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PHARMACOKINETICS |
From Johnson & Johnson Pharmaceutical Research & Development, Titusville, New Jersey (Dr Zhang, Dr Zannikos); Bordet Institute, Medical Oncology, Brussels, Belgium (Dr Awada, Dr Piccart-Gebhart); AZ St-Augustinus, Medical Oncology, Antwerp, Belgium (Dr Dirix); Centre G-F Leclerc, Medical Oncology Department, Dijon, France (Dr Fumoleau); and Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium (Dr Verhaeghe, Dr Francois, Dr De Porre).
Address for reprints: Steven Zhang, PhD, Pharmacokinetics, Modeling & Simulation, Centocor, 200 Great Valley Parkway, Malvern, PA 19355.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Tipifarnib • metabolite • protein binding • oral administration • intravenous infusion • pharmacokinetics
Farnesylated targets, such as Ras, RhoB, and phosphatidyl inositol-3 kinase (PI3K)/serine-threonine kinase protooncogene protein transduced by the acute transforming virus AKT8 (AKT) that are involved in cellular homeostasis and proliferation are often mutated or dysregulated in acute myeloid leukemia (AML).4 Inhibition of farnesylation prevents myeloid leukemia cell growth and progenitor colony formation in vitro. Leukemia cells obtained from cancer patients are significantly more sensitive to the growth-inhibitory effects of tipifarnib than are normal bone marrow cells.5 The identification of the specific downstream effectors by which inhibition of farnesylation results in antileukemic activity is a subject of ongoing research. Tipifarnib has shown signs of clinical activity in patients with hematologic malignancies including but not limited to acute myelogenous leukemia, myelodysplastic syndrome, and multiple myeloma and in patients with solid tumors including but not limited to glioblastoma and breast cancer.2
To date, several investigators have examined the pharmacokinetics of tipifarnib after oral administration.2,6-8 A dose-escalation study of tipifarnib was performed on 28 patients with advanced cancer.8 Within the 50- to 500-mg twice-daily dose range, a peak concentration range of 68 to 1458 ng/mL was achieved between 2 to 5 hours after oral administration. A linear increase in the plasma concentrations of tipifarnib was observed. Trough and peak plasma concentrations of tipifarnib observed in this study were within the range of antileukemic activity.
Tipifarnib is extensively metabolized after oral administration. The data from in vitro studies with human hepatocytes indicated that tipifarnib undergoes direct glucuronidation.9 The experiments with diagnostic inhibitors and heterologous expression systems also revealed that CYP3A4 was a predominant metabolic pathway for tipifarnib compared to other CYP450 enzymes such as CYP2C19, CYP2A6, CYP2D6, and CYP2C8/9/10.10 The metabolites of tipifarnib were inactive as farnesyl transferase inhibitor and antiproliferative agent in several preclinical studies.11,12 However, the pharmacokinetics of its individual metabolites has not been studied in humans. Several metabolites of tipifarnib were found in plasma samples after [14C]tipifarnib was orally administered to healthy male subjects.13 These metabolites included a glucuronide conjugate of tipifarnib and metabolites formed via oxidative demethylation, deamination, and loss of the methyl-imidazole moiety. Glucuronidation of the parent compound is a major pathway of biotransformation. However, the metabolism of tipifarnib after administration of this compound to cancer subjects has not been studied. In addition, potential differences in tipifarnib metabolite disposition that may occur after different routes of administration have not been systematically examined.
