Biomedical subjects

W J Loos

Publications and source records attributed to W J Loos.

At least 37 records · Page 2Linked to original sources

PubMed2000

Determination of camptothecin analogs in biological matrices by high-performance liquid chromatography.

Several analogs of the topoisomerase I inhibitor camptothecin (CPT) have been introduced in clinical practice in the last decade. All CPT analogs are sensitive to a pH-dependent reversible conversion between a pharmacologically active lactone form and its inactive, lactone ring-opened, carboxylate form. The reversible conversion is also dependent on the, sometimes species-dependent, protein binding properties of the two forms, resulting in different lactone to carboxylate plasma ratios for the various analogs. Pharmacokinetic analysis of the CPT analogs is helpful in understanding the pharmacodynamic outcome of drug treatment, in clinical as well preclinical studies. Measurement of these analogs is habitually complicated by the chemical instability of the lactone moiety and necessitates a rapid centrifugation of the blood sample, preferably at the bedside of the patient, to collect the plasma supernatant. Since the lactone forms of these drugs are able to diffuse across cell membranes, including those of the red blood cells, rapid collection and processing is even necessary in the case where only the total concentrations of the CPT analogs are to be measured. Sample pretreatment procedures of the CPT analogs topotecan, irinotecan, 9-aminocamptothecin and lurtotecan are summarized and discussed in this review.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Inter-relationships of paclitaxel disposition, infusion duration and cremophor EL kinetics in cancer patients.

Cremophor EL (CrEL) is a castor oil surfactant used as a vehicle for formulation of a variety of poorly water-soluble agents, including paclitaxel. Recently, we found that CrEL can influence the in vitro blood distribution of paclitaxel by reducing the free drug fraction, thereby altering drug accumulation in erythrocytes. The purpose of this study was to investigate the clinical pharmacokinetics of CrEL, and to examine inter-relationships of paclitaxel disposition, infusion duration and CrEL kinetics. The CrEL plasma clearance, studied in 17 patients for a total of 28 courses, was time dependent and increased significantly with prolongation of the infusion duration from 1 to 3 to 24 h (p<0.03). An indirect response model, applied based on use of a Hill function for CrEL concentration-dependent alteration of in vivo blood distribution of paclitaxel, was used to fit experimental data of the 3 h infusion (r2=0.733; p=0.00001). Simulations for 1 and 24 h infusions using predicted parameters and CrEL kinetic data revealed that both short and prolonged administration schedules induce a low relative net change in paclitaxel blood distribution. Our pharmacokinetic/pharmacodynamic model demonstrates that CrEL causes disproportional accumulation of paclitaxel in plasma in a 3 h schedule, but is unlikely to affect drug pharmacokinetics in this manner with alternative infusion durations.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Gender-dependent pharmacokinetics of topotecan in adult patients.

Gender-dependent differences in the clinical pharmacokinetic behavior of various drugs have been documented previously. Most commonly, these differences are associated with differences in body composition, renal elimination, drug absorption or hepatic metabolism. Gender-dependent differences in the pharmacokinetics of topotecan (Hycamtin) have not yet been described. In this report, pharmacokinetic data of the lactone and carboxylate forms of topotecan were derived from clinical studies in which topotecan was administered either orally or i.v. to a total of 55 males and 37 females. A significant difference (p=0.0082) of 38% was found between the apparent clearance of topotecan lactone after oral administration in males (237+/-105 l/h) and females (163+/-62.5 l/h). When adjusted for body surface area, this difference remained significant (p=0.031). Similarly, differences were noted in the percentage of topotecan in the lactone form (37.1+/-5.32 versus 41.7+/-6.51%, p=0.0076). Statistical analysis revealed that individual hematocrit values, which were consistently lower in females (p<0.023), were a significant predictor of the apparent topotecan lactone clearance. This was confirmed experimentally in in vitro incubation studies in whole blood using artificially altered hematocrit values and in blood samples from both male and female volunteers. Topotecan is thus subject to significant gender-dependent differences in pharmacokinetics that arise as a result of a physiological difference in hematocrit values between males and females. This finding may have significant implications for the interpretation of the relationships between pharmacokinetics and pharmacodynamic outcome of topotecan treatment, and may provide a basis for the development and refinement of future clinical protocols.

