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Pharmacokinetic and Pharmacodynamic Study of the Combination of Docetaxel and Topotecan in Patients With Solid Tumors

From the Program of Molecular Therapeutics and Drug Discovery and Biostatistics Facility, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, School of Pharmacy; Departments of Medicine and Pharmacology, School of Medicine; and Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; and Greenebaum Cancer Center, University of Maryland, Baltimore, MD.

Address reprint requests to William C. Zamboni, PharmD, University of Pittsburgh Cancer Institute, Biomedical Science Tower, E-1040, 200 Lothrop St, Pittsburgh, PA 15213; email zamboniwc{at}msx.upmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration.

PATIENTS AND METHODS: On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m² without filgrastim and at 60, 70, and 80 mg/m² with filgrastim on day 1, and topotecan was administered at 0.75 mg/m² as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CL_DOC) and topotecan (CL_TPT) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CL_DOC and CL_TPT were calculated using compartmental methods.

RESULTS: Mean ± SD CL_DOC in cycles 1 and 2 were 75.9 ± 79.6 L/h/m² and 29.2 ± 17.3 L/h/m², respectively (P < .046). Mean ± SD CL_TPT in cycles 1 and 2 were 8.5 ± 4.4 L/h/m² and 9.3 ± 3.4 L/h/m², respectively (P > .05). Mean ± SD neutrophil nadir in cycles 1 and 2 were 4,857 ± 6,738/µL and 2,808 ± 4,518/µL, respectively (P = .02).

CONCLUSION: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FOR MANY CHEMOTHERAPY agents, combination regimens containing these agents have increased antitumor activity compared with administration of the agents alone.^1,2 However, the sequence of administration of chemotherapeutic agents may alter their pharmacokinetics, toxicity, or antitumor effect. Thus the sequence of administration of anticancer agents when used in combination should be systematically evaluated in preclinical and early clinical trials.^3-5

Docetaxel is a taxane analog that has a wide range of antitumor activity when administered alone and in combination with other agents.⁶ Docetaxel undergoes primarily hepatic metabolism via cytochrome P450 (CYP) 3A4.^7,8 In addition, patients with elevated bilirubin and/or transaminases have a reduced docetaxel systemic clearance and increased risk of toxicity.^9-11

Topotecan is a camptothecin analog that undergoes primarily renal elimination^12-14 and may also undergo clinically significant oxidative metabolism via CYP.^15,16 Several studies have reported that topotecan forms an N-desmethyl metabolite, which is consistent with metabolism by CYP enzymes.¹⁷ Previously, we reported that phenytoin alters topotecan and N-desmethyl topotecan disposition.¹⁵ In addition, Goldwasser et al¹⁶ reported that topotecan decreased cyclosporine clearance, possibly via inhibition of CYP 3A metabolism.

The clinically significant oxidative metabolism of docetaxel and topotecan via CYP suggests that their coadministration might produce clinically significant alterations in the pharmacokinetics and clinical effects of each agent.^3,4,15 Thus, as part of a phase I trial, we evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when administered in combination on two schedules that altered their sequence of administration.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Pharmacokinetic studies of topotecan and docetaxel and pharmacodynamic studies were performed as part of a phase I study of topotecan and docetaxel. Before enrollment in the phase I study, written, informed consent, approved by the Institutional Review Board of the University of Maryland, was obtained from each patient. Eligible patients were older than 18 years of age and had histologically documented solid tumors refractory to standard therapy or for which no effective therapy existed. Other eligibility criteria included a Karnofsky performance status 60, a life expectancy of 3 months, more than 2 weeks since prior radiation, more than 2 weeks since prior surgery, more than 4 weeks since prior chemotherapy, and more than 6 weeks since prior administration of carmustine or mitomycin. In addition, patients were required to have granulocytes 1,500/µL, platelets 100,000/µL, bilirubin 1.3 mg/dL, serum creatinine 1.5 mg/dL, and creatinine clearance 50 mL/min. Complete blood cell counts were obtained weekly.