Moreover, cancer patients, both with solid tumors as well as with hematologic malignancies, regularly suffer from impaired oral intake. This factor can be due to direct tumor obstruction, leukemic gingival hyperplasia, mucosal bleeding, a surgical procedure affecting the aerodigestive tract, concomitant oral (fungal) infections, significant taste perversion or anorexia, or nausea and vomiting. Thus, the rationale of the present work was to evaluate an alternative route of administration (ie, parenteral) of tipifarnib for patients in whom oral administration is problematic. The objective of the current study was to identify intravenous regimens, either as continuous infusion or as a shorter-duration infusion, that would mimic the systemic exposure obtained after the current twice-daily oral administration of tipifarnib and would allow for similar clinical outcome as the oral administration. In addition, the degree to which tipifarnib is bound to plasma proteins was determined because this important pharmacokinetic parameter has not been studied in cancer patients. Finally, systemic exposure of tipifarnib's major metabolites after oral administration was compared with those observed after intravenous administration.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Tipifarnib (ZARNESTRA, R115777) was supplied as either 100-mg oral tablets or as lyophilized powders in vials containing 100 mg tipifarnib and 2.0 g hydroxy-propyl-ß-cyclodextrin (HPßCD). The lyophilized powders were reconstituted immediately prior to intravenous infusion. This aliquot was diluted in 0.9% sodium chloride (NaCl) and administered through a syringe driver with appropriate infusion lines.
Study Subjects
Men and women aged 18 years and older with pathologically confirmed cancer, not amenable to curative therapy, were eligible for this study. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status score 
2. Other requirements included an absence of radiation therapy or chemotherapy at least 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C) and adequate oral intake to maintain a reasonable state of nutrition.
Patients were excluded if they had significantly abnormal hematologic status as judged by a neutrophil count <1500/mm3, a platelet count <100 000/mm3, serum bilirubin >2.0 mg/dL, transaminase >5 times the upper limit of institutional normal, or creatinine >1.5 mg/dL. Concomitant administration of proton pump inhibitors (eg, omeprazole, lansoprazole, pantoprazole) was not allowed during the oral administration period of tipifarnib. Patients who had undergone surgery of the gastrointestinal (GI) tract likely to interfere with drug absorption through impaired gastric acidity or deviation of the upper GI tract were not eligible. The presence of any concurrent disease that in the opinion of the investigator would constitute a hazard for participating in this study, and specifically grade 
2 peripheral neuropathy, also rendered a patient ineligible.
Study Design
The objective of the first (dose-determination) phase of the study was to identify an intravenous regimen that was well tolerated. It was expected that this regimen would be equivalent to 50% to 60% of a clinically relevant oral dose (200 mg), based on a prior pilot determination of absolute bioavailability in healthy male volunteers.14 A first cohort of 3 subjects received the following uninterrupted 4-day consecutive treatments of tipifarnib: 30 mg as a 2-hour intravenous infusion twice daily on days 1 through 4, followed by 200 mg as oral administration twice daily on days 5 through 8, followed by 60 mg/d as a continuous intravenous infusion on days 9 through 12. A second cohort of 3 subjects received similar 4-day regimens of tipifarnib: 60 mg as a 2-hour intravenous infusion twice daily, followed by 200 mg as oral administration twice daily, followed by 120 mg/d as a continuous intravenous infusion. There was no washout period between each of the 4-day oral or intravenous treatments described.
The second and third subjects in the cohort were to be started only when the first subject completed the first intravenous and the oral treatment (ie, 8-day period) without a dose-limiting toxicity (DLT). Dose-limiting toxicity was defined as any of the following drug-related toxicity observed during the first 21 days of the study: nonhematologic toxicity grade 3 excluding nausea or vomiting that responds to symptomatic management; grade 1-2 neuropathy, lasting for >7 days, failing to recover or stabilize within 3 weeks; grade 3 neutropenia that lasts >7 days or is associated with fever >38.5°C and/or infection; grade 3 thrombocytopenia lasting >5 days or grade 4 neutropenia or thrombocytopenia of any duration. If a DLT occurred in 1 of 3 subjects of either the first or the second cohort, 3 supplementary subjects were to be added to that cohort. If more than 1 subject experienced DLT (either in the first 3 subjects or in the extended cohort of 6 subjects), dose escalation was to be terminated, and other subjects in that cohort had to complete their therapy at the same dose.
The second (intravenous-oral bridging) phase of the study was completed in a separate group of patients. Systemic exposure to tipifarnib after the selected 2-hour and continuous intravenous regimens (from the previous dose-determination phase) was compared to exposure after a 200-mg twice-daily oral regimen. The bridging phase was initiated when at least 2 subjects of the second cohort of the dose-determination phase were observed without DLT until day 21. In total, 24 subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences at the chosen intravenous regimens to account for potential sequence effects.
