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© 1999 American Society for Clinical Oncology Gemcitabine and Paclitaxel: Pharmacokinetic and Pharmacodynamic Interactions in Patients With Non–Small-Cell Lung CancerFrom the Departments of Medical Oncology and Pulmonology, University Hospital Vrije Universiteit, Amsterdam; and the Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands. Address reprint requests to Godefridus J. Peters, PhD, Department of Medical Oncology, University Hospital Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, the Netherlands; email gj.peters{at}azvu.nl
PURPOSE: To assess possible pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel in a phase I/II study in non–small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eighteen patients with advanced NSCLC received the following in a 3-week schedule: gemcitabine 1,000 mg/m2 (30 minutes, days 1 and 8) and paclitaxel 150 (n = 9) or 200 mg/m2 (n = 9) before gemcitabine (3 hours, day 1). Plasma pharmacokinetics and pharmacodynamics in mononuclear cells were studied. RESULTS: Gemcitabine did not influence paclitaxel pharmacokinetics at 150 and 200 mg/m2 (area under the concentration-time curve [AUC], 7.7 and 8.8 µmol/ L · h, respectively; maximum plasma concentration [Cmax], 3.2 and 4.0 µmol/L, respectively), and paclitaxel did not influence that of gemcitabine (Cmax, 30 ± 3 µmol/L) and 2',2'-difluorodeoxyuridine. Paclitaxel, however, dose-dependently increased the Cmax of gemcitabine triphosphate (dFdCTP), the active metabolite of gemcitabine, from 55 ± 10 to 106 ± 16 pmol/106 cells. No significant difference in the AUC of dFdCTP was observed. Moreover, the gemcitabine-paclitaxel combination significantly increased ribonucleotide levels, most pronounced for adenosine triphosphate (six- to seven-fold). Postinfusion paclitaxel AUC was related to pretreatment hepatic function (bilirubin: r = 0.79; P < .001) and to the percentage decrease in platelets (r = 0.61; P = .009). The latter was also related to the duration of paclitaxel concentration above 0.1 µmol/L (r = 0.62; P = .007). Gemcitabine Cmax was related to the percentage decrease in platelets (r = 0.58; P = .01), pretreatment hepatic function (bilirubin: r = 0.77; P < .001), and to plasma creatinine (r = 0.5; P = .03). The pharmacokinetics and pharmacodynamics were not related to response or survival. CONCLUSION: Gemcitabine and paclitaxel pharmacokinetics were related to the percentage decrease in platelets. Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This might enhance the antitumor activity of gemcitabine.
GEMCITABINE AND PACLITAXEL are new anticancer agents with significant single-agent activity against advanced non–small-cell lung cancer (NSCLC).1-3 Their different mechanisms of action and the partially nonoverlapping toxicities4,5 make gemcitabine-paclitaxel combination chemotherapy attractive for further clinical exploration in patients with unresectable NSCLC. Gemcitabine, a deoxycytidine analog, is phosphorylated to its mononucleotide by deoxycytidine kinase (dCK) and subsequently by nucleotide kinases to its active metabolite, gemcitabine triphosphate (dFdCTP). A strong correlation was found between the extent of dFdCTP formation, its incorporation into the DNA, and its inhibition of DNA synthesis.6,7 Several self-potentiating mechanisms have been described, including inhibition of ribonucleotide reductase, dCMP-deaminase, and CTP synthetase,4,8 enhancing the incorporation of dFdCTP into DNA and possibly also into RNA. The effect of gemcitabine on the cell cycle has been described as generally leading to an accumulation in G0/G1 and S phase.9-11 Paclitaxel acts as a mitotic spindle poison by blocking eukaryotic cells in the G2/M mitotic phase of the cell cycle.5 Paclitaxel promotes microtubule assembly and stabilization by preventing depolymerization.12 Paclitaxel does not have a direct action on DNA; DNA damage is observed only secondary to activation of apoptosis. Because of the different effects of each drug on cellular metabolism and cell cycle distribution, sequential administration of the drugs may result in potentiation of both single agents. No drug-drug interactions between gemcitabine and paclitaxel have been described in earlier clinical studies. For the combination of gemcitabine with cisplatin, we observed sequence-dependent interactions between both drugs in a pharmacokinetic/pharmacodynamic phase I/II study.13 Also for paclitaxel, several interactions have been described in the clinic. Rowinsky et al14 reported a sequence-dependent toxicity when paclitaxel administered as a 24-hour infusion was combined with cisplatin. When cisplatin was administered before paclitaxel, neutropenia was more pronounced, which could be explained by a decreased clearance of paclitaxel. However, no drug-drug sequence-dependent interaction was found between paclitaxel and carboplatin.15 In the present phase I/II study, gemcitabine was combined with paclitaxel, which was given as a 3-hour infusion before gemcitabine. We investigated whether gemcitabine would interfere with the pharmacokinetics of paclitaxel or vice versa and if this may affect toxicity and/or efficacy of this combination chemotherapy. For that purpose, we evaluated gemcitabine-paclitaxel pharmacokinetics and also measured the active metabolite of gemcitabine, dFdCTP, in mononuclear cells as a surrogate for tumor cells.