Dosage and Administration
On cycle 1, docetaxel was administered on day 1 and topotecan was administered on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4 and docetaxel was administered on day 4. Cycles were repeated every 21 days. Docetaxel was administered before topotecan as a 1-hour infusion at 60 mg/m² without filgrastim and at 60, 70, and 80 mg/m² with filgrastim. Topotecan was administered as a 0.5-hour infusion at 0.75 mg/m²/d. Dexamethasone was administered at 8 mg orally twice daily starting 24 hours before docetaxel and for a total of 3 days.

Sample Collection and Preparation
The sampling strategy for docetaxel was based on computation of the optimal sampling times using population pharmacokinetic parameter estimates obtained from phase II data.^11,17 This sampling strategy was obtained from Robert Earhart, MD, of Rhône-Poulenc Rorer Pharmaceuticals Inc (Collegeville, PA). Blood samples (3 mL) were obtained before the infusion, at the end of the infusion, and 0.25, 0.75, 2, 5.5, and 23 hours after the end of the docetaxel infusion. Blood was placed into heparinized tubes, centrifuged at 2,000 x g for 2 minutes, and the resulting plasma was decanted into a separate tube and stored at -70°C until analyzed.

Blood samples were obtained before the topotecan infusion and 0.25, 0.5, 1, 2, 4, and 6 hours after the end of the topotecan infusion. Blood was placed into heparinized, tubes, centrifuged at 2,000 x g for 2 minutes, and the resulting plasma was decanted into a separate tube and stored at -70°C until analyzed.

High-Performance Liquid Chromatography (HPLC) Analysis
The HPLC assay for docetaxel was modified from the assay of Loos et al¹⁸ and Ardiet et al.¹⁹ Octadecyl C18/14% (100 mg/mL) solid-phase extraction columns (Applied Separations, Allentown, PA) were preconditioned with two 1-mL aliquots of acetonitrile followed by two 1-mL aliquots of distilled water. Cephalomannine, the internal standard, was added (20 µL) to 1 mL of plasma to achieve a final concentration of 850 ng/mL. Plasma (1 mL) was then added to the solid-phase extraction columns. The columns were washed with two 1-mL aliquots of distilled water. Docetaxel was eluted from the column with 1 mL of acetonitrile, and the acetonitrile solution was evaporated to dryness with nitrogen. The dried residues were reconstituted with 100 µL of mobile phase, and 75 µL were injected into the HPLC. The HPLC system consisted of an HP1090 HPLC fitted with a diode array detector and a C18 silica-bonded separation column (5 µm, 3 x 250 mm; Uptisphere by Interchim, Montlucon, France). The mobile phase was methanol:water (70:30, v/v), with pH adjusted to 2.6 using orthophosphoric acid, and the flow rate was 0.6 mL/min. Docetaxel and internal standard were detected at 230 nm. Under these conditions, the retention time of docetaxel and cephalomannine were 11.7 and 9.5 minutes, respectively, and the run time was 20 minutes. The lower limit of quantitation was 30 ng/mL.

Plasma concentrations of topotecan total (sum of lactone and hydroxy acid) were measured with a modification of an isocratic HPLC assay using fluorescence detection.^20,21 Topotecan total concentrations were measured by adding 20 µL of 20% phosphoric acid to 400 µL of the methanolic solution. Excitation and emission wavelengths were 320 nm and 540 nm, respectively, and the retention time for topotecan was 7 minutes. The lower limit of quantitation was 0.5 ng/mL.

Pharmacokinetic Analysis
The pharmacokinetic analysis of docetaxel was performed using MAP Bayesian estimation in ADAPT II.²² A three-compartment, linear model was fit to docetaxel plasma concentration–time data, and population priors were obtained from McLeod et al.²³ Individual parameters estimated included the volume of the central compartment (V_c), intercompartment rate constants (k₁₂, k₂₁, k₁₃, k₃₁), and the elimination rate constant from the central compartment (k₁₀). Using standard equations, systemic clearance (CL_DOC) and elimination half-life (t_1/2) of docetaxel were calculated from parameter estimates.²² The area under the docetaxel plasma concentration–time curve (AUC) from zero to infinity was calculated using the log trapezoidal method.²²