Sequence 1. 100 mg twice daily administered as a 2-hour intravenous infusion on days 1 through 4, followed by 200-mg oral tablets twice daily on days 5 through 8 and then 200 mg/d administered as a continuous 4-day intravenous infusion on days 9 through 12.
Sequence 2. 200 mg/d administered as a continuous 4-day intravenous infusion on days 1 through 4, followed by 200-mg oral tablets twice daily on days 5 through 8 and then 100 mg twice daily administered as a 2-hour intravenous infusion on days 9 through 12.
Oral doses of tipifarnib were to be given immediately after the intake of food. The infusions of tipifarnib were administered either via a peripheral vein of the forearm or, for the higher doses, via a central vein.
Plasma Sampling and Assay
In both the dose-determination and the bridging phases, pharmacokinetic sampling was performed during a 10-hour period from the start of the morning dose on day 4 of each treatment. Whole blood samples were taken immediately before and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours after oral administration. For 2-hour intravenous infusion, blood samples were taken immediately before and 1, 2 (ie, just before the end of the infusion), 2.25, 3, 4, 6, 8, and 10 hours after dosing. Blood samples were taken immediately before and 2, 4, 6, 8, and 10 hours after the start of the continuous intravenous infusion.
A minimum of 7 mL blood for each pharmacokinetic sample was collected. Whole blood samples were immediately placed on ice and centrifuged within 2 hours after collection (10 minutes, 1000 x g). Separated plasma was frozen immediately at –18°C until assayed.
Plasma samples were thawed at room temperature, and individual samples were analyzed for tipifarnib using a previous published method.6 To 1-mL aliquots of human plasma, 200 ng internal standard (R121550, a structural analog) was spiked. After adding 1 mL sodium hydroxide (NaOH, 1 M), the samples were extracted twice with 4 mL heptane containing 10% isoamylalcohol. The combined organic phases were back-extracted with 2 mL hydrochloric acid (HCl, 2 M). After alkalization with concentrated ammonia, the aqueous phase was extracted once with 5 mL heptane containing 5% isoamylalcohol. This extract was evaporated under nitrogen at 65°C, and the residue dissolved in 100 µL injection solvent (Ammonium-acetate 0.01 M/acetonitile/methanol; 50/25/25). A 15 µL extract was injected into an high-performance liquid chromatography with UV detection (Agilent Technologies, Palo Alto, Calif) at a wavelength of 240 nm. Separation was performed on a 10 x 4.6-mm chromatographic column, packed with 3 µm C18 BDS-Hypersil (Alltech Corp, Deerfield, Ill). Elution was initially isocratic at 0.01 M ammonium acetate/acetonitrile (52/48) until elution of the compounds of interest, followed by a gradient to 90% acetonitrile at a flow rate of 0.8 mL/min. The total run time was 14 minutes. The assay was validated in the range 2.00 to 5000 ng/mL.
The metabolites of tipifarnib, in particular R130525, R107252, and R104209, were determined using liquid chromatography/tandem mass spectrometry. The chemical structure of these metabolites is published elsewhere.13 To determine the presence of glucuronidated metabolites, the plasma samples were also analyzed after deconjugation with Escherichia coli ß-glucuronidase (Boehringer Ingelheim GmbH, Ingelheim, Germany).13 The sample preparation was as follows: aliquots of 0.2 mL human plasma or 1.0 mL aliquots of the diluted, deconjugated plasma samples were spiked with a mixture of 3 internal standards at 5 ng each: a stable isotope-labeled compound, R198838, used for tipifarnib and R130525 and 2 structural analogs, R107252 and R121704, used for R101763 and R104209, respectively. After adding 1 mL 0.1 NaOH, samples were extracted twice with 3 mL heptane, containing 10% isoamyl-alcohol. The combined organic fractions were evaporated under nitrogen, and the residue was reconstituted in a mixture of 100 µL methanol and 100 µL 0.002 M ammonium acetate. Chromatographic separation was done on a C18 BDS-Hypersil 3 µm (3.2 mm ID x 50 mm) column. The injection volume was 25 µL. The isocratic mobile phase comprised 0.002 M ammoniumformate (pH 4 with formic acid)/acetonitrile (44/56) and pumped at 0.5 mL/min. Detection was by tandem mass spectrometry with turbo ion spray ionization (positive ion mode). The following mass transitions were used for monitoring the different compounds and internal standards: tipifarnib, 489.1 
407.1; R198838, 492.1 407.1; R130525, 475.1 393.1; R101763, 394.0 139.0; R104209 + R107252, 408.0 139.0; and R121704, 422.1 139.0. The assay was validated in the range 0.50 to 1250 ng/mL for each of the metabolites and 10.0 to 25 000 ng/mL for tipifarnib after deconjugation.
