Pharmacokinetics of teniposide (VM26) and etoposide (VP16-213) in children with cancer

Summary The clinical pharmacokinetics of VM26 and VP16-213 were assessed in 15 children (median age 10 years) with acute leukemia, using a new high-performance liquid chromatography—electrochemical assay. Pharmacokinetic parameters were calculated by both model-dependent and compartment model-independent methods. These studies demonstrated substantial differences in the central volumes of distribution (VD_c), steady-state volumes of distribution (VD_ss) and systemic clearances (Cl_s) of VM26 and VP16-213; with the VD_c, VD_ss, and Cl_s all being smaller for VM26. Systemic clearances determined by model-independent methods were 5.2±1.0 ml/min/m² (mean±SD) for VM26 and 17.8±11.2 ml/min/m² for VP16-213. The major metabolites detected in serum and urine were the hydroxy acids. Low levels of the picro-lactone isomers were detected in some patients while the aglycones were not detected in the serum or urine of any patients.Supported in part by Leukemia Program Project Grant CA20180, by Cancer Center CORE Grant CA21765 and by ALSAC     

Combination chemotherapy of the epipodophyllotoxin derivatives,Teniposide and Etoposide

Summary Previous studies in vitro on the influence of extracellular protein binding of Teniposide (VM26) and Etoposide (VP16-213) on subsequent cellular uptake by experimental murine tumor cells [Cancer Res 38: 2549 (1978); Drug Metab Rev 8: 119 (1978)] suggested that a timed-sequential combination of VM26 and VP16-213 may increase the bioavailability of VP16-213. This was studied clinically in six cancer patients with ascites (five ovarian, one rectal) whereby VM26 (20 mg/m²) was given i.p. 2 h prior to VP16-213 (100 mg/m²; i.p.). In some patients, this regimen was administered i.v. The i.v. regimen was found to be more toxic (myelosuppression, nausea, vomiting) than i.p. regimen at same doses of drugs. Several patients remained stable to disease during 1–2 courses of therapy (3 weeks per course), one patient had partial remission, and has been stable in her disease for more than 4 months.In two patients, plasma and ascites fluid was analyzed for VP16-213 and VM26 by a new reverse-phase high performance liquid chromatography method. Both VM26 and VP16-213 could be eluted isocratically (28% v/v acetonitrile in water) from a c₁₈ column with retention times of 6.6 and 13.3 min, respectively. Subsequent pharmacokinetic analysis of one patient suggests that protein binding displacement of VP16-213 in plasma and perhaps ascites fluid increased the pharmacokinetic volume of distribution (28 l) and reduced the elimination half-life (12 h). The data suggests that VP16-213 is distributed more widely in the body and is represented by a single compartment pharmacokinetic model. Analysis of VM26 in ascites and plasma suggests that the so-called deep pharmacokinetic compartment represents ascites equivalent space and that the plasma concentration represents VM26 as free and protein-bound drug in kinetic distinguishable compartments.Determinants of drug action are potentially composed of a multiplicity of physiological, biochemical, and other factors. The potential for manipulating the pharmacodynamic properties of drugs to achieve greater therapeutic potential needs further study.     

Dosing of thioTEPA for myeloablative therapy

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150–250 mg/m² given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thio TEPA and TEPA were measured by gas chromatography. At 22–24 h after initiation of a 4-h infusion, the mean ±SE plasma concentration of thioTEPA was 124±63 ng/ml, while that of TEPA was 235±69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC₅₀s of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC₅₀s of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a twocompartment model, the mean thioTEPA Vc was 47.4±4.7 l/m², t_1/2 19±5 min,t _1/2 3.7±0.5 h, and plasma clearance 302±21 ml/min per m². The mean AUCs were 6.9–16.2 mg h/l for thioTEPA and 8.9–21.2 mg h/l for TEPA, while the mean peak concentrations were 0.95–2.08 g/ml for thioTEPA and 0.88–1.90 g/ml for TEPA. There was a significant association of grades 2–4 maximum regimen-related toxicity (RRT) with TEPA peak >1.75 g/ml and with combined thioTEPA and TEPA AUC >30 mgh/l (5/6 vs 0/9,P=0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r=0.74,P=0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m² in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0,P=0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.Supported in part by a grant from the American Cyanamid Corporation     

