Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer

Purpose Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer.Methods PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m². Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection.Results PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55±18 min at the 1.8 g/m² dose and 77±22 min at the 2.5 g/m² dose. The half-life of PAG was 112±53 min at the 1.8 g/m² dose and 135±75 min at the 2.5 g/m² dose. The clearance of PAA was 66±33 ml/min per m² at the 1.8 g/m² dose and 60±24 ml/min per m² at the 2.5 g/m² dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (V_m and K_m) were (means±SD) 18.4±13.8 mg/m² per min and 152±155 g/ml, respectively. The volumes of distribution for PAA and PAG (V_d-PAA and V_d-PAG) were 7.9±3.4 l/m² and 34.4±16.1 l/m², respectively. The first-order elimination rate constant for PAG (k_e-PAG) was 0.0091±0.0039 min^–1.Conclusions The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.This work was supported in part by the National Institutes of Health (M01-RR00188), and the General Clinical Research Center, Baylor College of Medicine.     

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 VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.     

Prochlorperazine as a doxorubicin-efflux blocker: phase I clinical and pharmacokinetics studies

Summary Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i. v. administration of 15, 30, 50, and 75 mg/m² PCZ followed by a standard dose of 60 mg/m² DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m². Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were:t ₁/2 (±SE), 20.9±5.3 min;t1/2, 1.8±0.3 h; andt1/2, 21.9±5.3 h. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) for PCZ were 2254±886 l/m², 60.2±13.5 l m^–2h^–1, and 1624±686 ng ml^–1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i. v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.Supported in part by the Joan Levy Cancer Foundation and by NIH-NCI grants CA-44737 and CA-29360     

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.     

Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10^–3 M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016±143 mol/l. The mean dose delivered was 13.2±2 g/m². The clearance was 49.1±11.7 ml min^–1 m^–2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with at _1/2 of 2.66±0.82 h and at _1/2 of 15.69±8.63 h. The volume of distribution was 0.32±0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%–21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. Thet _1/2 and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P<0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significantly different from those of the group of nonsensitive patients.     

Clinical pharmacolinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1H-imidazol-2-yl)hydrazone]dihydrochloride

Summary We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120–250 mg/m² IV; one of these patients also received a second dose of 120 mg/m² 6 weeks later, and another received 150 mg/m² weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t_1/2 of 0.6±0.3 h and a terminal t_1/2 of 24.7±6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1±5.9 l/kg, and the total clearance was 1045.5±51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4%±1.1% of the dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t_1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.     

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     

Drug distribution and pharmacokinetic/pharmacodynamic relationship of paclitaxel and gemcitabine in patients with non-small-cell lung cancer

Background:Gemcitabine and paclitaxel are two of the mostactive agents in non-small-cell lung cancer (NSCLC), and pharmacologicinvestigation of the combination regimens including these drugs mayoffer a valuable opportunity in treatment optimization. The presentstudy investigates the pharmacokinetics and pharmacodynamics ofpaclitaxel and gemcitabine in chemotherapy-naive patients with advancedNSCLC within a phase I study. Patients and methods:Patients were given i.v. paclitaxel 100 mg/m² byone-hour infusion followed by gemcitabine 1500, 1750 and 2000mg/m² by 30-min administration. Plasma levels of paclitaxel,gemcitabine and its metabolite 2,2-difluorodeoxyuridine(dFdU) were determined by high-performance liquid chromatography (HPLC).Concentration-time curves were modeled by compartmental andnon-compartmental methods and pharmacokinetic/pharmacodynamic (PK/PD)relationships were fitted according to a sigmoid maximum effect(E_max) model. Results:Paclitaxelpharmacokinetics did not change as a result of dosage escalation ofgemcitabine from 1500 to 2000 mg/m². A nonproportionalincrease in gemcitabine peak plasma levels (C_max, from 18.56± 4.94 to 40.85 ± 14.85 µg/ml) and area under theplasma concentration-time curve (AUC, from 9.99 ± 2.75 to 25.01± 9.87 h·µg/ml) at 1500 and 2000mg/m², respectively, was observed, suggesting the occurrenceof saturation kinetics at higher doses. A significant relationshipbetween neutropenia and time of paclitaxel plasma levels 0.05µmol/l was observed, with a predicted time of 10.4 h to decreasecell count by 50%. A correlation was also observed betweenpercentage reduction of platelet count and gemcitabine C_max,with a predicted effective concentration to induce a 50% decreaseof 14.3 µg/ml. Conclusion:This study demonstratesthe lack of interaction between drugs, the nonproportionalpharmacokinetics of gemcitabine at higher doses and the E_maxrelationship of paclitaxel and gemcitabine with neutrophil and plateletcounts, respectively. In addition, gemcitabine 1500 mg/m² isthe recommended dosage in combination with paclitaxel 100mg/m² for future phase II studies, due to its predictablekinetic behaviour and less severe thrombocytopenia than expected.     