Tipifarnib Protein Binding Analysis
Tipifarnib was specifically labeled with [14C] at the asymmetric carbon atom. A 7-mL blood sample was taken from 24 patients at 4 hours after the start of the continuous intravenous infusion of tipifarnib on day 4. The plasma samples were fortified with [14C]-tipifarnib at 500 ng/mL. The fortified plasma samples were subjected to equilibrium dialysis against a 0.067 M phosphate buffer, pH 7.17 at 37°C for 4 hours in a Dianorm system with identical macro-1 Teflon cells and Diachema 10.17 dialysis membranes (molecular weight cutoff 10 000). Radioactivity levels were measured in duplicate 100-µL aliquots of the fortified plasma before and after equilibrium dialysis and in 1000-µL duplicate aliquots of the contents of buffer compartments of the dialysis cells admixed with methanol after dialysis in a Packard Tri-Carb 1900 TR liquid scintillation spectrometer (Packard Instrument Co, Meriden, Conn). The total protein concentration was determined with a colorimetric biureet method, Roche Diagnostics (Roche Diagnostics GmbH, Mannheim, Germany) kit 1929917. The albumin concentration was determined with a colorimetric bromocresol green method kit (Roche Diagnostics 1970909). The 
1-acid glycoprotein concentration was determined with an immuno-turbidimetric method kit (Roche Diagnostics 1557602). All these tests were performed on a Roche Hitachi Modular analyzer.
The fraction of unbound tipifarnib (fu) was calculated as the ratio of the unbound concentration (Cu) to the total concentration (C) as determined by radioactivity measurements in the buffer (Cu) and plasma (C) compartments of the dialysis cells: fu = Cu/C. The bound fraction is fb = 1 – fu.
Noncompartmental Pharmacokinetic Analysis
Individual plasma concentration-time data of tipifarnib during the 10-hour period from the start of the morning dose on day 4 of each administration period were analyzed by noncompartmental methods using the program WinNonlin version 3.1 (Pharsight Corp, Cary, NC). The area under the concentration-versus-time curve from time 0 to 10 hours (AUC0-10h) was calculated using the linear trapezoidal method. Maximum plasma concentrations (Cmax), plasma concentration at steady state (Css, only for the continuous intravenous infusion), and time to reach the peak plasma concentration (tmax) were the observed values. The bioavailability of tipifarnib after oral administration was calculated based on AUC0-10h values according to [AUCpo x DOSEiv/AUCiv x DOSEpo)] x 100%.
Statistical Analysis
Demographic information was summarized as minimum, median, and maximum. The pharmacokinetic data for tipifarnib and its metabolites were also summarized using descriptive statistics. The systemic exposures (plasma Cmax and AUC0-10h) to tipifarnib after oral and intravenous administrations from the subjects whose pharmacokinetic samples for all 3 treatments were available were evaluated using analysis of variance (ANOVA). The point estimates and corresponding 90% confidence intervals around the least squares mean ratio of intravenous infusion (test) versus oral administration (reference) for tipifarnib Cmax and AUC0-10h were calculated. The analysis was performed on logarithmically transformed pharmacokinetic parameters using the SAS version 6.12 statistical software program (SAS Institute, Cary, NC).
