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P-Glycoprotein Inhibitor Valspodar (PSC 833) Increases the Intracellular Concentrations of Daunorubicin In Vivo in Patients With P-Glycoprotein–Positive Acute Myeloid Leukemia

From the Department of Hematology, Örebro Medical Center Hospital, Örebro; Department of Hematology, Linköping University Hospital, Linköping; Department of Hematology, Huddinge University Hospital; Departments of Hematology and Clinical Pharmacology, Karolinska Hospital; Department of Hematology, Danderyds Hospital; Karolinska Institute, Stockholm, Sweden; and Novartis Pharma AG, Basel, Switzerland.

Address reprint requests to Ulf Tidefelt, MD, Karolinska Institute, Department of Medicine, Örebro Medical Center Hospital, S-701 85 Örebro, Sweden; email ulf.tidefelt{at}orebroll.se

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment.

PATIENTS AND METHODS: Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)–positive. dnr 100 mg/m² was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography.

RESULTS: The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 µmol/L in Pgp-negative samples and 13.5 µmol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 µmol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P < .05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed.

CONCLUSION: These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FAILURE OF TREATMENT with anticancer agents can be a result of their poor tumor cell selectivity, poor tumor cell exposure, or tumor cell resistance. When a previously sensitive tumor develops secondary resistance, it is clear that resistance at the cellular level is a major contributor to the clinical failure. Such resistance to anticancer agents has been widely studied in tumor cell lines and experimental animal models, and a number of possible mechanisms have been identified.^1,2

Multidrug resistance (MDR) is of particular significance because it involves a number of chemically unrelated anticancer agents such as anthracyclines, vinca alkaloids, taxanes, and epidophyllotoxins.³ An increased energy-dependent efflux of drug from resistant cells was early recognized as a mechanism of MDR. A transmembrane glycoprotein, called P-glycoprotein (Pgp) or P-170, is of central importance to this resistance.⁴ In tumor cell lines, the expression of Pgp correlates with the degree of resistance,⁵ and transfection of the mdr1 gene, which codes for Pgp, confers resistance.⁶ The finding that the resistance of Pgp-expressing cell lines can be completely reversed by simultaneous incubation with various noncytotoxic drugs such as calcium channel blockers, cyclosporins, and quinidine^7-9 is also of clinical interest. The proposed mechanism for this is that these reversing agents compete with the anticancer drugs for the binding site on Pgp and, thus, inhibit drug efflux.^8,10

Several studies have now demonstrated that Pgp expression also has clinical prognostic importance. In acute myeloid leukemia (AML), about one third of the patients express Pgp at diagnosis and more than 50% do so at a more advanced stage of disease.^1,8,9 The expression of Pgp is also increased in elderly patients, in patients with secondary leukemias, and in patients with unfavorable cytogenetics.¹¹ In multivariate analyses, Pgp expression is a strong and independent factor that predicts poor response to induction treatment and survival.^11-13

Although widely studied in experimental systems, the clinical relevance of MDR reversal is less clear. Interesting responses in case reports or small series of patients have been reported.¹⁴ These responses have not always been correlated with expression of Pgp.¹⁵ Side effects of the reversing agents (calcium channel blockers or cyclosporine) have been a problem because of difficulty with achieving adequate plasma concentrations.¹⁴

Valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) is a cyclosporine derivative that has been developed specifically for the reversal of MDR. In vitro, it is five to 30 times more potent for this purpose than cyclosporine and has no nephrotoxic or immunosuppressive side effects.^16-18 Phase I studies have defined the maximum tolerable doses when valspodar and anticancer drugs are given together, and phase II studies in relapsed or refractory patients have shown adequate response rates.^19-22 At present, the clinical benefit of valspodar in patients at high risk of developing resistance is being evaluated in phase III trials.

The rationale for clinical studies with valspodar and other resistance-reversal agents is that the concentration of the anticancer drug in the tumor cells will be raised and that this will result in a better treatment effect. However, the cellular pharmacokinetics of anticancer agents in conjunction with MDR-reversing agents has only been studied in a few patients treated with differing regimens.^23,24 The aim of this study was, therefore, to evaluate the effect of valspodar on the intracellular pharmacokinetics of daunorubicin (dnr) in patients being treated for AML. Our results show that, in patients with Pgp-positive leukemia, the intracellular concentrations of dnr in leukemic cells in vivo were increased by valspodar to a degree that could be of clinical value.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Ten patients with AML were studied. Age, sex, stage of disease, French-American-British classification, and WBC count at start of therapy are listed in Table 1. The study was approved by the local ethics committees, and all patients gave their written informed consent to participation in the trial.

