifepristone and
`the three active metabolites, and 5.0 ng/mL for
`ketoconazole. Data analysis was performed
`using MassLynx
`v.4.1
`(Waters, Milford,
`Massachusetts).
`Human plasma samples containing C-1073,
`RU 42633, RU 42698, RU 42848, a solution
`containing C-1073-d4, RU 42633-d4, RU
`42698-d4, and RU 42848-d4 (deCODE Genetics,
`Reykjavik, Iceland) as the internal standards,
`and sodium heparin as the anticoagulant were
`extracted using a mixture of hexane and methyl
`tert-butyl ether (MTBE). The organic layer was
`dried down under nitrogen and the residue was
`reconstituted in water/acetonitrile/formic acid
`(75:25:0.1, v/v/v). Sample extracts were ana-
`lyzed by reversed-phase chromatography using
`a phenyl column maintained at 50 °C. The
`mobile phase was nebulized using heated
`nitrogen in a Z-spray source/interface set to
`electrospray positive ionization mode. The
`ionized compounds were detected using a tan-
`dem quadrupole mass spectrometer (MS/MS).
`For determination of ketoconazole concen-
`trations, plasma samples containing ketocona-
`zole-d3 or ketoconazole-d8 (Toronto Research
`Chemicals Inc., North Yolk, Ontario, Canada)
`as
`the internal
`standard and tripotassium
`ethylenediaminetetraacetic
`acid or
`sodium
`heparin as the anticoagulant were adjusted to
`approximately pH 10.0 with ammonium
`hydroxide and extracted with an MTBE solu-
`tion. The samples were vortex mixed and
`
`centrifuged, and the lower portion was frozen in
`an ultra-cold freezer. The organic layer was
`transferred to a clean tube and then evaporated
`under nitrogen. The residue was reconstituted
`with acetonitrile. An aliquot was analyzed by
`reversed-phase HPLC using an Atlantis Hilic
`Silica column (Waters, Milford, Massachusetts),
`maintained at 40 °C. The mobile phase was
`nebulized using heated nitrogen in a Z-spray
`source/interface and the ionized compounds
`were detected using MS/MS.
`Accuracy and precision (percentage of varia-
`tion, %CV) were evaluated using replicate
`analyses of human plasma quality control
`samples prepared at concentrations of 30.0,
`300, and 1600 ng/mL for mifepristone and its
`metabolites and 15.0, 200, and 4000 ng/mL for
`ketoconazole. Deviation of the measured con-
`centration from the theoretical values (range
`± 2.00% to ± 8.67%)
`and %CV (range
`1.82–6.27%) of quality control
`samples of
`mifepristone,
`its metabolites (RU 42633, RU
`42698, and RU 42848), and ketoconazole were
`all within 15%.
`
`Pharmacokinetic Assessments
`
`For each individual, pharmacokinetic parame-
`ters were computed for mifepristone and its
`metabolites
`and
`ketoconazole
`using
`a
`non-compartmental analysis method using
`WinNonlin version 6.4 (Certara Inc, St. Louis,
`Missouri).
`Parameters
`included maximum
`plasma concentration (Cmax), area under the
`curve (AUC) using the linear trapezoidal rule,
`and time to maximum plasma concentration
`(tmax). For ketoconazole, AUC was calculated as
`AUC extrapolated to infinity (AUCinf)
`for
`day - 1 and AUC0–12 for day 17.
`
`Safety
`
`Safety and tolerability were assessed throughout
`the study by physical examinations, clinical
`laboratory tests, vital signs, ECGs, and adverse
`event (AE) reporting. The causal relationship of
`each AE to mifepristone and/or ketoconazole
`was assessed by the investigator as probably
`related, possibly related, or unrelated.