Clinical Assessment
Complete patient history was taken, and a physical examination (including vital signs), hematologic tests, and clinical chemistry tests were performed at baseline and during treatment. To assess cardiovascular safety, 12-lead electrocardiograms were recorded at screening, during cycle 1, and at the end of therapy. Although objective tumor response was not the primary objective of this study, an attempt was made to obtain appropriate measurements to assess response. All adverse events and clinically relevant laboratory abnormalities were graded according to the Common Toxicity Criteria (CTC version 2.0).15
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Demographic data from the 32 subjects recruited for the study are summarized in Table I. There were no obvious differences between the 2 randomized groups of cohort 3 (bridging phase).
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In the second cohort, 3 additional subjects received 4-day regimens of 60 mg tipifarnib twice daily as a 2-hour intravenous infusion, followed by 120 mg/d as continuous infusion. Systemic exposures to tipifarnib after these intravenous regimens were approximately 47% and 46% lower, respectively, relative to the exposure after a 200-mg oral dose (Tables II and IV). Again, no DLT was observed in this cohort. Based on these results, a twice-daily regimen of 100 mg administered as a 2-hour infusion and a 200-mg/d continuous infusion were chosen for the intravenous to the oral bridging study.
Plasma Pharmacokinetics of Tipifarnib
As expected, the shape of the tipifarnib plasma concentration-time profile was dependent on the route of administration and the dosing regimen (Figure 1). Peak plasma concentrations of tipifarnib were apparent after oral administration and the 2-hour intravenous infusion. In contrast, continuous intravenous infusion produced no obvious peak.
Maximum plasma concentrations were observed at approximately 2 hours after oral administration of 200 mg twice daily of tipifarnib for 4 consecutive days (Table IV). The range of tmax was 0.5 to 3 hours in 29 subjects; 1 subject had a maximum concentration at 8 hours. The arithmetic mean Cmax and AUC0-10h values (±SD, n = 24), after 4 days of twice-daily oral dosing were 994 ± 487 ng/mL and 3990 ± 1671 ng·h/mL, respectively.
Higher plasma concentrations of tipifarnib were observed when a 100-mg dose was given as a 2-hour intravenous infusion relative to a 200-mg oral dose (Table IV). On average, the Cmax and AUC0-10h values were 48.0% and 19.3% higher, respectively, when tipifarnib was administered as a 2-hour intravenous infusion (100 mg twice daily) than when administered orally (200 mg twice daily) (Table IV). The upper limit of the 90% confidence interval fell outside the 80% to the 125% range of bioequivalence.
The mean AUC0-10h values on day 4 were similar both after oral administration (200 mg twice daily) and continuous intravenous infusion (200 mg/d, Table V). The lower limit of the 90% confidence interval fell within the 80% to 125% range; however, the upper limit extended slightly beyond this range (Table V). In terms of total systemic exposure as measured by the AUC0-10h, the effect of dosing by continuous infusion was similar to that of dosing by oral administration. However, the shape of the profiles was different in that no peak tipifarnib concentration was apparent after the continuous infusion.
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After dose normalization, the mean absolute bioavailability of the oral tablet formulation (oral versus 2-hour intravenous) was 46.3%. Similarly, the mean absolute bioavailability (oral versus continuous intravenous infusion) of the oral tablet formulation was 40.9%.
Systemic exposure to tipifarnib was comparable after administration as continuous intravenous infusion (200 mg/d) or as 2-hour intravenous infusion (100 mg twice daily). Again, despite the differences in the shape of the plasma concentration-time profiles, the mean AUC0-10h values were similar. The upper and lower limits of the 90% confidence interval (81.1%-100.3%) fell within the 80% to 125% range.