Patients and Study Design Patient selection. Patients were considered to be eligible for this study based on the following criteria: stage III or IV NSCLC without prior chemotherapy; between 18 and 76 years of age; measurable or nonmeasurable but assessable disease; performance status  2 according to the World Health Organization scale; life expectancy  2 months; adequate bone marrow function (WBC count 4 x 109/L, absolute neutrophil count 2 x 109/L, and platelet count 100 x 109/L); adequate renal function (serum creatinine 120 µmol/L or creatinine clearance 60 mL/min); serum bilirubin level 1.25 times the upper normal limit; adequate cardiac function; no second tumor; no brain metastasis; and written informed consent. Results of the clinical part of this study are being reported separately (Giaccone et al, manuscript in preparation). Study design. Gemcitabine was administered on days 1 and 8 at a dose of 1,000 mg/m2 intravenously (IV) over 30 minutes. Paclitaxel was initially given at a dose of 150 mg/m2 (n = 9), and in the absence of hematologic toxicity, the dose was escalated in the second patient group to 200 mg/m2 (n = 9), given as a 3-hour IV infusion immediately before gemcitabine on day 1 of a 21-day cycle. The plasma pharmacokinetics of gemcitabine and paclitaxel on day 1 were compared with the plasma pharmacokinetics of both drugs given as single agents: with gemcitabine, pharmacokinetics were evaluated on day 8, and with paclitaxel, historical data sets were used.15 Additionally, the effect of the combination therapy on cellular ribonucleotides was studied. As a control for gemcitabine, data of patients treated with gemcitabine 800 mg/m2 24 hours before cisplatin were used,13 whereas for paclitaxel, additional pharmacokinetic assessments were performed in six patients who received paclitaxel 200 mg/m2 as a 3-hour IV infusion. Drugs. Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) was provided as a sterile solution (6 mg/mL) in a 5-mL vial in a mixture of polyoxyethylated castor oil (Cremophor EL) and dehydrated ethanol (1:1, volume to volume). This was diluted before use with 500 mL of 0.9% NaCl and infused over 3 hours with a constant-volume infusion pump. Because Cremophor EL may leach plasticizer from solution bags containing polyvinyl chloride, bags and sets containing polyvinyl chloride were avoided. Premedication consisted of dexamethasone 20 mg administered orally 12 and 6 hours before paclitaxel infusion, diphenhydramine 50 mg IV, and cimetidine 300 mg IV administered 30 minutes before paclitaxel. Prophylactic antiemetics were not routinely administered. Gemcitabine (2',2'-difluoro-2'-deoxycytidine; Gemzar; Eli Lilly & Co, Indianapolis, IN) was supplied as a lyophilized powder in sterile vials containing 200 or 1,000 mg of gemcitabine as the hydrochloride salt, mannitol, and sodium acetate. Gemcitabine was administered in 500 mL of 0.9% NaCl as a 30-minute IV infusion.