`
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`2376
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`Adv Ther (2017) 34:2371–2385
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`Statistical Analysis
`
`Statistical analyses for safety were performed
`using SAS version 9.2 or higher (Cary, North
`Carolina). Statistical analyses for pharmacoki-
`netic
`comparisons were performed using
`WinNonlin version 6.4 (Certara Inc. St. Louis,
`Missouri). The safety population was defined as
`all subjects who received at least one dose of
`study drug. The pharmacokinetic population
`was defined as all subjects who received study
`drug and for whom the pharmacokinetic profile
`could be adequately characterized. Pharma-
`cokinetic steady-state parameters of mifepris-
`tone when administered alone
`(period 1,
`day 12) were compared to the steady-state
`parameters when administered with concomi-
`tant ketoconazole at steady state (period 2,
`day 17) to estimate the magnitude of the effect
`of ketoconazole on mifepristone. A linear
`mixed-effects model was used to estimate the
`geometric least squares mean ratios (GMRs) and
`associated 90% confidence intervals (CIs) from
`the pharmacokinetic parameters
`(log-trans-
`formed values of Cmax and AUC). Comparisons
`of the steady-state pharmacokinetic parameters
`were considered not clinically different if the
`90% CIs around the GMR were within the
`standard bioequivalence interval of 80:125 [16].
`Median differences in tmax were computed using
`the Wilcoxon matched-pairs signed rank test for
`paired comparisons and the Mann–Whitney
`test for any unpaired comparisons; 90% CIs
`were computed using the Hodges–Lehmann
`method. Similar methods were used to compare
`GMRs and associated 90% CIs for the pharma-
`cokinetic parameters of ketoconazole following
`multiple doses of ketoconazole (200 mg twice
`daily) plus mifepristone on day 17 (log-trans-
`formed Cmax and AUC0–12) to a single dose of
`ketoconazole (200 mg) on day - 1 (Cmax and
`AUCinf).
`Sample size calculations determined that a
`sample size of 8 would achieve an 82% power to
`detect a mean of paired differences in AUC0–24
`of 18,857 ng h/mL with an estimated standard
`deviation (SD) of 15,963 ng h/mL and a signifi-
`cance level of 0.05 using a two-sided paired
`t test. A prespecified sample size of 16 subjects
`was selected for this study in order to account
`
`for an approximate discontinuation rate of up
`to 50%.
`Serum cortisol and plasma ACTH values were
`summarized with descriptive statistics (mean
`[SD] or median [range]). A Wilcoxon signed
`rank test was performed to examine the
`within-subject changes in cortisol and ACTH on
`day 17 of mifepristone plus ketoconazole com-
`pared with day 13 of mifepristone alone.
`
`RESULTS
`
`Study Population
`
`Overall, 16 healthy men (mean age 31.9 years
`[range 23–45 years]) were admitted to the study
`(Table 1); all received at least one dose of study
`drug and were included in the safety popula-
`tion. Two subjects discontinued mifepristone
`during period 1 because of AEs. Of the 14
`remaining subjects who completed the study,
`one subject had notably high mifepristone
`concentrations at all time points (3.01 times the
`mean) and was excluded prior to any mifepris-
`tone analysis as an outlier. The reason for this
`apparent outlier was unknown. In the reference
`study (1200 mg mifepristone), 24 subjects
`(mean age 42.7 years [range 22–61] years, 75%
`men, mean body mass index 27.0 kg/m2) were
`enrolled, of which 22 completed the study.
`
`Effects of Steady-State Ketoconazole
`on the Pharmacokinetics of Mifepristone
`and Metabolites
`
`Mean trough concentrations of mifepristone
`and its metabolites were increasing to steady
`state on days 10–12 before ketoconazole was
`administered
`(Fig. 3).