Blood Sampling
Five to 10 ml of peripheral blood was drawn in heparinized tubes before and at specified intervals throughout the dnr infusion. The tubes were immediately put in ice water, and the samples were thereafter handled at +4°C. After centrifugation, plasma was frozen at -80°C and leukemic blast cells (80% to 90% pure) were separated on sodium metrizoate/ficoll (Lymphoprep, Nyegaard & Co, Oslo, Norway; specific weight, 1.077) at 550 x g for 20 minutes, washed twice in ice-cold phosphate-buffered saline (pH, 7.4) at 1,000 x g for 10 minutes, and resuspended in 1 mL phosphate-buffered saline. The total cellular volume (mean cell volume x number of cells) of each sample was determined using a Coulter Multisizer (Coulter, Miami, FL), after which the samples were stored at -80°C until the time of analysis.

Pgp Determination
According to the protocol, Pgp expression was determined in isolated blast cells from peripheral blood by flow cytometry using the monoclonal antibodies NCL-JSB-1 (Novocastra, Newcastle upon Tyne, United Kingdom), MRK16 (Kamiya Biomedical Company, Seattle, WA), and C494 (Signet Laboratories, Dedham, MA). The fluorescence-activated cell sorter analysis was performed using 4 mL of fresh peripheral blood taken in a heparinized tube with 1 mL of 0.9% NaCl added. The viability of the leukemic cells was determined by trypan blue exclusion, and a viability of 60% was required to proceed with the analysis, which was performed with a FACsorter (Becton Dickinson, Mountain View, CA) with a Cyonics argon ion laser (JDS Uniphase Corporation, San Jose, CA). The appropriate gates were set on dot plots that displayed forward scatter versus side scatter and were confirmed by identification of lymphocytes versus monocytes/blasts with conjugated monoclonal antibodies CD45 and CD14 phycoerythrin (PE) (Dakopatts AB, Alvsjo, Sweden). Sublines of the human leukemic cell line HL-60 that express various degrees of Pgp positivity were used as a positive control,²⁵ and parent HL-60 cells, as well as fresh blood cells, from healthy donors were used as negative controls. The quadrant markers that designated positivity for fluorescein isothiocyanate (FITC) and PE, respectively, were drawn according to the negative population on the isotype control plot using mouse immunoglobulin G 1 FITC/immunoglobulin G2a PE (Dakopatts AB). Analyses were performed on logarithmically amplified cytograms and histograms. Evaluation of the Pgp expression was performed blinded by a hematopathologist and was based on the percentage of cells stained. Staining of more than 25% of the leukemic cells with two antibodies or more than 50% with one antibody was regarded as a significant Pgp expression (Table 1).

Independent of the study protocol, Pgp expression in CD34⁺ and CD38⁺ leukemic cells from bone marrow was determined blinded using the MRK16 and UIC-2 monoclonal antibodies and a functional assay using rhodamine-123 according to a previously described method.²⁶ In all 10 patients, the results from the flow cytometry analysis from the two laboratories were concordant, but in patient no. 9 (Pgp-negative), the rhodamine-123 assay was weakly positive. The possible impact of this is discussed below. All results are presented based on Pgp classification according to the study protocol by flow cytometry, as shown for individual patients in Table 1.

