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Randomized Crossover Study Evaluating the Effect of Gemcitabine Infusion Dose Rate: Evidence of Auto-Induction of Gemcitabine Accumulation

Peter Grimison, Peter Galettis, Susan Manners, Maria Jelinek, Ekkaphon Metharom, Paul L. de Souza, Winston Liauw, Matthew J. Links

From the Cancer Pharmacology Therapeutics Group, St George and Sutherland Hospitals; the University of New South Wales; and the Clinical Trials Unit, St George Hospital Cancer Care Centre, Sydney, Australia

Address reprint requests to Peter Galettis, PhD, Cancer Care Centre, St George Hospital, Gray St, Kogarah, NSW 2217, Australia; e-mail: Peter.Galettis{at}sesiahs.health.nsw.gov.au or p.galettis{at}unsw.edu.au

	ABSTRACT

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Purpose: Controversy exists over the optimal dose rate for administration of gemcitabine. There is a strong pharmacologic rationale for increased intracellular accumulation with prolonged infusions, but this failed to translate into a significant benefit in a large randomized study. The purpose of this study was to compare the intracellular pharmacokinetics of gemcitabine given for 30 minutes or for 100 minutes in a crossover design.

Patients and Methods: We randomly assigned 33 patients to a standard dose of 1,000 mg/m² over either 30 minutes or 100 minutes. At the second week, they were transferred to the alternate schedule. Blood samples were collected at various times after the gemcitabine infusion. Gemcitabine and difluorodeoxyuridine were measured in plasma by high-performance liquid chromatography (HPLC), and gemcitabine-triphosphate was measured by HPLC in leukocytes.

Results: Intracellular accumulation was greater during the 100-minute infusion, which was consistent with previous data. This effect was confounded by an increase in gemcitabine-triphosphate accumulation between weeks 1 and 2, which was consistent with self-induction of gemcitabine accumulation. There was significant heterogeneity: 27% of patients had greater WBC accumulation during the 30-minute infusion (regardless of treatment order). Patients with relatively greater levels of gemcitabine-triphosphate in WBCs tended to have less under-dosing and a greater reduction in midcycle neutrophils. However, this observation did not correlate with plasma gemcitabine levels.

Conclusion: This work identifies significant variations in intracellular gemcitabine-triphosphate accumulation between and within individuals, and it provides evidence that this variation has potential clinical significance. The observed self-induction of gemcitabine metabolism has broad implications for the dosing of nucleoside analogs.

	INTRODUCTION

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Gemcitabine (GEM; 2',2'-difluoro-2'-deoxycytidine; dFdC) is a nucleoside analog with demonstrated activity in a variety of cancer types. It has a favorable toxicity profile at conventional doses and had wide interpatient variation in pharmacokinetics. It is activated intracellularly by the enzyme deoxycytidine kinase (dCK) to GEM-triphosphate (GEM-TP), and it is inactivated by deamination to 2',2'-difluorodeoxyuridine (dFdU) via the enzyme cytidine deaminase (CDA). GEM-TP is thought to be the most important entity for cytotoxicity; however, GEM diphosphate also has some cytotoxic activity. The maximum tolerated dose is highly variable, and phase I trials have defined a maximum tolerated dose between 800 mg/m²/wk¹ and 1,500 mg/m²/wk.²

The optimal duration for infusion of GEM is not known. The most common schedule has been a 30-minute infusion, but there is considerable interest in more prolonged infusions of the drug. Abundant evidence shows that intracellular accumulation in leukocytes and leukemic blasts is increased by prolonging the infusion time, and this is reflected in greater cell cytotoxicity.³ This is the rationale for proposing a prolonged infusion time.