`Plasma
`concentra-
`tion–time curves for steady-state mifepristone
`and its metabolites before and after CYP3A4
`inhibition with ketoconazole are presented in
`Fig. 3a–c; pharmacokinetic parameters are pre-
`sented in Table 2. The pharmacokinetic profile
`following multiple doses of mifepristone alone
`showed that mifepristone was rapidly absorbed,
`with a median tmax of 4.25 h (Fig. 3a). Following
`concomitant
`ketoconazole
`administration,
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`Adv Ther (2017) 34:2371–2385
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`
`Table 1 Demographic and baseline characteristics
`
`Age, year, mean (SD)
`
`Race, n (%)
`
`Black
`
`White
`
`American Indian or Alaska native
`
`Native Hawaiian or Pacific
`Islander
`
`Height, cm, mean (SD)
`
`Weight, kg, mean (SD)
`BMI, kg/m2, mean (SD)
`
`All subjects
`(N 5 16)
`
`31.9 (6.7)
`
`8 (50)
`
`6 (37.5)
`
`1 (6.3)
`
`1 (6.3)
`
`177.8 (7.5)
`
`87.2 (10.8)
`
`27.6 (2.7)
`
`BMI body mass index, SD standard deviation
`
`concentrations of mifepristone were higher
`(day 17) than mifepristone administered alone
`(day 12). For mifepristone, the upper bound of
`
`the 90% CI for the calculated GMR of exposure
`exceeded 125% for Cmax and AUC0–24. The
`increase in mifepristone systemic exposure
`based on the GMRs was 28% for Cmax and 38%
`for AUC0–24 (Table 2), which was less than the
`5-fold or higher increase recommended for
`consideration as a sensitive CYP3A4 substrate.
`For metabolites RU 42848 and RU 42633, the
`calculated GMRs and 90% CIs of exposure ratios
`were within the FDA’s standard 80:125 com-
`parison interval,
`indicating that exposure to
`these metabolites was unaffected by ketocona-
`zole. The upper bound of the 90% CI of the
`calculated GMR exceeded 125% for Cmax and
`AUC0–24 for the RU 42698 metabolite, indicat-
`ing that concomitant administration with
`ketoconazole
`increased
`exposure
`to
`this
`metabolite (Table 2). Median tmax of mifepris-
`tone was unaltered (4.25 h on day 17 and
`day 12). There were no significant differences in
`tmax
`the medians of paired differences for
`between day 12 and 17 for mifepristone or any
`of
`the three metabolites. Half-life was not
`
`Fig. 3 Mean (SD) plasma
`trough concentrations of
`mifepristone (a) and its metabolites: RU 42633 (b), RU
`42698 (c), and RU 42848 (d) on days 10, 11, and 12 (left
`
`portion of graphs), followed by mean plasma concentra-
`tion–time profiles in the presence (day 17) and absence
`(day 12) of ketoconazole (right portion of graphs)
`
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`
`Table 2 Pharmacokinetic parameters for mifepristone and metabolites after administration of mifepristone plus keto-
`conazole (period 2, day 17) and mifepristone alone (period 1, day 12) (n = 13)
`
`Mifepristone 600 mg
`daily 1 ketoconazole
`200 mg twice daily
`
`Mifepristone
`600 mg alone
`
`GMR % (90% CI)
`(combination/alone)
`
`Parameter
`
`Mifepristone
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`4325 (732)
`
`4265
`
`3448 (836)
`
`3343
`
`47,473 (11,950)
`
`46,015
`
`4.25 (2.25–4.25)
`
`2078 (714)
`
`1983
`
`44,044 (15,789)
`
`42,098
`
`4.25 (4.25–12.00)
`
`596 (205)
`
`561
`
`12,743 (4545)
`
`11,947
`
`127.59 (116.66, 139.54)
`
`138.01 (127.12, 149.84)
`
`105.73 (95.92, 116.54)
`
`102.33 (94.31, 111.03)
`
`169.13 (156.36, 182.94)
`
`166.86 (155.06, 179.57)
`
`AUC0–24 (h ng/mL)
`
`Mean (SD)
`
`65,274 (15,686)
`
`GLSM
`a
`tmax
`
`(h)
`
`RU 42633
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`63,506
`
`4.25 (1.25–4.25)
`
`2225 (947)
`
`2096
`
`AUC0–24 (h ng/mL)
`
`Mean (SD)
`
`45,855 (20,039)
`
`GLSM
`a
`tmax
`
`(h)
`
`RU 42698
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`43,081
`
`8.25 (0.50–11.92)
`
`991 (285)
`
`949
`
`AUC0–24 (h ng/mL)
`
`Mean (SD)
`
`21,093 (6860)
`
`19,936
`
`GLSM
`a
`tmax
`
`(h)
`
`RU 42848
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`AUC0–24 (h ng/mL)
`
`8.25 (4.25–11.92)
`
`8.25 (4.25–12.00)
`
`1524 (389)
`
`1478
`
`1582 (353)
`
`1548
`
`95.48 (90.82, 100.38)
`
`Mean (SD)
`
`33,362 (7876)
`
`34,840 (6537)
`
`8
`
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`

`Adv Ther (2017) 34:2371–2385
`
`2379
`
`Table 2 continued
`
`Parameter
`
`Mifepristone 600 mg
`daily 1 ketoconazole
`200 mg twice daily
`
`Mifepristone
`600 mg alone
`
`GMR % (90% CI)
`(combination/alone)
`
`GLSM
`a
`tmax
`
`(h)
`
`32,511
`
`34,266
`
`94.88 (91.33, 98.56)
`
`4.25 (0.00–11.92)
`
`12.00 (0.00–23.80)
`
`GMRs and 90% CIs based on log-transformed values of AUC and Cmax
`AUC0–24 area under the curve from 0–24 h, CI confidence interval, Cmax maximum plasma concentration, GLSM geo-
`metric least squares mean, GMR geometric mean ratio, tmax time to maximum plasma concentration
`a tmax is presented as median (range)
`
`reported because the mean terminal elimina-
`tion half-life for mifepristone and its metabo-
`lites exceeded 64 h. As such, the measurement
`of half-life over the 24-h dose interval would be
`unreliable.