Disposition of total and unbound etoposide following high-dose therapy

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18–61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35–60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0±0.4 g/dl and 0.5±0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (% unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. Te mean (±SD) parameters for total etoposide included: clearance (CL), 31.8±17.7 ml min^–1 m^–2; volume of distribution (V_ss), 11.5±5.9 l/m², and terminal half-life (t _1/2 ), 7.2±3.7 h. Mean unbound CL was 209.6±62.7 ml min^–1 m^–2 and %unbound was 16%±5%. The mean etoposide %unbound was inversely related to serum albumin (r ²=0.45,P=0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively;P=0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of 3.0 g/dl than in those with levels of >3.0 g/dl (34.6 vs 23.5 ml min^–1 m^–2,P=0.05). Total CL was directly related to %unbound (r ²=0.61,P=0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.This study was supported in part by Bristol-Myers. Oncology Division     

The disposition of carboplatin in ovarian cancer patients

Summary Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170–500 mg/m². The ages, weights, and creatinine clearances (Cl_cr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Cl_cr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t_1/2 of 1.6 h and a t_1/2 of 3.0 h. The mean (±SD) residence time, total body clearance, and apparent volume of distribution were 3.5±0.4 h, 4.4±0.85 l/h, and 16±31l, respectively. C_max and AUC_inf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m². No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t_1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Cl_cr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12–16 h. All of the platinum in 24-h urine was carboplatin, and only 2%–3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Cl_cr of less than about 60 ml/min exhibited dose-disproportional increases in AUC_inf and MRT values. The latter were inversely related to Cl_cr (r=-0.98). Over a dose range of 300–500 mg/m², carboplatin exhibited linear, dose-independent pharmaco-kinetics in patients with a Cl_cr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.Supported in part by CA 16087, CRC-RR-96, AIFCR     

Pharmacokinetics of high-dose etoposide after short-term infusion

Summary The pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m² divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m² cytosine arabinoside (ara-C), 300 mg/m² carmustine (BCNU), or 1,200 mg/m² carboplatin. Plasma etoposide concentrations were determined by²⁵²Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629g min ml^–1 (normalized to a dose of 100 mg/m²); volume of distribution at steady state (Vd_ss), 6.6±1.2l/m²; and clearance (CL), 20.4±2.4 ml min^–1 m^–2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m²). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 g/ml, all patients exhibited undelayed hematopoietic reconstitution.     

Pharmacokinetics of unchanged carboplatin (CBDCA) in patients with small cell lung carcinoma

Summary The disposition of the cisplatin analogue carboplatin was studied in seven patients with small cell lung cancer. Carboplatin 100 mg/m² was administered without hydration by a 1-h infusion with VP16-213 120 mg/m² on days 1, 2 and 3 of each course. Plasma and urine collections were made on days 1 and 3 of the first course of treatment. Carboplatin levels in plasma ultrafiltrate and urine were quantitated using a specific and sensitive, highperformance liquid chromatographic assay which involved sample clean-up on a Dowex-2 column prior to injection. Estimates of pharmacokinetic parameters determined using either compartmental or non-compartmental methods were comparable. There was no difference between carboplatin pharmacolinetic parameters determined on days 1 and 3 of treatment. The mean (±SD) carboplatin half-life determined from plasma data on day 1 was 105±30.4 min and was not significantly different from that determined using urinary excretion rate data (107±51.7 min). Urinary excretion rate plots showed that carboplatin elimination was mono-exponential for up to 14 h after infusion. Totalbody clearance was 105±40.0 ml min^-1 m^-2, renal clearance 64.3±44.1 ml min^-1 m^-2, and volume of distribution 17.3±4.2 l/m² on the 1st day of treatment. Of the administered dose, 58.4%±21.2% was recovered in urine over a 24-h period after the start of the infusion. The mean renal clearance of carboplatin was comparable to creatinine clearance. Carboplatin disposition was clearly defined in the patients studied using analytical methodology specific for the unchanged drug.     