The pharmacokinetic analysis of topotecan was also performed using MAP Bayesian estimation in ADAPT II.²² A two-compartment, linear model was fit to topotecan total plasma concentration-time data, and population priors were obtained from Tubergen et al.²⁴ Individual parameters estimated included the V_c, intercompartment rate constants (k₁₂, k₂₁), and k₁₀. Using standard equations, topotecan total systemic clearance (CL_TPT) and t_1/2 were calculated from parameter estimates.²² The topotecan AUC from zero to infinity was calculated using the log trapezoidal method.²²

Statistical Analysis
The changes in CL_DOC, CL_TPT, neutrophil nadir, and platelet nadir were compared between cycles 1 and 2. Comparisons between cycles 1 and 2 were made using the exact, two-sided, Wilcoxon signed-rank test.^25,26 Statistical analysis was performed on absolute neutrophil count (ANC) and platelet nadirs from cycles 1 and 2 in patients with matched data.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Twenty-two patients were enrolled onto this phase I study. Patient characteristics are listed in Table 1. Patients were enrolled in cohorts of docetaxel 60 mg/m² in combination with topotecan without filgrastim (n = 6) and 60 (n = 4), 70 (n = 8), and 80 mg/m² (n = 4) in combination with topotecan and filgrastim. Each patient was scheduled to undergo docetaxel and topotecan pharmacokinetic studies on day 1 of cycle 1 and day 4 of cycle 2.

Docetaxel Pharmacokinetics
Docetaxel pharmacokinetic data from cycles 1 and 2 are listed in Table 2. The clearance of docetaxel was decreased in seven of eight patients in cycle 2 compared with cycle 1. The mean ± SD clearance of docetaxel in cycles 1 and 2 were 75.6 ± 79.6 L/h/m² and 29.2 ± 17.3 L/h/m², respectively (P = .046). In addition, when the ratio of docetaxel clearance in cycle 2 to that in cycle 1 was calculated for individual patients, the mean ± SD value was 0.53 ± 0.46 (median, 0.45; range, 0.10 to 1.50). The change in docetaxel clearance from cycle 1 to cycle 2 in individual patients is presented in Fig 1.

View larger version (19K): [in this window] [in a new window]   Fig 1. CLDOC on cycles 1 and 2. Individual CLDOC values are represented by •, and CLDOC from cycles 1 and 2 within the same patient are connected by solid lines. The average CLDOC for cycles 1 and 2 are represented by .

View larger version (17K): [in this window] [in a new window]   Fig 2. CLTPT on cycles 1 and 2. Individual CLTPT are represented by •, and CLTPT from cycles 1 and 2 within the same patient are connected by solid lines. The average CLTPT for cycles 1 and 2 are represented by .

View larger version (12K): [in this window] [in a new window]   Fig 3. CLTPT when coadministered with docetaxel doses of 60, 70, and 80 mg/m2. Individual CLTPT are represented by •, and the average CLTPT for each treatment group are represented by .

View larger version (18K): [in this window] [in a new window]   Fig 4. ANC nadirs on cycle 1 and cycle 2. Individual ANC nadirs are represented by •, and ANC nadirs from cycles 1 and 2 within the same patient are connected by solid lines. The average ANC nadirs are represented by .

View larger version (20K): [in this window] [in a new window]   Fig 5. Platelet nadirs on cycle 1 and cycle 2. Individual platelet nadirs are represented by •, and platelet nadirs from cycles 1 and 2 within the same patient are connected by solid lines. The average platelet nadirs are represented by .

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

In cycle 2 of this regimen, administration of docetaxel on day 4 after 3 prior days of topotecan treatment resulted in an approximately 50% decrease in docetaxel clearance compared with cycle 1, in which docetaxel was administered along with topotecan on day 1. Our results are consistent with those of previous studies that evaluated the sequence of administration of docetaxel and doxorubicin.^31,32 Administration of docetaxel after doxorubicin resulted in a 50% to 70% increase in docetaxel systemic exposure when compared with administration of docetaxel alone.³¹ However, our results differ from those of O’Reilly et al,²⁸ who evaluated the sequence of administration of topotecan and paclitaxel in a phase I trial. In this study, each patient received topotecan as a 30-minute infusion daily for 5 days and paclitaxel as a 24-hour infusion either before topotecan on day 1 or after topotecan on day 5. In this trial, the pharmacokinetics of topotecan and paclitaxel were not altered by the sequence of drug administration.