`
`Pharmacokinetics of Mifepristone
`with Concomitant Ketoconazole
`Compared to Mifepristone 1200 mg Alone
`(Cross-Study Comparison)
`
`Systemic exposure (Cmax and AUC) to mifepris-
`tone following multiple doses of mifepristone
`600 mg plus ketoconazole 200 mg twice daily was
`less than the exposure to mifepristone following
`multiple doses of mifepristone 1200 mg alone
`under similar fed conditions reported in the ref-
`erence study data (Table 3). The GMR of exposure
`to mifepristone was 85% and 87% of the exposure
`observed following the highest label dose of
`1200 mg/day for Cmax and AUC0–24, respectively.
`The upper bounds of the 90% CIs for the calcu-
`lated GMR of Cmax and AUC0–24 did not exceed
`the standard 125% interval limit (Table 3).
`For the metabolites RU 42633 and RU 42848,
`the upper bounds of the 90% CIs were less than
`125% for Cmax and AUC0–24, whereas
`for
`metabolite RU 42698, the upper bounds of the
`90% CIs exceeded the standard interval for Cmax
`and AUC0–24.
`
`Effects of Steady-State Mifepristone
`on the Pharmacokinetics of Ketoconazole
`
`Systemic exposure to ketoconazole following
`multiple doses of ketoconazole 200 mg twice
`
`daily administered with concomitant mifepris-
`tone 600 mg once daily over 5 days (day 17)
`were compared with the exposure following a
`single 200-mg dose of ketoconazole given alone
`(day - 1). Mean predose trough concentrations
`of
`ketoconazole
`during
`repeated
`dosing
`days 14–17 (1353.07–1615.64 ng/mL) suggested
`that
`steady state for ketoconazole in the
`presence of mifepristone was achieved by
`approximately day 16.
`The GMR of exposure for Cmax and AUC and
`their 90% CIs were all above 125%, indicating
`that ketoconazole exposure following steady-
`state twice-daily 200-mg ketoconazole plus
`concomitant steady-state mifepristone (day 17)
`was higher than ketoconazole exposure follow-
`ing single-dose 200-mg ketoconazole adminis-
`tered alone (day - 1) (Table 4). The increased
`exposure to ketoconazole with concomitant
`multiple doses of mifepristone vs single-dose
`ketoconazole alone was 2.53-fold higher for
`Cmax (GLSM 5224 vs 2067 ng/mL) and 3.65-fold
`higher for AUC (GLSM 37,653 vs 10,306 h ng/
`mL). Median tmax was 3.0 h (range 1.0–8.0 h)
`following single-dose ketoconazole vs 4.33 h
`(range 3.0–4.4 h) following steady-state keto-
`conazole plus steady-state mifepristone.