Clinical pharmacology of intracarotid etoposide

Summary Pharmacokinetics studies were performed in ten patients who received VP-16 by intracarotid infusion at 100–300 mg/m². VP-16 was analyzed by high-pressure liquid chromatography. ESTRIP and NONLIN were used to characterize VP-16 pharmacokinetics. VP-16 disappeared biphasically, with a t_1/2 of 6.1±1.4 h; the total clearance was 26.8±2.8 ml/min/m², and the V_ss was 8.8±1.6 l/m². The pharmacokinetics was not significantly different after administration by the IV route. However, at a lower dosage, <140 mg/m², the half-life appears to be shorter. This may or may not be significant, since VP-16 pharmacokinetics is quite variable and the number of patients studied is relatively small. Overall, the brain and brain tumor do not appear to have any first-pass effect on VP-16 pharmacokinetics.The study reported in this paper was supported by a grant from Bristol Laboratories, Syracuse, NY     

Clinical and cell kinetic studies of the effects of the epipodophyllotoxin VP16-213 during therapy of refractory acute nonlymphocytic leukemia

Summary After induction failure or relapse on primary therapy, acute nonlymphocytic leukemia (ANLL) has historically been highly resistant to reinduction chemotherapy. In order to evaluate a new drug combination for this condition, 24 children and young adults with ANLL failing to attain first remission [5] or in relapse [19] were treated with VP16-213 plus 5-azacytidine (5AZ). Each patient had previously received combination chemotherapy with several antileukemic agents, including anthracyclines and cytosine arabinoside. These patients received 5-day courses of VP16-213 (200 mg/m²) daily x 3 days, followed immediately by 5AZ (300 mg/m²) daily x 2 days, repeated every 1–2 days until the bone marrow became hypoplastic. After 2–4 courses, 19 patients demonstrated an objective anti-leukemic effect by achieving marrow hipoplasia without evidence of blasts. Eleven of these (11/24=46%) achieved complete remission after a median time of 45 days from the initiation of therapy, making this combination of VP16-213 and 5AZ the most active regiment we have tested for ANLL in relapse. In order to determine the effects of VP16-213 on leukemic blast proliferation in vivo, serial bone marrow aspirates were studied in eight of these children. VP16-213 200 mg/m² IV was given daily x 3 days, and the mitotic index, labeling index and fractions of cells in G₀/G₁, S and G₂+M by flow cytometric measurement of DNA content were determined. Bone marrow samples were obtained before, 4 h and 20–24 h after the third dose in all patients, and 20–24 h after the third dose in six of the patients. The cytokinetic studies 4 h after the first dose of VP16-213 consistently showed a G₂ phase arrest of the bone marrow myeloblasts, indicating uptake of the drug and production of the same cell kinetic lesion which has been shown for cells treated with VP16-213 in vitro. In each patient studied 24 h after the third drug dose, there was a decrease in the fraction of cells in S phase compared to the pretreatment study (median decrease 56%, range 24–67%). The blast count per ml of marrow decreased by a median of 84% (range 72–91%) over this same interval. The observed decrease of fraction of cells in S phase after three doses of the drug suggests selective kill of cells in S compared to G₀/G₁. We conclude that the activity of VP16-213 against ANLL blasts can be demonstrated in vivo by the production of G₂ phase arrest and reduction of marrow blast count with findings consistent with increased cytotoxicity for cells in S and G₂ phase of the cell cycle. In addition, this intensive combination of VP16-213 and 5AZ has shown clear evidence of effectiveness in patients with refractory ANLL, and thus may be useful during initial therapy.Supported in part by Public Health Service grants CA-21765, CA-20180, and CA-15956 from the National Cancer Institute, National Institutes of Health, and Department of Health, Education and Welfare, and by ALSAC     

Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer

Summary The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3–4 days, oestradiol levels fell to 31.1%±6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 g/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates forC _o (21.7±1.82 g/ml),K _m (2.66±0.68 g/ml) and V_max (0.86±0.06 g ml^–1 h^–1). On subsequent repeated dosing with PyG, both theK _m (4.31±0.48 g/ml) and the V_max (1.83±0.13 g ml^–1 h^–1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.Abbreviations PyG 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione - AG aminoglutethimide - CSCC cholesterol side-chain cleavage - HPLC high-performance liquid chromatography - AUC area under the concentration versus time curve This study was supported in part by grants to the Institute of Cancer Research (Royal Cancer Hospital) from the Cancer Research Campaign and Medical Research Council     

A limited sampling model for the pharmacokinetics of etoposide given orally

A limited sampling model of etoposide after oral administration to estimate the area under the plasma concentration-time curve from 0 to 24 h (AUC) by determination of the drug plasma levels at only two time points was developed by a multiple regression analysis on a training data set of 15 patients receiving oral doses ranging from 54 to 90 mg/m². The equation describing the model is AUC (g ml^–1 h)=5.183 (g ml^–1 h)+1.193 (h)×C_1h (g/ml)+8.439 (h)×C_4h (g/ml) (R ²=0.93,P=0.0001), whereC _1h andC _4h represent the plasma etoposide concentrations at 1 and 4 h, respectively. The model was validated prospectively on a test data set of 13 patients receiving oral doses ranging from 52 to 87 mg/m² and, additionally, on a data set of 7 patients receiving oral doses ranging between 176 and 200 mg/m², investigated in a previous study. Validation on both test data sets gave a relative mean predictive error of 0.1% and a relative root mean square error of 15.8% and 16.7%, respectively. The present study shows that it is possible to obtain a good estimate of the plasma AUC after oral administration of etoposide using a two-time-point sampling model. The model can be used to monitor the etoposide AUC in patients receiving chronic oral treatment.     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

A phase I trial of continuous infusion VP16-213 (Etoposide)

Summary Since there appears to be a schedule dose relationship for VP16-213, the current dose seeking study of 5 day continuous infusion was initiated. Patients not candidates for other treatments were started at 75 mg/m²/dayx5. Eight patients had prior chemotherapy, eight had radiotherapy plus chemotherapy and one patient had prior interferon. The median age was 53 (range 23–65) and the median performance status was 60 (range 50–90). Seventeen patients received 20 courses; two at 75 mg/m²/day, seven at 100 mg/m²/day, ten at 125 mg/m²/day, and six at 150 mg/m²/day. The major toxicity was hematologic and median WBC count nadirs (ranges) were respectively: 3.5 (2.3–4.7)x10³/l, 1.6 (0.2–3.4)x10³/l, 2.4 (0.1–3.6)x10³/l, 0.4(<0.1–0.7)10³/l. Platelet count nadirs were respectively: 150, 78 (20–189), 138 (26–326), 16 (9–88)x10³/l. The median days to WBC nadir and recovery and did not vary with dose and were 15 (9–21) and 24 (19–38) respectively. Median days to platelet count nadir were 12 (10–29) and recovery 24 (20–38) and did not vary with dose. Non-hematologic toxicities included mild nausea and vomiting, mild mucositis on six courses, diarrhea with two courses and fever during granulocytopenia during seven courses. Three patients manifested evidence of myocardial disease two with infarction and one with congestive failure during treatment. Two patients showed objective evidence of tumor regression, one patient with seminoma and one patient with renal cell carcinoma. The latter response was short. The current studies demonstrate that high dose continuous infusion VP16-213 is tolerable with acceptable toxicity using doses up to 125 mg/m²/day (625 mg/m² over 5 days).This investigation was supported in part by PHS grant number 1P50CA32107-1 Awarded by the National Cancer Institute, DHHS     

Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093)

Objective Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated.Patients and methods A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated.Results The apparent relative oral bioavailability of docetaxel was 26±8%. Orally administered docetaxel combined with oral OC144-093 resulted in a C_max of 415±255 ng ml^–1, an AUC_0– of 844±753 ng h ml^–1 and k_el of 0.810±0.296 h^–1. These values differed significantly from those following i.v. administration of docetaxel, with a C_max of 2124±1054 ng ml^–1, an AUC_0– of 2571±1598 ng h ml^–1 and a k_el of 1.318±0.785 h^–1 (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21.Conclusion The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

Clinical pharmacology of aminoglutethimide in patients with metastatic breast cancer

Summary The pharmacology of aminoglutethimide (AG) was studied in two subsequent trials without hydrocortisone supplementation. A total of 79 patients with metastatic breast cancer entered the study, and their plasma and urine samples were analyzed by high-performance liquid chromatography (HPLC). Thirty evaluable patients with a median age of 57 years (range, 37–79) were treated with the standard dose of 1000 mg/day, and 37 evaluable patients with a median age of 59 years (range, 35–79) received 500 mg/day. The median follow-up in the two groups was 5 months (range, 1–16) and 4 months (range, 1–21), respectively. After the first oral dose of 500 mg, peak plasma concentrations of AG were observed 1–4 h after administration in 15 patients. The elimination half-life was 10.1±1.7h (mean ±SD) after initial dosage; it decreased significantly to 6.9±1.2 h after 8 weeks of treatment. The area under the curve of AG concentrations was 92.5±14.2 g/ml x h. The total clearance rate was 5.5±0.91/h and the volume of distribution was 80±11 l. About 23% of the drug was excreted unchanged in the urine. The major metabolite, N-acetyl-AG (AAG), had the same half-life as AG. A comparison on day 7 of treatment revealed that doses of 1000 and 500 mg yielded AG plasma concentrations of 9.0±1.2 and 4.5±0.5 g/ml, respectively. After 1 month of treatment, however, AG plasma levels of 6–7 and 4–5 g/ml were observed, respectively. A 50% reduction of dose, therefore, resulted in only 30% lower AG levels during continuous treatment. Apparently, the induction of metabolism is of greater importance in standard-dose than in lower dose treatment. The plasma concentrations of AG did not bear a relationship to the clinical response.Abbreviations used AG aminoglutethimide - AAG N-acetylaminoglutethimide - G glutethimide - HPLC high-performance liquid chromatography - SD standard deviation - SE standard error of the mean - AUC area under the concentration versus time curve     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993     

Epirubicin metabolism and pharmacokinetics after conventional- and high-dose intravenous administration: a cross-over study