Pharmacology Gemcitabine and 2',2'-difluoro-2'-deoxyuridine Analysis. For gemcitabine and 2',2'-difluorodeoxyuridine (dFdU) analysis, 150 µL of plasma was extracted as described previously17 and analyzed by reverse-phase high-performance liquid chromatography (HPLC). Fifty microliters of 40% trichloroacetic acid (5% final concentration) was added to 150 µL of plasma, mixed, and chilled on ice for 20 minutes, followed by centrifugation for 5 minutes at 21,000 x g at 4°C. The supernatant was neutralized by adding 400 µL of freshly prepared trioctylamine: 1,1,2-trichlorotrifluoroethane (1:4). After centrifugation for 1 minute at 21,000 x g at 4°C, the nucleotide extract was carefully collected and stored at -20°C until HPLC analysis. Separation and quantification of gemcitabine and dFdU from the plasma was achieved with an isocratic HPLC system. The system consisted of a Gynkotek pump (model 480, Separations Analytical Instruments BV, Hendrik Ido Ambacht, the Netherlands), an automatic injection system Promis II (Separations Analytical Instruments BV), and a Waters M-440 fixed-wavelength detector (Millipore BV/Waters Chromatography, Etten-Leur, the Netherlands) set at 254 and 280 nm. From the 200 µL of extract, 50 µL was injected onto a µBondapak C18 column (Millipore BV; length, 300 mm; internal diameter, 3.9 mm; and particle size, 10 µm). The mobile phase used was Pic B7 reagens (Waters Chromatography) in 15% methanol (pH = 3.1) with a flow rate of 1.0 mL/min. Peak areas were quantified using the Chromeleon data acquisition program (Version 3.02, Chromeleon Chromatography Data Systems, Gynkotek HPLC, Germering, Germany). Standard samples of blank plasma were spiked with 5, 10, 25, 100, and 500µmol/L gemcitabine and dFdU, followed by extraction in the same way as patient samples and used for a calibration curve. Retention times of gemcitabine and dFdU were 7.1 and 13.5 minutes, respectively. The limit of quantification was approximately 25 pmol/50 µL (0.5 µmol/L) for both gemcitabine and dFdU. dFdCTP analysis. Cellular nucleotides were extracted and analyzed by HPLC as reported previously.18 Briefly, cells were suspended in 150 µL of ice-cold phosphate-buffered saline and extracted as noted for gemcitabine and dFdU. Separation and quantitation of the normal ribonucleotides and of dFdCTP was achieved with a gradient HPLC (Partisphere SAX anion exchange column, Whatman, Clifton, NJ; length, 110 mm; internal diameter, 4.7 mm; particle size, 5 µm) connected to photo-diode array detector set at 254 and 280 nm as described previously.18 Peaks were quantified using peak area and calculated using the data acquisition program Chromeleon Version 3.02. The detection limit for dFdCTP was 50 pmol per injection (175 µL); the quantification limit was 75 pmol. The cellular concentrations of dFdCTP and normal ribonucleotides were calculated as pmol/106 mononuclear cells. Paclitaxel analysis. Paclitaxel was analyzed in plasma using a sensitive HPLC assay with solid-phase extraction as the sample pretreatment procedure, as previously described.19 Briefly, an APEX octyl analytical HPLC column (Jones Chromatography, Littleton, CO; 4.6 x 150 mm; particle size, 5 µm) was used. The mobile phase consisted of acetonitrile methanol 0.02 mol/L ammonium acetate buffer, pH 5.0 (4:1:5, volume to volume to volume). Solid-phase extraction was performed with Cyano Bond Elut Columns (Varian, Harbor City, CA), and ultraviolet detection was performed at 227 nm. Paclitaxel concentrations as low as 12 nmol/L can be detected with this system.
Ex Vivo Incubation of Mononuclear Cells With Paclitaxel and Gemcitabine
Pharmacokinetic and Pharmacodynamic Analysis
Limited Sampling Model Validation
Toxicity Analysis and Statistics
0.1 µmol/L was related to the percentage decrease in granulocytes, WBCs, and platelets. Furthermore, we tested the effects of paclitaxel dose and paclitaxel AUC on the gemcitabine Cmax, dFdU AUC, dFdCTP AUC, and dFdCTP Cmax, and vice versa. A significant difference was indicated by a P value < .05. In addition, the slope of the regression line and its 95% confidence interval (CI) were evaluated. The computer program SPSS (Version 7.5, SPSS, Inc, Chicago, IL) was used for the statistical analysis.
Patient Characteristics Eighteen patients were entered into the pharmacokinetic part of the phase I/II study between October 1996 and July 1997. Patient characteristics are listed in Table 1. One patient initially diagnosed with metastatic large-cell carcinoma of the lung was reclassified as having metastatic melanoma after pathologic revision and new biopsies. No blood samples were obtained on day 8 from two of the patients.
Plasma Pharmacokinetics
The limited paclitaxel sampling, according to our gemcitabine sampling model, was tested with historical data sets.15 From these data sets, the AUC after end paclitaxel infusion and AUC based on the limited sampling model were superimposable, making this model feasible for evaluating paclitaxel pharmacokinetics. The plasma pharmacokinetics could be described for the postinfusion period. Plasma paclitaxel concentrations decreased rapidly after the end of the infusion. Table 2 also lists the pharmacokinetic parameters of paclitaxel. Because a 33% increase in paclitaxel dose resulted only in a mean 25% increase in Cmax and a 14% increase in AUC, it seems likely that paclitaxel pharmacokinetics are linear for this combination schedule and in this dose range of paclitaxel.
