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Evaluation of the Absolute Oral Bioavailability and Bioequivalence of Erlotinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in a Randomized, Crossover Study in Healthy Subjects

From CV Therapeutics, Inc, Palo Alto, California (Dr Frohna); Genentech, Inc, South San Francisco, California (Dr Lu, Mr Eppler, Dr Ling, Dr Kenkare-Mitra, Dr Lum); OSI Pharmaceuticals, Inc, Boulder, Colorado (Dr Hamilton, Ms Wolf); and Hoffmann-La Roche Pharmaceuticals, Nutley, New Jersey (Dr Rakhit).

Address for reprints: Bert L. Lum, PharmD, Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc, 1 DNA Way (MS-70), Room 20207, South San Francisco, CA 94080.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
A randomized, open-label, 2-period crossover study was conducted to evaluate the bioequivalence of 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg (arm A, n = 42) and the oral bioavailability of the 150-mg tablet versus a 25-mg intravenous infusion (arm B, n = 20) in healthy subjects. The washout period was 2 weeks between treatments. Plasma concentrations of erlotinib and its active metabolite, OSI-420, were measured after each dose. The ratios of geometric means for AUC_0- and C_max of erlotinib following 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg were (1 and 0.95) within the predefined bioequivalence range of 0.80 to 1.25. The mean absolute oral bioavailability, using compartmental analysis, was estimated as 59% (95% confidence interval, 55%-63%). Overall, 6 tablets of erlotinib 25 mg are bioequivalent to a single 150-mg tablet. Both intravenous and oral erlotinib were generally well tolerated with an estimated bioavailability of 59% following oral administration.

Key Words: Erlotinib • bioequivalence • bioavailability

Erlotinib provides a survival benefit as monotherapy in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) who have failed at least 1 prior chemotherapy^15,16 and in combination with gemcitabine for the first-line treatment of locally advanced or metastatic pancreatic adenocarcinoma.¹¹ Erlotinib is approved in the United States and Switzerland for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.^15,17

The recommended clinical dose of erlotinib is 150 mg orally per day (the maximum tolerated dose [MTD]),^4,15 which can be reduced in 50-mg decrements to help manage some adverse events.¹⁵ Data suggest the MTD differs depending on the regimen and setting and in individual patients. For example, a recent study of NSCLC patients receiving erlotinib first line in combination with docetaxel defined the MTD as 200 mg/d.¹⁸ Furthermore, a study is ongoing to investigate if the dose of erlotinib can be escalated above the current MTD in individual patients using the onset of rash as the stopping rule.¹⁹

To allow dosing flexibility in the clinic, erlotinib is formulated as oral tablets available in 3 dose strengths: 25 mg, 100 mg, and 150 mg. Although the active and inactive ingredients are the same for each dose strength, the erlotinib-to-excipient ratio is different in the 25-mg tablets compared with the 100-mg and 150-mg tablets. Therefore, the 25-mg tablets may result in different systemic exposure of erlotinib, compared to the extent of absorption achieved with the other tablet strengths. To evaluate the possible effects of different erlotinib-to-excipient ratios on exposure, the bioequivalence (BE) and other pharmacokinetic (PK) parameters of erlotinib given as six 25-mg tablets (equivalent to a combined dose of 150 mg) and one 150-mg tablet were compared in healthy adult subjects in arm A of this study.

The bioavailability (BA) of erlotinib tablets has not previously been characterized in humans. In arm B of this study, the absolute BA of the 150-mg tablet formulation, given as a single oral dose, was evaluated in healthy subjects who also received an intravenous (IV) dose of erlotinib as a comparator. Subjects participating in this arm were the first to receive IV erlotinib and therefore were monitored closely to ensure their safety.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Design and Treatment Schedule
This was a randomized, open-label, 2-period crossover study performed in a phase 1 clinic (PPD Development, Austin, Tex). The protocol was reviewed and approved by the study center's Institutional Review Board. Healthy, nonsmoking subjects with no clinically relevant conditions were eligible for inclusion. Key inclusion criteria were aged between 18 and 65 years; a body mass index between 18 and 30; men or women who were surgically sterilized, postmenopausal for the past year, or using 2 methods of contraception against pregnancy; and abstinence from all other medications, herbal supplements, and drugs of abuse with the exception of medication(s) to treat adverse events and oral contraceptives. Subjects were excluded from the study if they had any clinically significant laboratory abnormality or a positive urine drug screen, a history of smoking within the 4 weeks prior to day 1, used an oral inhibitor or inducer of CYP3A4 within 4 weeks of dosing, or received treatment with any experimental drug within 30 days or 6 times the elimination half-life of the drug prior to dosing.