Intracellular accumulation in mononuclear cells is saturable and plateaus at concentrations greater than 15 to 20 µmol/L (4.5 to 6 µg/mL).⁴ Prolongation of the GEM infusion time is associated with a linear increase in the maximum concentration in plasma (C_max) and an increase in the mononuclear cell GEM-TP area under the concentration-time curve (AUC). A target plasma concentration of 15 to 20 µmol/L is associated with optimal accumulation of GEM-TP in mononuclear cells, and a dose rate of 10 mg/m²/min has been suggested to achieve this concentration.⁴ This plasma level and infusion rate have been shown to increase intracellular accumulation in mononuclear cells when compared with a 30-minute infusion.¹ It is not clear whether this plasma level or this duration of administration is optimal for either efficacy or toxicity. More prolonged infusions are associated with increased toxicity and are logistically difficult. One study that evaluated a 10 mg/m²/min schedule found that eight of 13 patients achieved target plasma concentrations,⁵ which suggests that individualization of the dose rate may be required to achieve optimal dosing. Interest in a fixed dose-rate infusion was increased by a randomized, phase II study that showed a survival advantage with the prolonged infusion.⁶ However, a subsequent phase III study failed to show a significant overall advantage with the prolonged infusion schedule.⁷ Evaluation of both of these trials is complicated by the different doses administered in each arm. Understanding and predicting the cause of this interpatient variation could lead to individualized dosing and improved therapeutic efficacy. We therefore performed a randomized, crossover study of a 30 v 100-minute GEM infusion at a constant dose of 1,000 mg/m² to evaluate the optimal schedule and the variation in intracellular pharmacokinetics.

	PATIENTS AND METHODS

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Patients and Study Design
Participants. All patients older than 18 years who were undergoing chemotherapy with single-agent GEM, were willing to undergo required sampling, and were able to give informed consent were eligible to participate in the study. Pretreatment assessment of each patient age, performance status, clinical biochemistry, hematology, and demographic data was recorded according to routine practice. Ethics approval was obtained from the St George Hospital Ethics Committee.

Interventions and Random Assignment
Patients were randomly assigned to receive GEM 1,000 mg/m² over either 30 minutes (arm 1) or 100 minutes (arm 2). They received the allocated rate in weeks 1, 3, and 4. On week 2, they received the alternate schedule. Subsequent treatment was administered at the discretion of the treating physician. A computerized, random-number generator provided randomization sequences. Allocation was by sequentially numbered, opaque, sealed envelopes. Patients and investigators were not blinded to the randomization arm. Drug dosages were calculated according to the patient body-surface area, determined according to the actual patient height and weight measured at the beginning of each cycle.

Sample Collection
Only the first 2 weeks of the 4-week cycle were subject to pharmacokinetic sampling. Plasma and leukocytes were collected at the following times: preinfusion for a zero-drug level; at end of infusion; at 5, 10, 20, 40, and 60 minutes; and 6 and 24 hours after the end of infusion.

All samples were collected in heparinized tubes that contained 0.25 mg of a CDA inhibitor (tetrahydrouridine) and were immediately placed on ice. Post-treatment leukocytes were extracted by centrifugation to obtain a buffy coat, by lysis buffer to remove any remaining red cells, and then by perchloric-acid extraction for analysis of intracellular GEM-TP levels. Viable cells were identified and counted by trypan-blue exclusion, and intracellular GEM-TP levels were expressed as pmol/million cells.

Sample analysis included plasma GEM and dFdU by high-performance liquid chromatography (HPLC), using a previously published method.⁸ GEM-TP was also analyzed by HPLC, as previously described.¹

Hematologic/Nonhematologic Toxicity Monitoring
Toxicity after weeks 1 and 2 was assessed using standard National Cancer Institute Common Toxicity Criteria (version 2) toxicity grading. The degree of myelosuppression was assessed before each treatment day by full blood counts on weeks 1 to 4 of treatment.

Analysis
Outcome measures. Indications of an optimal treatment schedule were defined as follows: GEM-TP AUC within leukocytes; attainment of maximal plasma GEM AUC; and degree of myelosuppression, determined by %D, which is defined as ([pretreatment granulocyte – granulocyte after week 1] ÷ pretreatment granulocyte) x 100%.

Assessable disease was not a requirement for the study, which was not powered to detect differences in response. Therefore, tumor response was not an end point of this study.

Statistical analysis. The AUC was calculated using the linear trapezoidal rule for GEM; for its activated form, intracellular GEM-TP; and for the deaminated metabolite dFdU. Data values were expressed as means ± standard deviation. Interpatient variations in pharmacokinetic parameters were determined by a coefficient of variation. Analysis of variance (ANOVA) was used to determine the relationship between the rate and order of infusions for GEM-TP, GEM, and dFdU. Nonlinear regression analysis was used to demonstrate the relationship between pharmacokinetic parameters (GEM-TP, GEM, dFdU) and %D. Differences were considered significant with P < .05. Data analysis was performed using GraphPad Prism, version 4.00 for Windows (GraphPad Software, San Diego, CA) and SPSS statistical package, version 11.0 for Windows (SPSS Inc, Chicago, IL).