In a pharmacokinetics study, six patients were treated i.v. with epirubicin (EPI) at the two dose levels of 60 and 120 mg/m², whereas a further six patients were treated at 75 and 150 mg/m². Both groups were studied according to a balanced cross-over design; the aim of the study was to assess the pharmacokinetic linearity of epirubicin given at high doses. Both the absolute goodness of fit and the Akaike Information Criterion (AIC) point to a linear, tricompartmental open model as the choice framework for discussing EPI plasma disposition after 16/24 administrations, independent of the delivered dose. After 8 treatments, the minimal AIC value corresponded to a nonlinear tissue-binding model. However, even in these cases, second-order effects were present only during the early minutes following treatment. In a model-independent framework, mean EPI plasma clearance was identical at the two dose levels of 60 and 120 mg/m² (65.4±8.0 vs 65.3±13.4 l/h,P=0.92). Both the mean residence time (MRT) and the volume of distribution at steady-state (V_ss) were similar as well (MRT: 22.6±2.9 vs 24.2±3.7 h;P=0.46; V_ss: 21.3±1.5 vs 22.6±6.5 l/kg,P=0.46). No statistically significant difference could be found in mean statistical-moment-theory parameters determined after 75- and 150-mg/m² EPI doses (plasma clearance, PICI: 83.4±13.5 vs 68.5±12.8 l/h,P=0.12; MRT: 22.6±4.8 vs 21.9±3.9 h,P=0.60; V_ss: 26.7±10.5 vs 21.2±7.0 l/kg,P=0.17). Analysis of variance also failed to reveal any significant correlation between dose and plasma clearance. However, when data relative to single patients were examined, a trend toward nonlinear drug distribution as well as a consequent increase in peripheral bioavailability could be observed in 4/6 patients of the 75-mg/m² vs the 150-mg/m² group. No significant dose-dependent variation was observed in the ratio between the molecular-weight-corrected areas under the concentration-time curve for the metabolites and those for EPI [60 vs 120 mg/m²: epirubicinol (EPIol), 0.23±0.10 vs 0.22±0.06,P=0.20; epirubicin glucoronide (G1), 0.46±0.14 vs 0.62±0.40,P=0.26; epirubicinol glucuronide (G2), 0.21±0.05 vs 0.30±0.16,P=0.06; and 75 vs 150 mg/m²: EPIol, 0.33±0.22 vs 0.32±0.19,P=0.42; G1, 0.51±0.23 vs 0.46±0.17,P=0.53; G2, 0.18±0.10 vs 0.22±0.10,P=0.34]. In conclusion, all the metabolic pathways seemed well preserved when the dose was doubled, and no evident sign of saturation kinetics could be found.     

Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities

This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m² per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m²). A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by highperformance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUC_FUrd) and for FdUrd (AUC_FdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUC_FUrd values (mean±SEM, 2.9±0.7 g ml^–1 h) and high AUC_FdUrd values (14.1±2.7 g ml^–1 h), respectively, whereas courses with myelosuppression (WHO grades 2–4) showed inverse profiles with high AUC_FUrd values (16.3±2.3 g ml^–1 h) and low AUC_FdUrd values (3.1±1.0 g ml^–1 h), respectively. A statistically significant difference in AUC_FdUrd values was also observed between cycles with and those without mucositis (P=0.0027), with AUC_FdUrd values being 22.6±5.6 and 7.8±1.9 g ml^–1 h, respectively. Whereas hematotoxicity could be correlated with both AUC_FUrd and AUC_FdUrd values, mucositis was associated with high AUC_FdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P=0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.     

Lack of effect of cisplatin on i. v. L-PAM plasma pharmacokinetics in ovarian cancer patients

Summary Melphalan (L-PAM) pharmacokinetics were investigated in nine ovarian cancer patients before and after cisplatin (DDP) treatment. When L-PAM was given 24 h before DDP, the elimination half-life (t_1/2), plasma clearance (Clp), and volume of distribution (Vd) of L-PAM were, respectively: 46.4±6.7 min, 20.5±3.7 l/m², and 306.8±34.4 ml/min per square meter. When L-PAM was inoculated 24 h after DDP, t_1/2, Clp, and Vd were 47.5±6.3 min, 20.4±2.8 l/m², and 322.0±54.1 ml/min per square meter. Thus, DDP pretreatment does not significantly affect L-PAM pharmacokinetics. Regression analysis showed a significant correlation between the L-PAM elimination rate constant () and renal function assessed by creatinine clearance. One patient who received this sequence of treatment for six courses showed a threefold decrease of L-PAM clp after the last treatment. The reported high myelotoxicity of the combination of DDP and L-PAM when DDP was given 24 h before L-PAM cannot be attributed to DDP-induced changes in L-PAM kinetics but might to some extent be related to a loss of renal function consequent to many courses of treatment.This work was supported by a Grant from the Swiss League against Cancer