Subjects were assigned to arm A (n = 42; BE) or arm B (n = 20; BA) using static randomization tables. Subjects in each arm were then randomized 1:1 to 1 of 2 treatment sequences. Subjects in arm A received single oral doses of erlotinib (Tarceva, CP-358,774, OSI-774; Genentech, San Francisco, Calif; OSI Pharmaceuticals, Melville, NY; and F. Hoffmann-La Roche, Basel, Switzerland; Iressa AstraZeneca, Wilmington, Del), given as six 25-mg tablets (lot no. X101442, Schwarz Pharma product code number 3225) and as one 150-mg tablet (lot no. X102132, Schwarz Pharma product code number 3250) in random order separated by a 2-week washout period. Subjects in arm B received a single oral dose of erlotinib as one 150-mg tablet and a single 25-mg IV infusion of erlotinib solution (formulated in 6% [w/v] Captisol at a concentration of 10 mg/mL; lot no. 802249A Baxter project code 222-101-100) over 30 minutes in random order separated by a 2-week washout period. As this was the first time that IV erlotinib was being administered to human subjects, a relatively conservative IV dose of 25 mg was selected for this study. All doses were administered in the morning, with subjects required to fast for a minimum of 6 hours before and 2 hours after receiving each dose of study drug. Following the 2-week washout period after the first dose of erlotinib, subjects crossed over to the remaining treatment in their respective study arm.

Blood Sampling and Analysis
Plasma samples for analysis were collected immediately before drug administration and at 15 minutes, 30 minutes, and 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours postdose. Plasma concentrations of erlotinib and OSI-420, the major metabolite of erlotinib, were analyzed using an isocratic reverse-phase high-performance liquid chromatographic tandem mass spectroscopy method (MDS Pharma Services, Saint-Laurent, Montreal, Quebec, Canada). Briefly, diluted buffered plasma was fortified with an internal standard (CP-396,059), which is a methylated derivative of OSI-774, and loaded on a diatomaceous earth cartridge. A liquid/liquid extraction was performed with t-butyl methyl ether. Following a dry down and resuspension, the analytes were separated by a Waters Symmetry C-18 column (50 x 4.6 mm, 3.5 µm) using 30% 10 mM ammonium formate buffer (pH = 4.8) and 70% methanol as the mobile phase. Once OSI-774, OSI-420/413, and internal standard were eluted from the column, ionized by Heated Nebulizer, the mass transitions were monitored at 394.3/278.0 m/z and 380.3/278.0 m/z, respectively. Erlotinib can be o-demethylated at 2 positions on the molecule, resulting in the formation of 2 metabolites, OSI-420 and OSI-413. The method does not distinguish between these 2 forms, so they are collectively reported as OSI-420. Assay ranges for erlotinib and OSI 420 were 1 to 3000 ng/mL and 1 to 1000 ng/mL, respectively. The lower limit of quantitation (LLOQ) was set at the concentration of the lowest nonzero standard (1 ng/mL for each compound). All measures below the LLOQ were excluded when calculating PK parameters.

PK and Statistical Methods
The following noncompartmental PK parameters were derived for both erlotinib and OSI-420 using standard methods: AUC from time 0 to infinity (AUC_0-) and from time 0 to the time of the last measurable concentration (AUC_0-t), maximum observed plasma concentration (C_max), time to reach C_max (t_max; oral doses only), and terminal elimination half-life (t_1/2,z), where _z is the terminal elimination rate constant. Because the data for both AUCs were very similar, only the data for AUC_0-, the more commonly used end point in BE studies, are reported here. For assessment of BE, the analysis of variance model appropriate for a 2-way crossover design was applied to the log₁₀ transformation of AUC_0- and C_max for erlotinib. Results for AUC_0- and C_max were reported as the ratios of the geometric means along with 90% confidence intervals (CIs) using the one 150-mg tablet group as the reference. BE was concluded if the 90% CI fell within 0.80 to 1.25 for AUC_0- and C_max.

For assessment of absolute BA (F), the F value was first calculated using noncompartmental approach: F = (AUC_oral/Dose_oral) x (Dose_iv/AUC_iv). Then a secondary, compartmental analysis was performed using the NONMEM program (version V, level 1.0; Globomax, Hanover, Md) fitting oral and IV PK data simultaneously.

In addition, the effect of gender on erlotinib PK was evaluated using the subjects in arm A. This preliminary analysis was performed by comparing the log-transformed erlotinib AUC_0- and C_max between men and women using t tests, with P values of <.05 considered statistically significant.