Pharmacokinetics of BW12C and mitomycin C,given in combination in a phase 1 study in patients with advanced gastrointestinal cancer

The effect of combining the oxygen-transport-modifying drug BW12C with mitomycin C was investigated in a phase 1 study of 26 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 60 mg/kg. Dose-limiting toxicity of vomiting was experienced at doses greater than 50 mg/kg. This corresponded to whole blood levels 700 g/ml and to >50% haemoglobin modification. Whole blood concentrations of BW12C and modification of the haemoglobin oxygen saturation curve were linearly dependent on dose. BW12C whole blood pharmacokinetics were best described by a one-compartment model and were clearly dose-dependent. The half-life increased from 2.1 h at a dose of 20 mg/kg to 7.2 h at a dose of 60 mg/kg. The AUC increased in a similar non-linear fashion with increasing dose. Mitomycin C was given at a fixed dose of 20 mg/m² at the end of the BW12C infusion. Mitomycin C plasma pharmacokinetics fitted a two-compartment model, giving a mean beta half-life of 50±7 min and AUC of 1.1±0.08 g/ml h, and were unaffected by the combined treatment. There was no evidence of increased mitomycin C toxicity.     

Phase I clinical trial of continuous infusion cyclopentenyl cytosine

Cyclopentenyl cytosine (CPE-C) is an investigational drug that is active against human solid tumor xenografts. The 5-triphosphate of CPE-C inhibits CTP synthase, and depletes CTP and dCTP pools. We conducted a phase I clinical trial of CPE-C given as a 24-h continuous i. v. infusion every 3 weeks in 26 adults with solid tumors. The starting dose rate, 1 mg/m² per h, was selected on the basis of both preclinical studies and pharmacokinetic data from two patients obtained after a test dose of 24 mg/m² CPE-C as an i. v. bolus. Dose escalation was guided by clinical toxicity. A total of 87 cycles were given, and ten patients received four or more cycles. The mean CPE-C steady-state plasma levels (Cpss) increased linearly from 0.4 M to 3.1 M at dose levels ranging from 1 to 5.9 mg/m² per h (actual body weight); the mean total body clearance was 146±38 ml/min per m². CPE-C was eliminated by both renal excretion of intact drug and deamination to cyclopentenyl uracil in an apparent 21 ratio. CTP synthase activity in intact bone marrow mononuclear cells was inhibited by 58% to 100% at 22 h compared to matched pretreatment samples at all CPE-C dose levels. When all data were combined, flux through CTP synthase was decreased by 89.6%±3.1% at 22h (mean ± SE,n=16), and remained inhibited by 67.6%±7.7% (n=10) for at least 24 h post-CPE-C infusion. Granulocyte and platelet toxicities were dose-dependent, and dose-limiting myelosuppression occurred during the initial cycle in two of three patients treated with 5.9 mg/m² per h. Four of 11 patients (4 of 20 cycles) who received 4.7 mg/m² per h CPE-C experienced hypotension 24–48 h after completion of the CPE-C infusion during their first (n=2), third (n=1) and sixth cycles (n=1), respectively. Two of these patients died with refractory hypotension despite aggressive hydration and cardiopulmonary resuscitation. One of 12 patients (28 total cycles) treated with 3.5 mg/m² per h CPE-C experienced orthostatic hypotension during cycle 1, and this patient had a second episode of orthostatic hypotension at a lower dose (3.0 mg/m²per h). Hypotension was not seen in patients receiving 2.5 mg/m² per h CPE-C. The occurrence of hypotension did not directly correlate with either CPE-C Cpss, CPE-U plasma levels, pretreatment cytidine plasma levels, baseline CTP synthase activity, or with the degree of enzyme inhibition during treatment. While the hypotension appeared to be dose-related, its unpredictable occurrence and the uncertainty concerning the mechanism preclude a recommendation of a tolerable dose for future studies.     