	RESULTS

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Patient Data
Between September 2003 and June 2005, 33 patients were recruited onto the study. A further 17 patients were screened but were not eligible for the study because of schedule conflict (three patients), poor venous access (three patients), anticipated intolerance of the dose of the study drug (two patients), poor renal function (two patients), bloodborne virus (one patient), or refusal to participate (six patients). The most common tumor types were pancreatic cancer (11 patients), non–small-cell lung cancer (nine patients), bladder cancer (three patients), and hepatobiliary cancers (two patients). Consent was withdrawn in two patients following randomization but before commencing the study because of lack of venous access in one patient and because of a syncopal event in one patient; these patients were not included in data analysis. Severe constipation not related to the study led one patient to withdraw after week 1 of the study. Thirty patients completed the 2-week, pharmacokinetic phase of the study, and 22 patients completed all 4 weeks of the study. Intracellular GEM-TP data and plasma pharmacokinetic data were obtained in 31 patients.

Pharmacokinetics
Variations of intracellular Gem-TP with infusion rate and order of infusion. Mean GEM-TP accumulation was significantly increased in the 100-minute infusion compared with the 30-minute infusion (P = .03; Fig 1A). This effect was complicated by the difference in GEM-TP accumulation between week 1 and week 2 (P = .04; Fig 1B). A significant interaction was observed between the week of administration and the rate of administration. Because of this effect, the variations in GEM-TP accumulation and infusion rate were only seen when the 30-minute infusion was given on week 1 (P = .018). Reversing the order of administration abolished the increase (Fig 1C).

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Intracellular accumulation of gemcitabine triphosphate according to (A) rate of infusion; (B) week of treatment; (C) rate and order of infusion; (D) 100 minutes versus 30 minutes, expressed as a ratio. (Horizontal bar indicates the mean.)

Variations of plasma GEM and metabolites with infusion rate and order of infusion. Pharmacokinetic data are recorded in Table 1. The mean GEM C_max and GEM AUC were significantly greater for the 30-minute infusion than for the 100-minute infusion (P .0001), regardless of the order of infusion (P = .302). No significant differences in the mean dFdU AUC were noted between the 30-minute infusion and the 100-minute infusion, regardless of order of infusion. The GEM C_max correlated with the GEM AUC (Fig 2). None of the patients on the 30-minute infusion and 35% of the patients on the 100-minute infusion achieved the target plasma concentration of 15 to 20 µmol/L (Fig 3). However, the relationship between plasma GEM levels and GEM-TP was weak. This suggests that plasma levels are of limited value in predicting the optimal dose.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Linear correlation of gemcitabine maximum concentration and gemcitabine area under the curve for both the 30- and 100-minute infusions. The lines indicate the regression fit, with r2 = 0.625 for 30 minutes and r2 = 0.685 for 100 minutes.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Relationship between gemcitabine maximum concentration (GEM Cmax) and gemcitabine triphosphate area under the curve. Data shown are for each patient at both 30 and 100 minutes. The shaded area represents the suggested optimal plasma GEM Cmax of 15 to 20 µmol/L.

Relationship between pharmacokinetics and pharmacodynamics. A relationship was found between the GEM-TP AUC and %D, with best fit using a sigmoid E_max model (Fig 4A) and r² = 0.3739. When GEM-TP samples were divided at the median (81.0 µmol/million cells x h) into high and low groups, the high GEM-TP group was associated with greater %D (P < .01; Fig 4B).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Correlation between percentage fall in neutrophil count after week 1 (%D) and intracellular accumulation of gemcitabine triphosphate after week 1 (GEM-TP AUC W1). (A) %D: subjects divided at median according to high or low GEM-TP AUC W1 (B).

	DISCUSSION

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Controversy exists about the optimal dosing regimen for GEM. The pharmacologic rationale for prolonging infusion times to saturate intracellular accumulation is strong. The ability to achieve this with a dose rate of 10 mg/m²/min and the resultant clinical benefit are unclear. A number of randomized, phase II trials have evaluated the benefits of a fixed dose rate, alone⁹ or in combination,^10,11 with no demonstrable benefit. The one randomized, phase II study with a positive survival benefit⁶ stimulated much interest, but the confirmatory phase III trial showed only a nonsignificant trend toward increased survival.⁷ However, the prolonged-infusion arm received both a higher dose and a prolonged dose rate, which makes interpretation difficult.