dnr Determination
Plasma and intracellular concentrations of dnr were determined by high-pressure liquid chromatography.²⁷ Cell samples were thawed and sonicated at 20 kHz for 30 seconds at 75 W. A 0.2-mL aliquot of the cell sample or plasma was added to 0.2 mL of 0.1 mol/L borate buffer (pH, 8.3) that contained 0.1 µmol/L doxorubicin as an internal standard. The drugs were extracted with 2.0 mL of chloroform/methanol (4:1 by volume). The organic phase, including the drugs, was evaporated under nitrogen. Then, 150 µL mobile phase (0.05 mol/L KH₂PO₄:acetonitril [69:31]) was added. The chromatographic procedure was performed in a reversed-phase system. A 100 µL aliquot of the mobile phase was injected into the high-pressure liquid chromatography system and the LiChroCart RP-18 column (Merck & Co, Inc, Whitehouse Station, NJ) at a flow rate of 1.0 mL/min. Drug concentrations were determined by fluorometry (excitation and emission wavelengths were 480 nm and 560 nm, respectively) using a Jasco spectrofluorometer FP 920 (JASCO Corporation, Tokyo, Japan). The retention times were 5.5 to 6.3 minutes for dnr and 2.6 to 2.8 minutes for doxorubicin. The validated detection limit of the system was 1 pmol, which corresponds to a sample concentration of 5 nmol/L. Drug concentrations were calculated using an EZ-chrome integration program (EZChrome Scientific Software, Inc, San Ramon, CA). Intracellular drug concentrations were related to the cell volume and expressed as µM.

Valspodar Determination
Blood levels of valspodar were determined by a radioimmunoassay, as previously described.²⁸

Pharmacokinetic Evaluation
The effect of valspodar was determined from the steady-state concentrations of dnr in plasma and leukemic cells before and after the start of treatment with valspodar. In addition, the effect of valspodar on the ability of the cells to concentrate dnr was evaluated from the ratio of the area under the curve (AUC) for drug concentration versus time in leukemic cells to the AUC for drug concentration to time in plasma. AUC was calculated according to the trapezoidal rule. The study was not designed to evaluate classical pharmacokinetic parameters such as t_1/2, volume of distribution, or clearance.

Statistical Evaluation
Differences in steady-state concentrations and AUCs between patients whose cells did or did not show an increased expression of Pgp were analyzed using Student’s t test for paired or unpaired data. Any correlation between plasma and intracellular concentrations was investigated using simple regression analysis.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Baseline patient characteristics are listed in Table 1.

Plasma Concentration of Valspodar
The mean ± SD plasma concentration of valspodar was 2,122 ± 872 nmol/mL. A single patient sample taken at the end of the infusion showed a value of 679 nmol/mL. Except for this sample, all patients achieved stable concentrations greater than the desired level of 1,000 ng of valspodar/mL in plasma from the end of the loading dose and throughout the infusion time. Ten hours after the end of the infusion, the mean concentration of valspodar in plasma was still 692 nmol/mL.

Plasma Concentrations of dnr
The mean plasma concentration of dnr for all patients is shown in Fig 1. At the end of the first 24 hours, there seemed to be a stable concentration of approximately 0.02 µmol/L. During the first 8 hours after the start of valspodar infusion, there was an approximately 50% increase in plasma concentration, to a steady-state level between 0.03 and 0.035 µmol/L. There were no significant differences between blasts from patients with Pgp-positive and those from patients with Pgp-negative leukemia.

View larger version (13K): [in this window] [in a new window]   Fig 1. Concentrations of dnr (solid line) and its main metabolite, daunorubicinol (dashed line), in plasma (the two lower curves) and leukemic cells (the two upper curves) for all patients (mean + SD).

Intracellular Concentrations of dnr
The intracellular concentrations of dnr are shown for each patient in Fig 1 and as mean values for patients with Pgp-positive and those with Pgp-negative leukemia in Fig 2. In the seven patients with Pgp-positive leukemia, the steady-state intracellular concentration between 16 and 24 hours after infusion was 13.7 µmol/L, compared with 18.8 µmol/L in the three patients with Pgp-negative leukemia (P = not significant [NS]). In the first 8 hours after the start of valspodar infusion, there was marked increase in the intracellular concentrations in all patients. The increase was more pronounced in the samples from patients with Pgp-positive leukemia and resulted in a new steady-state intracellular concentration of 24.0 µmol/L in Pgp-positive and 25.8 µmol/L in Pgp-negative samples (P = NS). There was a correlation between the concentrations of dnr in leukemic cells and those in plasma during the first 24 hours (r² = .855 for patients with Pgp-positive and .661 for patients with Pgp-negative leukemias), but thereafter, the correlation was poor (r² = .203 for patients with Pgp-positive and .210 for patients with Pgp-negative leukemias).