`
`Effects of Concomitant Ketoconazole
`and Mifepristone on Cortisol and ACTH
`
`Mean serum cortisol and plasma ACTH levels
`increased relative to baseline (screening period)
`and were elevated above the upper limit of
`normal (ULN) starting on day 6 of mifepristone
`alone (period 1) and remained elevated during
`
`9
`
`

`

`2380
`
`Adv Ther (2017) 34:2371–2385
`
`Table 3 Pharmacokinetic parameters for mifepristone and metabolites after administration of mifepristone plus keto-
`conazole (period 2, day 17) vs mifepristone alone (reference data, day 7)
`
`Parameter
`
`Mifepristone
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`AUC0–24 (h ng/mL)
`
`Mean (SD)
`
`GLSM
`
`RU 42633
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`AUC0–24 (h ng/mL)
`
`Mean (SD)
`
`GLSM
`
`RU 42698
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`AUC0–24 (h ng/mL)
`
`Mean (SD)
`
`GLSM
`
`RU 42848
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`
`AUC0–24 (h ng/mL)
`
`Mean (SD)
`
`GLSM
`
`Mifepristone 600 mg
`daily 1 ketoconazole 200
`mg twice daily
`
`Mifepristone
`1200 mg alone
`
`GMR % (90% CI)
`(combination/alone)
`
`4325 (732)
`
`4265
`
`65,274 (15,686)
`
`63,506
`
`2225 (947)
`
`2096
`
`45,855 (20,039)
`
`43,081
`
`991 (285)
`
`949
`
`21,093 (6860)
`
`19,936
`
`1524 (389)
`
`1478
`
`33,362 (7876)
`
`32,511
`
`5237 (1460)
`
`5039
`
`75,428 (20,328)
`
`72,766
`
`2264 (668)
`
`2176
`
`48,858 (13,702)
`
`47,164
`
`850 (258)
`
`814
`
`17,600 (5266)
`
`16,869
`
`1867 (584)
`
`1793
`
`41,571 (12,938)
`
`39,927
`
`84.64 (72.92, 98.23)
`
`87.27 (74.72, 101.94)
`
`96.31 (80.83, 114.75)
`
`91.34 (76.95, 108.43)
`
`116.55 (97.47, 139.38)
`
`118.18 (97.90, 142.66)
`
`82.45 (70.31, 96.70)
`
`81.43 (69.71, 95.11)
`
`GMRs and 90% CIs based on log-transformed values of AUC and Cmax
`AUC0–24 area under the curve from 0–24 h, CI confidence interval, Cmax maximum plasma concentration, GLSM geo-
`metric least squares mean, GMR geometric mean ratio
`
`10
`
`

`

`Adv Ther (2017) 34:2371–2385
`
`2381
`
`Table 4 Pharmacokinetic parameters for ketoconazole plus mifepristone (period 2, day 17) and ketoconazole alone
`(day - 1) (n = 14)
`
`Mifepristone 600 mg 1
`ketoconazole 200 mg
`twice daily
`
`Ketoconazole
`200 mg alone
`
`GMR % (90% CI)
`(combination/alone)
`
`2194 (792)
`
`2067
`
`10,910 (3826)
`
`10,306
`
`3.00 (1.00–8.00)
`
`252.71 (214.85, 297.26)
`
`365.36 (333.78, 399.93)
`
`Parameter
`
`Ketoconazole
`
`Cmax (ng/mL)
`
`Mean (SD)
`
`GLSM
`AUCa (h ng/mL)
`
`5317 (1315)
`
`5224
`
`Mean (SD)
`
`38,709 (11,451)
`
`GLSM
`b
`tmax
`
`(h)
`
`37,653
`
`4.33 (3.00–4.33)
`
`GMRs and 90% CIs based on log-transformed values of AUC and Cmax
`AUC area under the curve, Cmax maximum plasma concentration, CI confidence interval, GLSM geometric least squares
`mean, GMR geometric mean ratio, tmax time to maximum plasma concentration
`a AUC for combination was AUC0–12 (day 17) and for ketoconazole alone (day - 1) was AUCinf
`b tmax presented as median (range)
`
`period 2 with the addition of ketoconazole
`(Fig. 4a, b). Serum cortisol and plasma ACTH
`levels decreased to within normal
`limits by
`study end in all but one and four subjects,
`respectively. Mean serum cortisol levels were
`significantly lower on day 17 compared to
`day 13 (35.1 vs 41.9 lg/dL; p = 0.0107) (Fig. 4a).