These trials are difficult to interpret because of heterogeneity in doses, designs, and tumor types evaluated. Several messages are observed about the effect of an increased dose rate: intracellular accumulation for GEM-TP is increased^11,12; toxicity is increased^9,11; and a trend toward increased survival, which is not significant, occurs.^6,7,9,10

This work confirms and extends the data of a pharmacologic effect for a prolonged, 100-minute infusion of GEM. Intracellular GEM-TP accumulation was significantly increased and GEM accumulation was significantly decreased with the 100-minute infusion, which is consistent with previous data.⁷

Our study design contrasts others in the literature, because patients in both arms were treated with the same dose, intracellular GEM-TP was measured up to 24 hours postexposure, and patients were crossed-over between a standard and a prolonged rate of infusion during weeks 1 and 2, which allowed intrapatient comparisons. Under our experimental conditions, the pharmacologic benefit of the prolonged infusion was limited to arm 1 of the study (a 123% increase in GEM-TP with the 30-minute infusion on week 1 and the 100-minute infusion on week 2); no difference was observed in arm 2 (a 3% increase in GEM-TP), in which the 100-minute infusion was given on week 1. The reasons for this are the two significant causes of variation in GEM-TP within the crossover design: the rate of drug administration and the influence of the week of administration.

The increased intracellular accumulation of GEM-TP between weeks 1 and 2 suggests autoinduction of GEM metabolism. We hypothesize that this was because of an increase in the threshold required to saturate GEM-TP accumulation. This observation is supported by in vitro data that dCK activation occurs after administration of a variety of drugs, including nucleotide analogs, that inhibit DNA synthesis,^13,14 The implication of this increase is that the optimal dose rate for saturation of intracellular accumulation may change over time, and 10 mg/m²/min will not be optimal for all patients all of the time. It also implies that the pharmacologic benefit of a prolonged dose-rate infusion will be overestimated in a study design that takes samples only on week 1. This may explain the failure of the prolonged dose rate to produce a sustained clinical benefit.

High interpatient variability exists; 27% of patients achieved a lower GEM-TP AUC with the 100-minute infusion. Under these circumstances, it is not surprising that even a large randomized trial will not show a net benefit. Understanding and predicting the cause of this variability could lead to individualized dosing and to improved efficacy. Work is in progress to better identify potential predictive factors of GEM metabolism, namely the pharmacogenetic and phenotypic characteristics of the enzymes CDA and dCK, as an extension of previous work¹⁵. Our ultimate aim is to individualize GEM dosing and provide better efficacy and tolerability.

We have identified a relationship between pharmacokinetic and pharmacodynamic outcomes and have presented preliminary evidence that a greater GEM-TP AUC correlates with greater myelosuppression. If confirmed, this would be the first significant pharmacodynamic relationship observed for standard-dose GEM, and it would support the use of a pharmacologically guided dosing strategy. However, the relatively low correlation coefficient suggests that intracellular accumulation does not determine the majority of the variation in drug response (for neutrophils). Events downstream of drug accumulation require further investigation. Ribonucleotide reductase M1 is one such protein with which there is clinical evidence that variation in its expression affects its response to GEM.¹⁶

It is important to determine whether this relationship translates into a clinically relevant difference in the deliverable dose before considering a dose-modification strategy based on pharmacokinetics or on a surrogate marker such as phenotype or genotype. Thus, the important questions identified by this work are as follows: what are the intracellular pharmacokinetics of GEM with repeated administration, and what are the relationships among phenotype, genotype, and the deliverable dose.

This work used leukocytes as an accessible and relevant surrogate for hematologic toxicity. The relevance of leukocyte uptake for predicting changes in tumor uptake also needs to be explored.