Administration, Oral↗

PubMed2000

Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

Adult↗

PubMed2000

Topotecan lacks third space sequestration.

The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan. Four patients with histological proof of malignant solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate form. The apparent topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of lactone:total drug in plasma were similar between courses within each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space topotecan total drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely administered to patients with pleural effusions or ascites and that there is substantial penetration of topotecan into these third spaces, which may prove beneficial for local antitumor effects.

Adult↗

PubMed2000

Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens.

Anticancer drugs still are dosed based on the body-surface area (BSA) of the individual patient, although the BSA is not the main predictor of the clearance for the majority of drugs. The relevance of BSA-based dosing has not been evaluated for topotecan yet. A retrospective pharmacological analysis was performed of kinetic data from four clinical Phase I studies in which topotecan was administered p.o. as a single agent combined with data from a combination study of topotecan and cisplatin. A strong correlation (r = 0.91) was found between the area under the plasma concentration time curve of the lactone and carboxylate forms of topotecan by plotting 326 data sets obtained from 112 patients receiving oral topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient variability, studied in 47 patients sampled for 3 or more days, for the apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median, 20%). The interpatient variabilities in the lactone clearance, calculated with the data of all studied patients, expressed in liter/h/m2 and in liter/h were 38% and 42%, respectively. In view of the relatively high inter- and intrapatient variabilities in topotecan clearance, in contrast to a variability of only 12% in the BSA of the studied patients, no advantage of BSA-based dosing was found over fixed dose regimens.

Administration, Oral↗

PubMed2000

Measurement of fraction unbound paclitaxel in human plasma.

The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly nonlinear, with disproportional increases in systemic exposure with an increase in dose. We have recently shown that Cremophor EL, the formulation vehicle used for i.v. administration of paclitaxel, alters drug distribution as a result of micellar entrapment of paclitaxel, and we speculated that the free drug fraction (fu) is dependent on dose and time-varying concentrations of Cremophor EL in the central plasma compartment. To test this hypothesis, a reproducible equilibrium dialysis method has been developed for the measurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37 degrees C in a humidified atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments were carried out with 260-microliter aliquots of plasma containing a tracer amount of [G-(3)H]paclitaxel with high-specific activity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were measured by both reversed-phase HPLC and liquid scintillation counting. Using this method, fu has been measured in three patients receiving three consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and 225 mg/m(2) and found to range between 0.036 and 0.079. The method was also used to define concentration-time profiles of unbound drug, estimated from the product of the total plasma concentration and fu.

Antineoplastic Agents, Phytogenic↗

PubMed1999

Determination of 5-fluorouracil in microvolumes of human plasma by solvent extraction and high-performance liquid chromatography.

In the present study, a new reversed-phase HPLC method has been developed and validated for the quantitative determination of 5-fluorouracil (5-FU) in human plasma using only 100-microl samples. The sample extraction and clean-up procedure involved a simple liquid-liquid extraction after addition of 5-chlorouracil (5-CU), used as internal standard, with 5 ml ethyl acetate. Chromatographic separations were performed on an Inertsil ODS-3 column (250x4.6 mm ID; 5 microM particle size), eluted with a mobile phase composed of acidified water (pH 2.0). The column effluent was monitored by UV absorption measurement at a wavelength of 266 nm. The calibration curves were constructed over a range of 0.20-50.0 microM and were fitted by weighted (1/x) linear regression analysis using the ratio of peak heights of 5-FU and 5-CU versus concentrations of the nominal standards. Extraction recoveries over the total range averaged 92 and 93% for 5-FU and 5-CU, respectively. The lower limit of quantitation was established at 0.20 microM (approximately 26 ng/ml), with within-run and between-run precisions of 4.2 and 7.0%, respectively, and an average accuracy of 109.3%. The within-run and between-run precisions at four tested concentrations analyzed in quintuplicate over a time period of four days were < 1.4 and < 4.4%, respectively. The accuracy at the tested concentrations ranged from 98.4 to 102.3%. Compared to previously described validated analytical methods for 5-FU, our present assay provides equivalent to superior sensitivity, using only microvolumes of sample.

Antimetabolites, Antineoplastic↗

PubMed1999

Liquid chromatographic analysis and preliminary pharmacokinetics of methotrexate in cancer patients co-treated with docetaxel.