The ability of topotecan to alter the disposition of docetaxel and not alter paclitaxel may be due to hepatic metabolism of these two taxanes by different CYP isoenzymes.^4,7,33 Paclitaxel undergoes oxidative metabolism via CYP2C and CYP3A4,^33,34 whereas docetaxel undergoes metabolism primarily via CYP3A4.^7,8 Thus topotecan may alter the disposition of docetaxel via inhibition of CYP3A4 but need not alter the overall systemic disposition of paclitaxel due to the additional metabolism by CYP2C. In addition, the difference between the two studies may also reflect the different infusion schedules used for paclitaxel and docetaxel and the associated concentrations of drug that were achieved.²⁸ One limitation of our study is that the sequence of administration was not randomized. Therefore, we cannot rule out the possibility that the decreased docetaxel clearance on cycle 2 compared with cycle 1 is related to previous treatment.

The ratio of topotecan clearance from cycle 2 to cycle 1 was 1.1 ± 0.4, indicating no significant change in topotecan clearance from cycle 1 to cycle 2. Pharmacokinetic studies of topotecan in cycles 1 and 2 were both performed after coadministration of docetaxel, and thus we cannot evaluate the affect of docetaxel on topotecan disposition. However, the topotecan clearance in the current study was similar after coadministration of docetaxel doses of 60, 70, and 80 mg/m², which suggests that docetaxel may not alter the disposition of topotecan. In addition, the topotecan clearance in our study is similar to that previously reported in studies of topotecan administered alone as a 30-minute infusion.^24,35 Thus topotecan alters the disposition of docetaxel, but docetaxel does not seem to alter the disposition of topotecan. These results are consistent with studies evaluating the combination of docetaxel and doxorubicin, wherein doxorubicin inhibited the clearance of docetaxel but docetaxel did not alter the pharmacokinetics of doxorubicin.^31,32

Consistent with the decrease in docetaxel clearance and subsequent increase in systemic exposure when docetaxel was administered on day 4 after 3 previous days of topotecan, the ANC nadir was significantly lower (median reduction of 64%) during cycle 2 as compared with cycle 1 (P = .02). In those patients who received more than two cycles of therapy, the ANC nadir was consistently lower in cycle 2 as compared with cycle 1 and in cycle 4 as compared with cycle 3. In addition, the ANC nadir was similar in cycles 1 and 3 and in cycles 2 and 4, which suggests that the toxicity was not cumulative. The platelet nadir was similar in all cycles, indicating that the increase in docetaxel systemic exposure did not lead to increased thrombocytopenia. This is consistent with previous studies suggesting that the primary dose-limiting toxicity associated with docetaxel and topotecan is neutropenia rather than thrombocytopenia.^14,24,36,37

Combination regimens of chemotherapeutic agents are sometimes empirically designed; however, the sequence of administration can greatly affect the pharmacokinetics and drug effect (antitumor and toxicity).^28,29 Previous studies have evaluated potential pharmacokinetic interactions involving docetaxel; however, this was the first study evaluating the disposition of docetaxel and topotecan in combination. Administration of topotecan for 3 days before the combination of topotecan and docetaxel resulted in an approximately 50% decrease in docetaxel clearance and increased the severity of neutropenia. To prevent this alteration in the disposition of docetaxel and associated increased neutropenia, docetaxel should be administered on day 1 and topotecan on days 1 to 4. The results of this study underscore the need to perform pharmacokinetic studies as part of phase I trials that evaluate the combination of antitumor agents and to consider the importance of different sequences of administration.

	ACKNOWLEDGMENTS

 
Supported by Rhône-Poulenc Rorer Pharmaceuticals Inc., Collegeville, and SmithKline Beecham Pharmaceuticals Inc., Philadelphia, PA.

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Submitted December 28, 1999; accepted May 1, 2000.

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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 Zamboni, W. C. Articles by Tkaczuk, K. H. Search for Related Content PubMed PubMed Citation Articles by Zamboni, W. C. Articles by Tkaczuk, K. H. Social Bookmarking                            What's this?