Tumor-tissue and plasma concentrations of platinum during chemotherapy of non-small-cell lung cancer patients

Summary Tumor-tissue and plasma concentrations of platinum were studied prospectively in two groups of eight patients who were suffering from advanced non-small-cell lung cancer. Treatments including two different schedules of cisplatin administration (25 vs 100 mg/m² on day 1) were compared. At 30 min after the beginning of the cisplatin infusion, blood samples and bronchoscopically obtained biopsy specimens were taken for determinations of platinum concentrations by means of flameless atomic absorption spectrophotometry. The procedure did not induce any complication. Total plasma platinum concentrations at 30 min were significantly lower (P<0.01) in patients receiving 25 mg/m² (0.49±0.23 g Pt/ml) than in those receiving 100 mg/m² (1.44±0.62 g Pt/ml), whereas no significant difference was observed in tumor-tissue platinum concentrations (22.49±53.89 ng Pt/mg in patients receiving 25 mg/m² vs 51.13±65.52 ng Pt/mg in those receiving 100 mg/m²). There was a weak correlation between simultaneous plasma and tumor-tissue platinum concentrations at 30 min. Tumor-tissue platinum concentrations seem to be poorly influenced by the cisplatin dose. This finding suggests a great interindividual variability of platinum tumor-diffusion properties in non-small-cell lung cancer.Supported in part by a grant from the Ligue Nationale Française contre le Cancer     

Pharmacokinetic study of fludarabine phosphate (NSC 312887)

Summary Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m² daily x5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentrationtime curves yielded an average distribution half-life (t1/2) of 0.60 h and a terminal half-life (t1/2) of 9.3 h. The estimated plasma clearance was 9.07±3.77 l/h per m² and the steady state volume of distribution, 96.2±26.0 l/m². There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r=-0.94, P<0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r=0.828; P<0.1). Aproximately 24%±3% of 2-FLAA was excreted renally over the 5-day course of drug administration.Abbreviations used 2-FLAA-9--D arabinofuranosyl-2-fluoroadenine - 2-FLAMP the 5'-monophosphate of 2-FLAA, also known as fludarabine phosphate - AUC area under the curve - AGC absolute granulocyte count - TPC total plasma clearance - Vd_ss volume of distribution at steady state - Vd volume of distribution - Creat Cl creatinine clearance - SGOT serum glutamic-oxaloacetic transaminase - WBC peripheral white blood cell count This study was supported by contract NCI N01-CM-27542, NIH grant RR-01346 and by the VA Research Service.     