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Protein Binding of Tipifarnib in Plasma
Tipifarnib was extensively bound to plasma proteins in all samples analyzed (Figure 2). The mean free (unbound) fraction was 0.62% (range, 0.45%-0.88%) in the plasma samples drawn 4 hours after the start of the continuous intravenous infusion. The fraction of unbound tipifarnib was independent of total drug plasma concentration in the range of 211 to 812 ng/mL. No data are available on protein binding from subject samples taken after oral administration or after 2-hour intravenous infusion. However, the median plasma concentration after 200 mg twice daily oral administration for 4 days during the 10-hour dose interval is in the range of 159 to 788 ng/mL.
The mean concentrations (range) of serum albumin, 1-acid glycoprotein, and total protein were 4.1 g/100 mL (3.1-4.7 g/mL), 131 mg/100 mL (90-218 mg/100 mL), and 6.8 g/100 mL (4.7-7.9 g/mL), respectively.
Metabolites of Tipifarnib in Plasma
Plasma pharmacokinetic data of tipifarnib metabolites were analyzed on days 4, 8, and 12 after 4 days' administration as oral tablet (200 mg twice daily), 2-hour intravenous infusion (60 and 100 mg twice daily), or continuous intravenous infusion (120 and 200 mg/d). The metabolites analyzed included R130525, R101763, R104209, and tipifarnibglucuronide, R101763-glucuronide, R130525-glucuronide, and R104209-glucuronide. The chemical structures of these metabolites were determined by Garner et al.13 The major metabolites observed in the systemic circulation were R130525 and the tipifarnib-glucuronide (Figure 3). The major and minor metabolites of tipifarnib determined in intravenous routes were the same as those in oral administration.
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Systemic exposure (Cmax and AUC0-10h) to the R130525 metabolite increased with an increase in the tipifarnib dose intravenously administered (Table VII). The mean ratio of AUC0-10h values for the R130525 relative to tipifarnib was one fifth for the oral administration and approximately one tenth for 2-hour intravenous infusion and continuous intravenous infusion.
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Other metabolites of tipifarnib after oral administration of 200 mg tipifarnib were also measured in plasma including R101763 (Cmax, 14.8 ng/mL; AUC0-10h, 101 ng·h/mL), R104209 (Cmax, 69.7 ng/mL; AUC0-10h, 447 ng·h/mL), R130525-glucuronide (Cmax, 53.0 ng/mL; AUC0-10h, 320 ng·h/mL), R10176 [GenBank] -glucuronide (Cmax, 12.0 ng/mL; AUC0-10h, 63.9 ng·h/mL), and R104209-glucuronide (Cmax, 64.0 ng/mL; AUC0-10h, 434 ng·h/mL). The concentrations of these metabolites were much lower than those of R130525 and tipifarnib-glucuronide. The exposure to these metabolites after the intravenous administrations was lower than those after the oral administration.
Clinical Assessment
All subjects were evaluable for toxicity. One subject was withdrawn after 3 days as it was discovered she was not eligible for the study: no adverse events were reported. One subject had myelodysplastic syndrome. This subject had periods of grade 3-4 neutropenia, managed by dose reductions and delays. Platelet counts remained normal. No significant non-hematologic toxicity was observed. A summary, for the remaining 30 subjects, of the treatment-emergent drug-related hematologic and nonhematologic toxicities during cycle 1 and all cycles is shown in Table VIII.
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Grade 3 or 4 drug-related hematologic toxicity, neutropenia, was observed in 9 of 30 patients (30%). Febrile neutropenia was reported in 1 subject (3%). The main drug-related nonhematologic toxicities, mainly grade 1, were fatigue (60%), nausea (40%), anorexia (20%), vomiting (17%), and diarrhea (13%). Phlebitis was observed in 3 subjects, all when intravenous bolus was given via a peripheral venous access; this toxicity was not observed when using a central vein.
Thirty-one subjects were evaluable for efficacy: the subject with myelodysplastic syndrome had a hematologic improvement (durable increase in hemoglobin as per International Working Group criteria for response in myelodysplastic syndrome) for 8 months. No objective tumor responses were observed, and 14 subjects had stable disease for at least 6 months.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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On average, the exposures (AUC0-10h) to tipifarnib were comparable and within a narrow range (3990-4487 ng·h/mL) when tipifarnib was administered as an oral tablet (200 mg twice daily), 2-hour intravenous infusion (100 mg twice daily), or continuous intravenous infusion (200 mg/d). When the shape of the profiles of the 2 intravenous regimens is considered, the 2-hour infusion more closely mimicked oral administration.