A new HPLC method has been developed for the quantitative determination of methotrexate (MTX) and its 7-hydroxyl metabolite in human plasma. Samples were purified by protein precipitation with acetone and methanol, and a sample clean-up with a mixture of n-butanol and diethyl ether. The analytes were separated on an RP Inertsil ODS-80A column and eluted in a solvent system containing 5% (v/v) tetrahydrofuran in water (pH 2.0). UV absorption measurement was performed at 313 nm, and the detector response was linear in a concentration range of 10-10,000 ng/ml. The lower limit of quantitation of MTX was 10 ng/ml using 1 ml sample aliquots. Values for accuracy and (within-run and between-run) precision were between 95.5-111% and 3.69-11.0%, respectively, at four concentrations analyzed in quintuplicate on four separate occasions. The assay was applied to study the effects of docetaxel co-administration on the pharmacokinetics and metabolism of MTX in cancer patients.

Acetone↗

PubMed1999

Femtomole quantitation of 7-ethyl-10-hydroxycamptothecine (SN-38) in plasma samples by reversed-phase high-performance liquid chromatography.

7-Ethyl-10-hydroxycamptothecine (SN-38) is the active metabolite of the topoisomerase I inhibitor and antineoplastic agent, irinotecan (CPT-11). Here, we present a new and sensitive reversed-phase high-performance liquid chromatographic method for the determination of SN-38 in human plasma samples. Sample pretreatment involves a protein precipitation of 1-mL samples with 2 mL of acetonitrile, followed by a one-step solvent extraction with 5 mL of chloroform, with camptothecine used as internal standard. Chromatographic separation was achieved on an analytical column packed with Hypersil ODS material (100 x 4.6 mm i.d., 5 microm P.S.), and isocratic elution with a mixture of acetonitrile:0.1 M ammonium acetate containing 10 mM tetrabutylammonium sulfate (23:77, v/v), pH 5.3 (hydrochloric acid). The column effluent was monitored at excitation and emission wavelengths of 380 and 556 nm, respectively. The limit of quantitation of the method presented was at the low femtomole level ( approximately 8.4 fmol; equivalent to 5 pg/mL), with the standard curves being linear over nearly three orders of magnitude. Intraassay precision was <9%, while interassay variations were between 2 and 5%. The extraction efficiency was concentration independent and averaged 88.0 +/- 14.3% (mean +/- standard deviation; n = 59). The described method will be used in future studies to assess the extent of enterohepatic recirculation of SN-38 in cancer patients following intravenous CPT-11 treatment.

Antineoplastic Agents, Phytogenic↗

PubMed1999

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications.

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios.

Aged↗

PubMed1999

Determination of doxorubicin and doxorubicinol in plasma of cancer patients by high-performance liquid chromatography.

A high-performance liquid chromatographic assay with fluorescence detection has been developed for the determination of doxorubicin and its metabolite doxorubicinol in plasma of cancer patients. Quantitative extraction was achieved by a single protein-precipitation step of 1-ml samples with 500 microl of acetone in the presence of 100 microl of zinc sulfate [70% (w/v) in water]. Doxorubicin and doxorubicinol were separated isocratically on a column packed with Inertsil ODS-80A material and a mobile phase composed of water:acetonitrile:tetrahydrofuran (76:24:0.5, v/v/v). The related compound daunorubicin was used as internal standard. The column effluent was monitored fluorimetrically at an excitation wavelength of 480 nm and an emission wavelength of 560 nm, with a band width of 40 nm. The calibration graphs of doxorubicin and doxorubicinol were linear over a range of 1.0 to 100 and 0.50 to 50. 0 ng/mL, respectively, with lower limits of quantitation of 1.0 and 0.50 ng/ml. Results obtained from a 4-day validation study demonstrated excellent accuracy (91.0-106%) and precision (0.90-10. 2%) across the calibration ranges for both compounds. The developed method has been applied extensively to a clinical study to examine the pharmacokinetics and metabolism of doxorubicin in patients cotreated with a potent inhibitor of MDR1 P-glycoprotein activity, GF120918.

Antineoplastic Agents↗

PubMed1999

Clinical pharmacokinetics of encapsulated oral 9-aminocamptothecin in plasma and saliva.