Cellular Pharmacology
Increased dFdCTP accumulation might be related to altered metabolism of cofactors involved in the synthesis of dFdCTP. Therefore, we also determined the concentrations of ribonucleotides such as adenosine triphosphate (ATP), which is a cofactor in gemcitabine phosphorylation, and cytidine triphosphate (CTP) and uridine triphosphate (UTP), which may regulate dCK.20 Combined gemcitabine-paclitaxel treatment increased CTP, UTP, ATP, and guanosine triphosphate (GTP) 2 and 4 hours after gemcitabine administration, as listed in Table 4. At 20 hours after gemcitabine exposure, ribonucleotide concentrations returned to pretreatment levels, even though UTP levels were still significantly higher at both paclitaxel doses of 150 and 200 mg/m2 (P = .043 and P = .02, respectively). To determine whether the observed ribonucleotide shift was related to the gemcitabine-paclitaxel combination or to one of the single agents, the ribonucleotide levels were compared with data of patients treated with gemcitabine 800 mg/m2 administered as a 30-minute IV infusion13 and with results of additional pharmacokinetics of six patients who received paclitaxel 200 mg/m2 as a 3-hour IV infusion. For each patient treated with gemcitabine or paclitaxel as a single agent, pretreatment ribonucleotide levels were set at 100%, and relative levels after 4 hours (peak of the combination) are also listed in Table 4. Although gemcitabine alone did not significantly increase ribonucleotide levels, ATP and GTP significantly increased after paclitaxel infusion at 4 hours (P = .002 and .029, respectively).
Ex Vivo Experiments
Pharmacokinetics-Toxicity Relationships In a previous study, we were able to determine a relationship between the duration of paclitaxel concentration above 0.1 µmol/L and the percentage of decrease in absolute neutrophil count.19 However, this relationship was not observed in the present combination study, although the duration of paclitaxel concentration above 0.1 µmol/L and postinfusion paclitaxel AUC (Fig 2B) were related to a percentage decrease in platelets (r = 0.62, P = .007; and r = 0.61, P = .009, respectively). In addition, gemcitabine Cmax was also related to a percentage decrease in platelets (r = 0.58, P = .01) (Fig 2A).
Multiple linear regression analysis indicated that higher pretreatment plasma bilirubin and plasma creatinine levels were related to higher gemcitabine Cmax levels (r = 0.77, P < .001; and r = 0.50, P = .034, respectively). Moreover, pretreatment hepatic function, bilirubin, AST, and ALT were related to paclitaxel AUC. This relationship was strongest for bilirubin (r = 0.79; P < .001) compared with AST (r = 0.71, P = .001) and ALT (r = 0.65 and P = .005).
Gemcitabine and paclitaxel are both new, active agents in patients with advanced NSCLC and other malignancies, such as breast and ovary cancers. In this study, we observed pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel. Drug-drug interactions, both at a cellular and pharmacokinetic level, may influence the potency of the combination. When using mononuclear cells as a surrogate for the target, we observed a paclitaxel dose-dependent increase of cellular dFdCTP compared with single-agent gemcitabine.
From previous studies with gemcitabine alone, it is known that accumulation and retention of gemcitabine nucleotides by target cells are critical for the cytotoxicity of the drug. Gemcitabine elimination is rapid, with a t1/2 A definite relationship was observed between paclitaxel dose and dFdCTP level: at the higher paclitaxel dose, dFdCTP levels increased almost two-fold. The underlying mechanism for this phenomenon is not clear; several speculations can be made. Similar to its influence on bcl-2 phosphorylation in lymphoid and solid tumor cells,23,24 paclitaxel might affect the phosphorylating activity of dCK to produce an increase in dFdCTP accumulation. Preliminary in vitro experiments with tonsillar lymphocytes, however, failed to show a direct effect on dCK (unpublished results). However, the substantial increase in ribonucleotide levels may also affect gemcitabine phosphorylation. The ATP increase was most pronounced, possibly inducing a higher intracellular energy level and leading to an increased dFdCTP synthesis. Moreover, UTP and ATP are both excellent phosphate donors for deoxycytidine kinase,20 which is the rate-limiting enzyme in the phosphorylation of gemcitabine to its active metabolite dFdCTP. The increase in UTP and ATP pools might thus be another self-potentiating effect of gemcitabine favorable for dCK activity. In the ex vivo studies, no effect on ATP was observed, which may explain the absence of an effect of paclitaxel on dFdCTP ex vivo. Another interesting finding was the shift in dFdCTP peak level from 2 hours for gemcitabine as a single agent21,22 and in combination with paclitaxel at 150 mg/m2 to 4 