View larger version (17K): [in this window] [in a new window]   Fig 2. Mean values of the concentration of dnr (•,) and the main metabolite daunorubicinol (,) in leukemic cells in seven Pgp-positive (, •, solid lines) and three Pgp-negative (, , dashed lines) patients. Valspodar infusion was started at 24 hours. Abbreviation: inf, infusion.

Ratio of Intracellular AUC/Plasma AUC
The ability of the leukemic cells to concentrate dnr, which is expressed as the ratio of the AUC for dnr concentration versus time in the leukemic cells to the AUC for dnr concentration versus time in plasma, is shown for each 24-hour period separately in Fig 3 and Table 2. There was a marked intracellular concentration in all patients. In the three patients with Pgp-negative leukemia, the mean ratio was 853 on day 1, which increased by 12% to 956 on day 2 (P = NS). In contrast, in the seven patients with Pgp-positive leukemia, the mean ratio (545) was lower on day 1, but during the second day, a significant increase of 52% to 830 was observed (P < .05). Compared with that on day 2, the ability to concentrate dnr intracellularly was somewhat lower on day 3 in both groups. For daunorubicinol in plasma and leukemic cells, the ratio remained constant in both patients with Pgp-positive and those with Pgp-negative leukemias (data not shown).

View larger version (35K): [in this window] [in a new window]   Fig 3. The mean ratio of the AUC for dnr concentration versus time in leukemic cells to the AUC for dnr concentration versus time in plasma (AUC leukemic cells/AUC plasma) is shown separately for each 24-hour period: Day 1 (), day 2 (), and day 3 (). The asterisk designates a statistically significant difference (P < .05).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We have shown that valspodar significantly increases the concentrations of dnr in leukemic cells in vivo during treatment of patients with Pgp-positive AML. The number of patients to be included was chosen to ensure that the leukemic cells from at least some of the patients were positive for Pgp. Because of the low number of patients with Pgp-negative leukemia that were actually included in our study, we are not able to draw definite conclusions regarding a difference in the effect of valspodar on Pgp-positive and Pgp-negative leukemias. However, in the Pgp-negative leukemias studied, the intracellular concentrations of dnr before valspodar were higher and no significant increase in the cell-to-plasma ratio was observed after the start of infusion. This may indicate that the effect of valspodar is selective to cells from patients with Pgp-positive leukemia.

The study was designed with the infusion of dnr continuing 12 hours after the infusion of valspodar was stopped to evaluate a possible decrease in intracellular concentrations. In the samples taken 2 hours after the end of valspodar infusion, there seemed to be a decrease in intracellular dnr, but this was not seen in the last two samples. At this time, the number of circulating blast cells were declining in many patients, which makes determination less certain and which is why we do not want to make any conclusion regarding this time period. However, the reduced concentration gradient (intracellular AUC/plasma AUC) on day 3 compared with day 2 can at least partly be explained by this.

The determination of Pgp is difficult. In our study, we decided to use flow cytometry with a panel of established antibodies. We used more than 25% positive cells with two antibodies or more than 50% positive cells with one antibody as criteria for Pgp positivity. This was done to make sure that a sufficient number of cells were Pgp positive so that they could detect an effect of valspodar in the whole cell population. If we had used more than 10% positive cells, a more commonly used criteria for Pgp positivity, the overall interpretation of Pgp status would have been the same. In all Pgp-positive leukemias, at least one antibody showed more than 50% positive cells. Regarding the Pgp classification based on immunocytochemistry, there was complete agreement between the results assayed by two independent laboratories. However, in one of the laboratories, a functional assay for Pgp was also performed. In this assay, one patient with Pgp-negative blast cells, patient no. 9, showed a weak positivity. If this patient had been included in the Pgp-positive group, the conclusions of the study would not have changed: the mean ratio of the AUC of dnr in the leukemic cells to the AUC of dnr in plasma was 609 for day 1 without valspodar, compared with 871 for day 2 with valspodar (P < .05).