OBJECTIVE: To study the pharmacokinetics and pharmacodynamics of the novel topoisomerase I inhibitor and antitumor agent 9-amino-20(S)-camptothecin in patients with solid tumors after repeated oral administration. METHODS: Thirty-two patients with cancer received oral 9-aminocamptothecin formulated in capsules with polyethylene glycol-1000 as excipient at doses that ranged from 0.25 to 1.5 mg/m2/day. Serial plasma and saliva samples were obtained on days 1 and 6 or days 1 and 8 of the first cycle and analyzed for the lactone and carboxylate forms of 9-aminocamptothecin by HPLC. RESULTS: 9-Aminocamptothecin showed linear and dose-independent pharmacokinetics, with extremely small intrapatient kinetic variability (coefficient of variation: <10%). However, interpatient variability in plasma pharmacokinetics was large (coefficient of variation: 99%). The relative extent of lactone to carboxylate interconversion was large (>90%) and predictable from individual pretreatment serum albumin values (P = .0099). The 9-aminocamptothecin concentration ratio in plasma and saliva was strongly patient dependent, and highly variable around a mean value of <0.8, suggesting that saliva is an unreliable matrix for kinetic monitoring. The area under the curve of the lactone form of 9-aminocamptothecin was significantly correlated with the dose-limiting hematologic toxicity (P < .001). CONCLUSION: Our data indicate that the large interindividual pharmacodynamic variability in response to 9-aminocamptothecin is caused mainly by a variability in kinetic characteristics, suggesting that a kinetic-dynamic guided study design is warranted in future clinical investigations.

Administration, Oral↗

PubMed1999

The accumulation of topotecan in 9L glioma and in brain parenchyma with and without dexamethasone administration.

The accumulation of the topoisomerase I inhibitor topotecan in brain tumor as well as in brain around tumor (BAT) and normal brain following an intravenous bolus of topotecan of 0.5 mg/kg was investigated in rats bearing a 9L glioma. Also the influence of dexamethasone (Dex) on the uptake of topotecan was examined. Tumor, BAT and brain tissue as well as whole blood were collected at 1 h after an i.v. bolus of topotecan. Concentrations of total topotecan in tumor, BAT and brain were quantified with high-performance liquid chromatography (HPLC) and compared with concentrations in plasma of total topotecan. In brain tumor tissue the mean total topotecan concentration was 96 +/- 33 ng/g which was 20-fold higher than the accumulation of topotecan in normal brain tissue. In BAT intermediate concentrations of 13 +/- 4.9 ng/g were reached. Mean total topotecan concentration in plasma was 100 +/- 25 ng/ml. We did not find an influence of Dex on the uptake of topotecan in either tissue. We conclude that high tissue concentrations of topotecan can be reached in experimental brain tumors in rats. This observation may be useful in the design of clinical studies with topotecan.

Animals↗

PubMed1999

Sparse-data set analysis for irinotecan and SN-38 pharmacokinetics in cancer patients co-treated with cisplatin.

The clinical pharmacokinetics of the antineoplastic agent irinotecan (CPT-11) are associated with substantial interpatient variability. The degree to which this variability in CPT-11 exposure impacts upon the response and toxicity of the drug has not yet been properly determined. In general, the area under the plasma concentration-time curve (AUC) is an appropriate indicator of exposure, but requires collection of up to 17 timed blood samples. This presents difficulties if large-scale population samplings are required. The present study involved the development and validation of a strategy to estimate the AUCs of the lactone and total (i.e. lactone plus carboxylate) forms of CPT-11 and its active metabolite SN-38 from a limited number of blood samples in patients co-treated with cisplatin. Using data from 24 patients, univariate and multivariate regression analyses were employed to generate the models. The best predictive models for simultaneous estimation of CPT-11 and SN-38 AUCs were obtained with three time points at 0.5, 1.67 and 5.50 h after start of the 90 min i.v. infusion of CPT-11. The models were tested separately in another group of 24 patients receiving the same combination treatment. This validation set demonstrated that CPT-11 and SN-38 AUCs after standard dose administration could be predicted sufficiently unbiased and precisely with three timed samples to warrant clinical application.

Adult↗

PubMed1999

Phase I and pharmacologic study of the arotinoid Ro 40-8757 in combination with cisplatin and etoposide in patients with non-small cell lung cancer.