hours after gemcitabine infusion at paclitaxel 200 mg/m2. The increase in ribonucleotides is possibly related to the increase in ATP, which is a phosphate donor for the synthesis of nucleotides. Moreover, an increase in UTP could be explained by CTP-synthetase inhibition by dFdCTP, because UTP is the substrate for CTP-synthetase. The elevated ribonucleotide levels seem to be an effect of the combination therapy in which gemcitabine and paclitaxel potentiate each other. Although gemcitabine alone did not significantly increase the ribonucleotides in patients, in vitro ribonucleotide elevations after gemcitabine have been described.18 For paclitaxel, ATP and GTP levels were already significantly increased at 4 hours. The relationship between abnormal liver biochemistry tests and altered paclitaxel pharmacokinetics has been described before,25-27 yet we found a strong relationship between normal, pretreatment hepatic function and paclitaxel AUC. For bilirubin, normal was defined as less than 30 µmol/L. This relationship was not present when normal was defined as less than 10 µmol/L, suggesting that indices of normal liver function for bilirubin less than 30 µmol/L also predict alterations in drug clearance. The gemcitabine-paclitaxel combination was well tolerated, and the mild toxicity allowed an increase of the paclitaxel dose from 150 to 200 mg/m2. The main dose-limiting toxicity of paclitaxel is neutropenia, which is reduced by reduction of the infusion time to 3 hours. Gemcitabine has a relatively mild toxicity profile, with myelosuppression being the main toxicity. Earlier pharmacokinetic studies with paclitaxel combinations showed a relationship between paclitaxel pharmacokinetics and a percentage decrease in neutrophils.19,28 In this combination study, pharmacokinetics were not related to a percentage decrease in neutrophils, but the pharmacokinetics of both gemcitabine and paclitaxel were related to a percentage decrease in platelets. Currently, several new combinations with gemcitabine are being evaluated preclinically and clinically. The interactions between gemcitabine and cisplatin have been studied in vitro and in vivo and have shown both additive and synergistic effects.29 In patients, several phase II studies have shown promising response and survival rates.30,31 The value of the gemcitabine-paclitaxel combination awaits further evaluation. Both compounds have shown activity against advanced NSCLC as a single agent. The present study demonstrated an interaction between both agents at a cellular level. Preclinical data of Theodossiou et al32 showed additivity and slight antagonism between gemcitabine and paclitaxel, irrespective of sequence of administration. Our preliminary data with NSCLC cell lines also indicated additivity,33 although paclitaxel seemed to enhance gemcitabine metabolism. The clinical value of the gemcitabine-paclitaxel combination is currently being studied in a randomized trial of the European Organization for Research and Treatment of Cancer, in which the gemcitabine-paclitaxel, cisplatin-paclitaxel, and the cisplatin-gemcitabine combinations are being compared. In conclusion, no drug-drug interactions on the plasma pharmacokinetics of gemcitabine and paclitaxel were observed, although paclitaxel affected dFdCTP accumulation. The gemcitabine-paclitaxel combination clearly increased ribonucleotide levels in mononuclear cells. In this study, both gemcitabine and paclitaxel pharmacokinetics were related to a percentage decrease in platelets. Pharmacokinetic monitoring in subsequent studies will be necessary tofurther explain the effect of paclitaxel dose on dFdCTP and to increase the efficacy of combinations, thereby improving treatment.
We thank G. Veerman for his technical assistance with the start of this study and Dr P.D. Bezemer for his statistical advice.
This study was financially supported by the Dutch Cancer Society (grant no. VU 94-753) and by Eli Lilly & Co, International and the Netherlands.
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Crino L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non–small-cell lung cancer: A phase II study. J Clin Oncol 15:297-303, 1997 31. Abratt RP, Sandler A, Crino L, et al: Combined cisplatin and gemcitabine for non-small cell lung cancer: Influence of scheduling on toxicity and drug delivery. Semin Oncol 25:35-43, 1998 (suppl 9) 32. Theodossiou C, Cook JA, Fisher J, et al: Interactions of gemcitabine with paclitaxel and cisplatin in human tumor cell lines. Int J Oncol 12:825-832, 1998[Medline] 33. Kroep JR, Tolis C, Voorn DA, et al: Paclitaxel and gemcitabine cell cycle interactions in non–small-cell lung cancer (NSCLC) cell lines. Proc Am Assoc Cancer Res 40:678, 1999 (abstr) Submitted November 24, 1998; accepted March 11, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) was calculated as 0.693/
z, where 
of 8 minutes,