Human pharmacokinetics of marcellomycin

Summary In conjunction with two phase I clinical trials, we have investigated the pharmacokinetics of marcellomycin (MCM), a new class II anthracycline antibiotic, in nine patients with normal renal and hepatic functions and no third-space fluid accumulation. MCM was infused IV over 15 min at a dosage of 27.5, 40, or 50 mg/m². Plasma and urine samples were collected up to 72 h. MCM and metabolites were assayed by thin-layer chromatography and quantified by specific fluorescence. The disappearance of total MCM-derived fluorescence from plasma followed first-order kinetics and lacked the rebound in total fluorescence that has been described for the structurally similar agent, aclacinomycin A. After 40–50 mg/m², the peak MCM concentration in plasma was 1.67±0.61 M; MCM disappeared from plasma in a triexponential fashion and was undetectabel by 48 h after infusion. The area under the plasma concentration-time plot (AUC), including the infusion time, was 1.11±0.39 Mxh; plasma clearance of MCM was 1.50±0.88 l/min/m². Five other fluorescent compounds were consistently observed in plasma. M2 was a contaminant present in the parent drug. P1 and P2 were conjugates of MCM and M2, respectively. G1 and G2 were aglycones. The peak concentrations of the metabolites were 25% or less or the peak concentration for MCM, but their persistence resulted in higher AUCs than that for MCM. For the dosage of 27.5 mg/m², fewer data were available; but the pharmacokinetics of MCM and metabolites appeared to be similar to that at higher dosage. Urinary excretion of total fluorescence amounted to 8.0%±1.6% of the total dose at 40–50 mg/m², and to 7.0%±2.3% at 27.5 mg/m². No correlation was detected among the various pharmacokinetic parameters and toxicities encountered in these patients.This work was presented in part at the Annual Meeting of the American Society of Clinical Oncology, San Diego, CA, May 1983     

Phase I trial of sequential administration of raltitrexed (Tomudex) and 5-iodo-2''-deoxyuridine (IdUrd).

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase with clinical activity in colorectal cancer. The combination of raltitrexed and 5-iodo-2-deoxyuridine (IdUrd, a cytotoxic pyrimidine analog) resulted in increased IdUrd incorporation into DNA and exhibited in vitrosynergism against colon and bladder human carcinoma cell lines. We designed a phase I trial to determine the MTD, pharmacokinetics, and biologic effects of escalating doses of the combination of IdUrd given as a 24-hour infusion after a raltitrexed 15-minute infusion every three weeks. Thirty-four patients received 95 courses of raltitrexed and IdUrd at doses ranging from raltitrexed 1 mg/m² and IdUrd 750 mg/m² to raltitrexed 2.5 mg/m² and IdUrd 10,400 mg/m².The median number of cycles administered was 2 (range 1–10). Dose limiting hematologic toxicity occurred at doses of raltitrexed 2.5 mg/m² and IdUrd 10,400 mg/m². In addition, we determined the mean plasma concentrations C_ss of IdUrd, the iodouracil level at 22 hours and the IdUrd clearance. Raltitrexed did not appear to affect the pharmacokinetics of IdUrd in the dose range tested. The recommended phase II dose is raltitrexed 2 mg/m² and IdUrd 10,400 mg/m² repeated every three weeks. Evidence of potential antitumor activity was observed: 1 patient (with colon cancer) had a partial response while 15 others had stable disease.     

The pharmacologic fate of the antitumor agent 2-amino-1,3,4-thiadiazole in the dog

Summary Anticipating the renewed clinical trial of the antitumor agent 2-amino-1,3,4-thiadiazole (AT, NSC-4728), we have studied the pharmacologic fate of AT-5-¹⁴C in beagle dogs. The drug was only minimally metabolized in 5 h; the radioactivities in the urine, and particularly in the plasma, resided almost entirely in unchanged AT. In four dogs, after IV administration of AT-5-¹⁴C at 10 mg/kg (200 mg/m²), 150–200 Ci per animal, the terminal plasma t_1/2 of AT was 13 h, and less than 10% of the administered dose appeared in the urine in 5 h. When the dose was raised to 25 mg/kg (500 mg/m²) in four dogs, the average plasma t_1/2 of AT was 10 h; the 5-h cumulative excretion of the agent was 9% of the dose in the urine, 0.3% in the bile, and 0.1% as ¹⁴CO₂ in the expired air. The average total clearance of AT was 0.70 ml/kg/min. Drug concentrations in the cerebrospinal fluid were 95% of those in the plamsa at semi-steady state. At autopsy 5 h after dosing, more than 75% of the administered radioactivity was retained in the body, the highest amounts in terms of micrograms per gram of wet tissue being in the liver, kidney, lung and stomach. No appreciable changes in AT pharmacokinetics were evident upon simultaneous IV administration of allopurinol at 30 or 60 mg/kg. AT was less than 7% bound to dog plasma protein at 25° C in concentrations of 12–100 g/ml.     