Safety
Subject safety assessments included adverse events, clinical laboratory tests (hematology, serum chemistry, and urinalysis), assessment of vital signs, and electrocardiograms.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subject Demographics and Disposition
Baseline characteristics for all enrolled subjects are summarized in Table I. There were more subjects in both arms who were female and Caucasian; mean ages were similar. Sixty-two subjects were eligible and were enrolled (42 in arm A and 20 in arm B); 6 subjects (9.7%) withdrew from the study before period 2 (4 in arm A; 2 in arm B). In addition, 1 subject from arm A was not included for evaluation of BE because of the nearly horizontal slope of the concentration-time curve. The final PK population was 37 subjects for BE (arm A) and 18 subjects for BA (arm B).

All 62 subjects received at least 1 dose of erlotinib and were included in the safety assessment.

Bioequivalence
Plasma erlotinib and OSI-420 concentration-time plots are presented in Figure 1. Peak levels were observed approximately 2 to 3 hours after oral erlotinib administration. The plasma concentrations of erlotinib and its main metabolite, OSI-420, declined biexponentially with time. The concentration-time curves after oral administration of six 25-mg tablets and one 150-mg tablet of erlotinib were almost superimposable for both erlotinib and OSI-420 throughout the entire sampling period. In accordance, PK parameters were similar following oral administration of the 2 formulations (Table II).

View larger version (22K): [in this window] [in a new window]   Figure 1. Mean (±SEM) plasma concentrations of erlotinib and OSI-420 over time (linear) after oral administration of six 25-mg tablets and one 150-mg tablet of erlotinib. Values below the quantifiable limit were set at 0. PO = orally.

The ratio of geometric means for erlotinib AUC_0- for the 2 doses was 1.00 (90% CI = 0.96-1.05). The ratio of geometric means for C_max was 0.95 (90% CI, 0.88-1.04; Table III). Because the 90% CIs of the ratios of both AUC_0- and C_max are within the range of 0.80 to 1.25, the six 25-mg and one 150-mg treatments are considered bioequivalent. The data for OSI-420 were similar (Table III).

Bioavailability
After an oral dose of 150-mg erlotinib or an IV dose of 25-mg erlotinib, plasma erlotinib and OSI-420 declined biexponentially with time (Figure 2). Oral administration of erlotinib had a similar dose-normalized AUC_0- value for erlotinib compared with IV erlotinib but resulted in an approximately 50% higher dose normalized AUC_0- value for OSI-420 than after IV administration (Table IV).

View larger version (21K): [in this window] [in a new window]   Figure 2. Mean (±SEM) plasma concentrations of erlotinib and OSI-420 over time (linear) after administration of one 150-mg tablet orally or a 25-mg IV dose. Values below the quantifiable limit were set at 0. PO = orally; IV = intravenous.

Based on the noncompartmental analysis (NCA), the BA of erlotinib was estimated to be 106% (95% CI, 99%-114%) after the administration of one 150-mg tablet. The different half-lives observed after IV and oral administration suggest different elimination rates. As a result, the standard NCA of the data led to an overestimation of BA. A secondary analysis of BA was performed using a 2-compartment nonlinear model. Using this approach, the mean oral BA of erlotinib was calculated to be 59% (95% CI = 55%-63%), which provided more reasonable estimates.

Effect of Gender on Erlotinib PK
Of the evaluable subjects in arm A, 23 were women and 19 were men. Female subjects had greater AUC_0- and longer t_1/2 than men did for both treatments (P < .03), as well as greater C_max than men for the six 25-mg tablet treatment (P = .0078; Table V).

Safety
Erlotinib was generally well tolerated, regardless of dose level and route of administration. There were no serious or severe adverse events (AEs). Of the 136 AEs reported during the study, almost all were mild, including headache (29.0%), dizziness (12.9%), rash (11.3%), nausea (8.1%), and diarrhea (6.5%). Only 7 moderate AEs were reported. Seventy-one AEs (53%) were considered at least possibly related to study drug. The only AE that was considered probably drug-related and resulted in subject withdrawal was moderate rash observed in 1 subject in arm B who had received one 150-mg tablet.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The results of this study demonstrate that the six 25-mg and one 150-mg formulations of erlotinib are bioequivalent and can be used interchangeably in the clinic. Therefore, different ratios of erlotinib to excipient in the 25-mg and 150-mg tablets do not affect systemic drug exposure. Dose reduction in 50-mg decrements is recommended in the prescribing information for the management of some adverse events, such as rash and diarrhea,¹⁵ and the commercial availability of 25-mg and 100-mg tablets allows for easy dose reduction from the recommended clinical dose of 150 mg/d.