The mean Cmax and AUC0-10h values after oral administration of 200 mg tipifarnib twice daily dose were 994 ng/mL and 3990 ng·h/mL, respectively. This finding is in good agreement with a previous study in which 150 and 300 mg tipifarnib was orally administered twice daily (mean Cmax of 443 and 974, respectively; mean AUC0-12h values of 2495 and 4674 ng·h/mL, respectively).8
The mean oral bioavailability of tipifarnib tablet administered under fed conditions was 46.3% (by reference to 2-hour intravenous infusion twice daily) and 40.9% (by reference to continuous intravenous infusion). These results represent an approximation of absolute oral bioavailability, because plasma samples were collected for only 10 hours after the last drug administration. However, it is clear that tipifarnib has relatively good bioavailability when administered with food.
Previous studies in humans indicated that tipifarnib is metabolized extensively, and the unchanged parent compound is a relatively small constituent in plasma.13 After oral administration, concentrations of unchanged tipifarnib were, on average, 42 times lower than total radioactivity concentrations in non-precipitated samples and approximately 8 times lower in deproteinized samples. No unchanged drug was excreted in the urine, and less than 7% of the oral dose administered was recovered in feces as tipifarnib.
Consistent results were obtained in the present study. The plasma AUC0-10h values of tipifarnib-glucuronide were 3- to 30-fold higher than those of tipifarnib. This finding is probably attributable to the first-pass effect through the liver (ie, loss of the parent compound prior to systemic absorption) associated with dosing via the oral route. Tipifarnib possesses amino and keto groups in its structure. Therefore, direct conjugation is to be expected. Of importance, in vitro studies with NIH 3T3 H-ras cell line and farnesyl protein transferase enzyme indicated that the glucuronide-metabolite of tipifarnib is not an inhibitor of farnesyltransferase.16 Other metabolites of tipifarnib formed via oxidative biotransformation were measured in the plasma of patients including R130525 and R104209 and their respective glucuronidated conjugates and R101763 in the present and previous studies.13 In addition, the metabolites identified in this study were independent of the administration routes. The results indicate tipifarnib has the same metabolic pathways through intravenous administration compared to those by oral administration.
Exposure to the 2 predominate metabolites of tipifarnib, the glucuronide conjugate and N-dealkylated species R130525, increased with an increase in the intravenous dose of tipifarnib administered. These pathways are apparently not saturated within the dose range studied. Relative exposure to R130525 after each route of administration was comparable. In contrast, the plasma concentrations of the glucuronidated metabolite were approximately 2-fold higher after oral dosing than after intravenous administration. More extensive glucuronidation during first-pass metabolism in the liver after oral administration is the most likely explanation of this route-dependent difference in the relative concentrations of tipifarnib-glucuronide. The results are also indicative of a metabolite-specific impact of first-pass metabolism on the exposure to each metabolite.
The value of the plasma protein binding of tipifarnib from the ex vivo measurement on cancer subjects in this study is very close to that (99.22% bound) obtained from an in vitro experiment with the plasma samples from 5 healthy men.17 In this in vitro study, the blank plasma samples from these healthy subjects were fortified with 14C-tipifarnib at 1000 ng/mL, and the measurement procedure was the same as one used in the current study. The in vitro plasma protein binding of tipifarnib was also independent of the total tipifarnib concentrations in the range of 100 to 5000 ng/mL.
In conclusion, the plasma concentration-time profiles from the 2-hour intravenous regimen closely resembled the profiles after oral administration. Systemic exposure to tipifarnib was comparable for the first 10 hours after dosing when 100 mg was given twice daily as a 2-hour intravenous infusion or 200 mg was given via the oral route. No unusual adverse events were associated with intravenous tipifarnib.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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