To determine the true effect of valspodar on the transport of dnr across the cell membrane of the tumor cells, we had to analyze the ratio of drug concentration in the cells to that in plasma, because some of the increased intracellular concentrations of dnr that were observed after the start of valspodar infusion could have been attributed to increased concentrations of plasma dnr. Previous studies of plasma pharmacokinetics have shown that there is a significant interaction between MDR-affected anticancer drugs and MDR-reversing agents such as cyclosporine and valspodar. Because of reduced clearance, the plasma concentrations of dnr, epipodophyllotoxins, and mitoxantrone are increased.^19-21,24 The proposed mechanism for this pharmacokinetic interaction is blockage of elimination by the bile and renal tubuli, organs that are known to express high levels of Pgp.⁹ In our study, this was demonstrated as an approximately 50% increase in the mean plasma concentration of dnr after the start of valspodar infusion. The rate of increase in the main metabolite, daunorubicinol, also increased both in plasma and leukemic cells after the start of valspodar treatment. However, only the patients with Pgp-positive leukemias showed a significantly increased ratio of dnr AUC in the leukemic cells to dnr AUC in plasma after the start of valspodar infusion. This strongly supports the hypothesis that valspodar causes an increased intracellular concentration of dnr, not only by its effect on plasma pharmacokinetics, but also by interacting directly with Pgp.

Increasing intracellular concentrations of anticancer agents in the tumor cells is the basic concept behind clinical studies with MDR-reversing agents. Nevertheless, there are only a few published observations to support this. In a previous study, we analyzed the intracellular pharmacokinetics of doxorubicin in combination with high-dose intravenous verapamil or oral verapamil plus intravenous injections of cyclosporine in two patients with refractory leukemic lymphomas.²³ A marked increase in intracellular doxorubicin was observed. Another study has shown that concentrations of idarubicin in leukemic cells are increased when administered in combination with cyclosporine.²⁴ None of these studies provided a rigorous analysis of the possible contribution of altered plasma pharmacokinetics.

The maximum-tolerated dose of dnr alone has not been formally investigated, but the standard dose in the treatment of AML is 45 to 60 mg/m² administered as a short infusion.²⁹ Previous phase I studies have determined that the maximum-tolerated dose of dnr in combination with valspodar 10 mg/kg per 24 hours is 45 mg/m²/d.^21,22 Assuming this dose is equitoxic with 60 mg/m², this would mean that, when used in combination with valspodar, the dose of dnr must be reduced by 25%. This is in agreement with what is expected from plasma pharmacokinetics. In the present study, the mean intracellular concentration of dnr was increased by almost 100% after the use of valspodar. This finding also supports the idea that valspodar has effects on anticancer drug levels in Pgp-positive cells in addition to those achieved by simple dose escalation.

Because of the small number of patients, many of whom had resistant leukemia, we cannot draw any conclusions about the clinical effect of valspodar. Even though, as this study shows, MDR-reversing agents can increase the intracellular efficacy concentrations of anticancer drugs in vivo, this does not necessarily lead to improved treatment results. In in vitro systems, increased anticancer drug concentration in Pgp-positive tumor cells generally results in increased cell death. In the clinical situation, the problem is more complex. Although tumor cell lines often express only one mechanism for resistance, clinical drug resistance is often multifactorial.² Tumor cells may develop additional mechanisms for resistance, such as increased drug metabolism, altered or reduced target enzymes, increased DNA repair, or altered regulation of apoptosis.³⁰ If this occurs, increasing the intracellular concentration of the anticancer drug may not be sufficient to overcome resistance. This is more likely at advanced stages of the disease, and the major benefit of MDR-reversing agents might be in patient groups with low levels of markers for resistance or early in patients not heavily treated.

In conclusion, our study shows that valspodar increases the intracellular concentrations of dnr in vivo during treatment of patients with Pgp-positive AML. The reduction in dnr dose required to maintain efficacy and avoid toxicity can be accurately determined. This finding also shows that the concept of MDR reversal, which has previously been based on in vitro results, seems to be valid in vivo as well. The clinical benefit of this concept must be further evaluated in randomized phase III trials.

	ACKNOWLEDGMENTS

 
Supported by grants from the Swedish Cancer Society, Lion Research Foundation, and Örebro Council Research Committee.

We thank Eva Hellberg and Sofia Bengtzén for skillful technical assistance.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted December 8, 1998; accepted January 10, 2000.

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