The BA of erlotinib had not previously been measured in humans and was initially estimated to be 106% using standard NCA in this study, which is higher than predicted from preclinical studies and clinical observations. Preliminary studies in animal models indicated that the oral BA of erlotinib is 77% and 45% to 88% in rats and dogs, respectively.²⁰ In this study, the initial standard NCA analysis of the plasma concentration data was thought to overestimate the mean BA due to different elimination rates observed after oral and IV doses, with the lower, 25-mg IV dose being cleared more rapidly than the higher, 150-mg oral dose. The limitation of the initial calculation of BA using the NCA method led to a secondary PK analysis using the compartmental approach fitting both oral and IV PK data simultaneously. Four different compartmental structural models were evaluated including 1- and 2-compartment models, each with linear or nonlinear elimination processes. The final model, a 2-compartment model with a nonlinear elimination process, was selected based on the objective function value (-2 times the log likelihood of the data) and visual inspection of the goodness-of-fit plots. This approach accounted for the faster clearance of erlotinib at the lower 25-mg IV dose. Using this model, the mean BA of a 150-mg tablet was estimated as 59% (95% CI, 55%-63%) in fasted subjects. Based on these results and observations, the compartmental model with nonlinear elimination was determined to provide a more accurate estimate of the actual BA of the 150-mg erlotinib tablet than the NCA method.

This study was performed under the fasted condition. In a separate study, data indicated that the mean BA of erlotinib could be increased by almost 100% by coadministration with food.¹⁵ However, administering erlotinib with food to increase serum exposure is not recommended as the effect of food on AUC is highly variable. Because of this, the manufacturer recommends that erlotinib be given on an empty stomach (at least 1 hour before or 2 hours after the ingestion of food).¹⁵ Interestingly, an approximately 50% higher dose-normalized mean AUC_0- value for OSI-420 was observed after oral than IV administration. Presumably, this is a result of the first-pass metabolism of erlotinib to OSI-420 following an oral dose compared with an IV dose. Previous studies show that erlotinib is extensively metabolized, primarily by CYP3A4 and CYP1A2, with metabolites excreted via the biliary system.^4,15 Interestingly, gefinitib, another small-molecule HER1/EGFR TKI that is approved in the United States for advanced NSCLC after the failure of both platinum-based and docetaxel chemotherapies,²¹ appears to be metabolized by CYP3A4 but not CYP1A2.²²

The calculated BA of erlotinib from this study (59%) is comparable with that of gefitinib, another EGFR TKI.²³ The mean oral BA of gefitinib is 60% after a 250-mg dose.^23-25 While the BA of erlotinib and gefitinib are comparable, the actual serum exposure when the agents are given at their approved clinical doses (150-mg erlotinib vs 250-mg gefitinib) differs greatly, with total plasma exposure to erlotinib being approximately 7-fold greater.^4,23 It is unclear if the difference in exposure to the agents is a factor in their differing effect on overall survival noted in phase 3 trials in patients with advanced NSCLC who have failed at least 1 prior therapy.^15,16,26

In this study, female subjects achieved significantly greater exposure (25%-43%) than men did following a single oral 150-mg dose of erlotinib. However, it is worth mentioning that this gender effect on exposure has not been observed in cancer patients.¹⁵ Therefore, this finding might not translate to an effect on clinical outcome in female patients. Gender differences in exposure to gefitinib were not investigated in early PK analyses of healthy volunteers (male subjects only) or patients with NSCLC or other solid tumors in phase 1 trials.^23-25,27

Erlotinib was generally well tolerated by all subjects, regardless of dose level and route of administration. There were no severe or serious AEs. The only AE possibly related to erlotinib that resulted in withdrawal from the study was moderate skin rash. This pustular/papular-type rash has been seen in previous trials with erlotinib^4-6,16 and other HER1/EGFR inhibitors.^23-25,28 It is generally mild to moderate^4-6,16 and can usually be managed by dose reduction or interruption of therapy.¹⁵

In conclusion, the 2 different 150-mg doses of erlotinib tested in this study, six 25-mg tablets and one 150-mg tablet, are bioequivalent, so plasma exposure and efficacy will not be affected if 25-mg tablets are substituted for a dose. Erlotinib is well absorbed following oral administration, with a calculated BA of 59%.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Previous presentations of (part of) this work occurred at the American Society for Clinical Pharmacology and Therapeutics (ASCPT), Orlando, March 2005, and the American Society of Clinical Oncology (ASCO), May 2005. The authors would like to acknowledge the following individuals for their assistance in completing this study: Aziz Laurent, MD (PPD Development, Austin), Robert Quesenberry, Clinical Trial Manager (Genentech, Inc), and Mubashira Malik, MS (Genentech, Inc). Genentech, Inc provided research support.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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