Optimal efficacy of GEM requires optimal dose and scheduling. In the overall population, prolongation of infusion times has not translated into improved outcomes. Our data supports the concept that this is related to interindividual and intraindividual variation in intracellular accumulation. Existing work has identified polymorphism in genes involved in GEM metabolism, including CDA, the promoter of dCK, the RRM1 promoter, and others.^17-19 This work demonstrates that environmental influences, such as prior GEM exposure, modulate the effect of genotype. Ongoing work aims to explore the relationship between genotype and the phenotypic differences identified in this study. The prospect exists for defining an optimal dosing schedule for individuals based on a combination of pharmacokinetic and possibly genotypic data.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Matthew J. Links, Eli Lilly Australia Stock: N/A Honoraria: N/A Research Funds: Peter Galettis, Eli Lilly Australia; Matthew J. Links, Eli Lilly Australia Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Peter Galettis, Matthew J. Links

Financial support: Peter Galettis, Matthew J. Links

Provision of study materials or patients: Peter Grimison, Peter Galettis, Paul L. de Souza, Winston Liauw, Matthew J. Links

Collection and assembly of data: Peter Grimison, Peter Galettis, Susan Manners, Maria Jelinek, Ekkaphon Metharom

Data analysis and interpretation: Peter Grimison, Peter Galettis, Susan Manners, Ekkaphon Metharom, Paul de Souza, Matthew J. Links

Manuscript writing: Peter Grimison, Peter Galettis, Paul de Souza, Matthew J. Links

Final approval of manuscript: Peter Grimison, Peter Galettis, Susan Manners, Maria Jelinek, Ekkaphon Metharom, Paul de Souza, Winston Liauw, Matthew J. Links

	ACKNOWLEDGMENTS

 
We thank the participating patients; the research nurses who assisted with sample collection, Michael Szwajcer, BSc, RN, and Tanya Flynn, RN; and David Goldstein, MBBS, FRACP, for helpful discussion.

	NOTES

 
This study was supported by a research grant from Eli Lilly Australia.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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3. Plunkett W, Huang P, Searcy CE, et al: Gemcitabine: Preclinical pharmacology and mechanisms of action. Semin Oncol 23:3-15, 1996 (5 suppl 10)[Medline]

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7. Poplin E, Levy DE, Berlin J, et al: Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201). J Clin Oncol 24:LBA4004, 2006

8. Freeman KB, Anliker S, Hamilton M, et al: Validated assays for the determination of gemcitabine in human plasma and urine using high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Appl 665:171-181, 1995[CrossRef][Medline]

9. Cappuzzo F, Novello S, De Marinis F, et al: A randomized phase II trial evaluating standard (50 mg/min) versus low (10 mg/min) infusion duration of gemcitabine as first-line treatment in advanced non-small-cell lung cancer patients who are not eligible for platinum-based chemotherapy. Lung Cancer 52:319-325, 2006[CrossRef][Medline]

10. Ceribelli A, Gridelli C, De Marinis F, et al: Prolonged gemcitabine infusion in advanced non-small cell lung carcinoma: A randomized phase II study of two different schedules in combination with cisplatin. Cancer 98:337-343, 2003[CrossRef][Medline]

11. Soo RA, Wang LZ, Tham LS, et al: A multicentre randomised phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer. Ann Oncol 17:1128-1133, 2006[Abstract/Free Full Text]

12. Liebes L, Levy DE, Poplin E, et al: Gemcitabine (G) plasma and intracellular pharmacokinetics in E6201: Greater metabolite levels using fixed dosing rate (FDR) delivery. J Clin Oncol 24:2024, 2006

13. Csapo Z, Sasvari-Szekely M, Spasokoukotskaja T, et al: Activation of deoxycytidine kinase by inhibition of DNA synthesis in human lymphocytes. Biochem Pharmacol 61:191-197, 2001[CrossRef][Medline]

14. Kong XB, Tong WP, Chou TC: Induction of deoxycytidine kinase by 5-azacytidine in an HL-60 cell line resistant to arabinosylcytosine. Mol Pharmacol 39:250-257, 1991[Abstract]

15. Kroep JR, Loves WJ, van der Wilt CL, et al: Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther 1:371-376, 2002[Abstract/Free Full Text]

16. Rosell R, Danenberg KD, Alberola V, et al: Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 10:1318-1325, 2004[Abstract/Free Full Text]

17. Bepler G, Zheng Z, Gautam A, et al: Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. Lung Cancer 47:183-192, 2005[CrossRef][Medline]

18. Shi JY, Shi ZZ, Zhang SJ, et al: Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients. Pharmacogenetics 14:759-768, 2004[CrossRef][Medline]

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Submitted February 11, 2007; accepted August 1, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grimison, P. Articles by Links, M. J. Search for Related Content PubMed PubMed Citation Articles by Grimison, P. Articles by Links, M. J. Related Articles Related Editorial