This phase I study was performed to assess the feasibility of combining cisplatin/etoposide (VP-16) with the arotinoid Ro 40-8757 and to determine the dose-limiting toxicity (DLT) of Ro 40-8757 in this combination. Patients with non-small cell lung cancer were eligible. Treatment consisted of Ro 40-8757 p.o. day 1-21, cisplatin 100 mg/m2 i.v. on day 2 and VP-16 100 mg/m2 i.v. on day 2-4, repeated every 3 weeks. Eighteen patients were evaluable for toxicity and response. The doses of Ro 40-8757 ranged from 84 mg/m2 once daily to 42 mg/m2 thrice daily (tid). DLT consisting of delayed nausea/vomiting was reached at 42 mg/m2 tid. Consequently, the maximum tolerated dose was set at one dose level below the DLT, i.e. 28 mg/m2 tid. Skin toxicity occurred but was well manageable. Pharmacological analyses showed a small increase in the volume of distribution of cisplatin and VP-16 between the first and third course. However, no relationship with side effects was found. A response was achieved in 50% of patients. The combination of cisplatin/VP-16 with Ro 40-8757 appears to be feasible at a dose schedule of 28 mg/m2 tid. The response rate was at the upper rate of what can be expected with cisplatin and VP-16.

Adult↗

PubMed1999

Role of erythrocytes and serum proteins in the kinetic profile of total 9-amino-20(S)-camptothecin in humans.

9-Amino-20(S)-camptothecin (9-AC) is a water-insoluble topoisomerase I inhibitor with evident schedule-dependent antitumor activity in preclinical studies. The pharmacokinetic behavior of 9-AC given as a bolus i.v. infusion (1.0 mg/m2 over 5 min) was recently characterized in 12 patients in a bioavailability study. Remarkable rebound concentrations of 9-AC total drug (i.e. lactone plus carboxylate forms) were observed at about 2-3 h after dosing. In vitro experiments indicated that this phenomenon was associated with a substantial uptake of 9-AC lactone by erythrocytes immediately after dosing and its subsequent release followed by accumulation of 9-AC carboxylate in the plasma compartment mediated by a pH-dependent hydrolysis of the lactone form, which is unable to diffuse across cell membranes. The preferential binding of 9-AC carboxylate to human serum albumin shifts the equilibrium between the lactone and carboxylate forms of 9-AC to the pharmacological inactive carboxylate form.

Animals↗

PubMed1999

Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein.

Previous clinical investigations with doxorubicin indicated that modulators of P-glycoprotein dramatically decrease the systemic clearance of the drug, which complicates the interpretation of toxicity and response data. In the present study, we examined the pharmacokinetics of doxorubicin and GF120918, a novel potent P-glycoprotein inhibitor, in cancer patients in a search for more selective modulation of multidrug resistance (MDR). Seven cohorts (46 patients) received sequential treatments with doxorubicin alone by a 5 min i.v. bolus (50-75 mg/m2), oral GF120918 alone (50 mg q.d.-400 mg b.i.d.), and the combination of doxorubicin and GF120918. Serial blood and urine samples were taken during both treatment courses and analyzed for doxorubicin and its metabolite doxorubicinol by a liquid chromatographic assay. The pharmacokinetic characteristics of doxorubicin in the presence or absence of GF120918 indicate a very minor overall effect of the modulator, except at the highest combined dose level (i.e. 75 mg/m2 plus 400 mg b.i.d.). A limited number of patients experienced significantly increased exposure to doxorubicinol upon combined treatment, which was associated with concomitantly higher plasma levels of GF120918. Sigmoidal maximum-effect models revealed significant correlations (p<0.02) between the area under the curve of doxorubicinol and the percent decrease in neutrophils and platelets. Sigmoidicity factors in the fitted Hill equation were similar between both treatment courses, suggesting no pharmacodynamic potentiation of doxorubicinol myelotoxicity by GF120918. Our data indicate that GF120918 at the tested doses of combination treatment achieves plasma concentrations that reverse MDR in experimental models and it lacks the significant kinetic interaction with doxorubicin observed previously with other modulators. Hence, it may be possible in future trials to assess the contribution of a potent inhibitor of P-glycoprotein activity to the toxicity and activity of doxorubicin with the knowledge that profound plasma pharmacokinetic interactions are unlikely.

ATP Binding Cassette Transporter, Subfamily B, Mem↗