`Mean ACTH levels were higher on day 17 com-
`pared to day 13, but the differences were not
`statistically significant
`(178 vs 148 pg/mL;
`p[0.05) (Fig. 4b).
`
`Safety
`
`At least one treatment-emergent AE was repor-
`ted in nine subjects (56.3%) during adminis-
`tration of mifepristone alone (period 1) and in
`eight subjects (57.1%) during coadministration
`of mifepristone and ketoconazole (period 2).
`The AEs were categorized as mostly mild in
`severity; four moderate AEs occurred, including
`three during period 1 (hypertension, rash, and
`vomiting) and one during period 2 (headache).
`There were no serious AEs or events of adrenal
`insufficiency reported during the study.
`
`Fig. 4 Mean (SD) serum cortisol (a) and plasma ACTH
`(b). ULN upper limit of normal
`
`Two participants were discontinued from the
`study during period 1. One subject with ele-
`vated blood pressure upon study entry was dis-
`continued on day 6 after
`the 5th dose of
`
`11
`
`

`

`2382
`
`Adv Ther (2017) 34:2371–2385
`
`mifepristone because of moderate hyperten-
`sion. The AE was classified by the investigator to
`be possibly related to mifepristone; however, an
`alternate etiology of anxiety was also noted.
`One other subject was discontinued on day 11
`after the 10th dose of mifepristone because of a
`moderate bilateral rash, which was classified by
`the investigator as related to mifepristone and
`resolved within 4 days without sequelae. Mildly
`elevated liver enzymes were reported for one
`subject during the mifepristone plus ketocona-
`zole dosing period, starting approximately 1 day
`after the first dose of ketoconazole. During the
`concomitant dosing period, aspartate transam-
`inase and alanine transaminase ranged from 45
`to 76 U/L (normal range 0–37 U/L) and 85 to
`126 U/L (normal range 6–45 U/L), respectively.
`Both returned to normal ranges during the
`washout period. There were no clinically
`meaningful changes in hematology, biochem-
`istry, ECG, urinalysis findings, or orthostatic
`vital signs.
`
`DISCUSSION
`
`This study was conducted to examine the
`pharmacokinetic effects following concomitant
`mifepristone and ketoconazole administration.
`Coadministration of mifepristone 600 mg daily
`plus ketoconazole 200 mg twice daily resulted
`in a mean increase in exposure to mifepristone
`of approximately 28% for Cmax and 38% for
`AUC0–24. The increased exposure was approxi-
`mately 85% of the maximum exposure follow-
`ing the highest labeled dose of mifepristone
`(1200 mg) and less than the at least 5-fold
`increase needed to be considered a sensitive
`substrate [16]. Coadministration with keto-
`conazole had little effect on the exposure to
`mifepristone’s mono-demethylated (RU 42633)
`or di-demethylated (RU 42848) metabolites;
`exposure to the hydroxylated metabolite (RU
`42698) increased by approximately 70%. The
`mechanisms for the increased exposure to this
`metabolite could not be determined from this
`study. While it is unknown what the clinical
`effect of the increased exposure to the RU 42698
`metabolite would be, its lower affinity for the
`glucocorticoid receptor than mifepristone likely
`
`minimizes its clinical importance relative to the
`exposure to mifepristone and the other active
`metabolites.
`As expected, the GLSM Cmax and interval
`AUC0–12 of ketoconazole following multiple
`doses of ketoconazole 200 mg twice daily plus
`mifepristone was substantially higher (2.53- and
`3.65-fold) than the Cmax and AUCinf following a
`single dose of ketoconazole 200 mg. The
`increased interval AUC0–12 (day 17) vs AUCinf
`after a single dose (day - 1) is consistent with the
`nonlinear pharmacokinetics of ketoconazole,
`which has shown greater than expected increases
`in AUC following multiple dosing [23]. Factors
`contributing to the increased exposure to keto-
`conazole in this analysis could include inhibition
`of CYP3A4 by mifepristone and/or autoinhibi-
`tion of CYP3A4 by ketoconazole.