Pharmacokinetic study of doxifluridine given by 5-day stepped-dose infusion

Summary Doxifluridine (5-deoxy-5-fluorouridine, 5-dFUR) metabolism has been reported to be saturable and associated with a fall in clearance of the drug as the dose is increased. The aim of the present study was to determine the disposition of 5-dFUR and 5-fluorouracil (5-FU) when 5-dFUR was given as a 5-day infusion, with the infusion rate increased stepwise every 24 h. Measurement of plasma and urinary levels of 5-dFUR and 5-FU at steadystate for each infusion rate enabled the estimation of 5-dFUR renal (Cl_R) and nonrenal (Cl_NR) clearance and 5-FU renal clearance. A total of 28 patients with histologically proven malignancy received 5-day courses of 5-dFUR ranging in dose from 3.75 to 20 g/m² per 120 h. The lowest dose given over 24 h was 0.25 g/m², and the highest was 5 g/m². Steady-state plasma levels of 5-dFUR ranged from 167 to 6.519 ng/ml. At these plasma levels there was no evidence of significant saturation of 5-dFUR metabolism; steady-state plasma levels of 5-dFUR increased approximately linearly with dose, and nonrenal clearance did not change significantly with dose. There was also no evidence of nonlinearity in 5-dFUR renal clearance. The mean (±SD) Cl_R of 5-dFUR was 108.9±53.6 ml/min per m² (range, 45.7–210 ml/min per m²), and the Cl_NR was 728±181 ml/min per m² (range, 444–1,119 ml/min per m²). Renal clearance comprised 13% of the total 5-dFUR clearance. The mean renal clearance of 5-FU was 100.8±48.6 ml/min per m² (range, 23.5–198 ml/min per m²). There was considerable interpatient variability in 5-dFUR renal and nonrenal clearance, event at the same dose level. We concluded that the administration of 5-dFUR by the infusion method described avoided the saturation of nonrenal elimination processes reported to occur with shorter infusion schedules.This study was supported by a grant from F. Hoffmann-La Roche, Basel, Switzerland     

A phase I and pharmacokinetic study of 12-h infusion of flavone acetic acid

Summary This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m². One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m². The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m² for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12–16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101–402 g/ml and AUC (0–48 h) values were 75–470 mg ml^–1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%–77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m².     

The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717)

Summary The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation. The drug was administered at doses of 100–550 mg/m² in 1-h and 12-h infusions, resulting in peak plasma concentrations of CB 3717 of 40–200 M. There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels. Following a 1-h infusion, drug levels in the plasma decayed biphasically (t_1/2=49±9 min, t_1/2=739±209 min). 27%±2% of the dose was excreted in urine in the 24-h period after treatment, suggesting that the major route of elimination was via the bile. Furthermore, the parent compound CB 3717 and its desglutamyl metabolite, CB 3751, were found in a faecal collection although the metabolite was not detected in plasma or urine samples. Plasma protein binding of CB 3717 was extensive (97.6%±0.1%). Significant quantities of CB 3717 penetrated into ascitic fluid but not into cerebrospinal fluid.Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m² CB 3717. Thus, dose-limiting renal toxicity (maximum tolerated dose 600 mg/m²) may be due to drug precipitation in the renal tubules. Elevation of liver enzymes, in particular transaminases, occurred frequently as a toxic manifestation of CB 3717 therapy. In 11 patients studied after their first treatment there was a positive correlation between the rise in serum alanine transaminase and peak drug levels (r=0.69, P=0.02)These pharmacokinetic studies have shown that, by analogy with experimental systems, cytotoxic plasma levels of CB 3717 are archieved in man. In addition, they have been valuable in interpreting toxicities observed during phase-I clinical studies.This work was supported by grants from the Medical Research Council and Cancer Research Campaign, U. K.     

Phase I and pharmacokinetic study of KW-2170, a novel pyrazoloacridone compound,in patients with malignant tumors

Purpose The primary purposes of this study were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), to recommend a dose for phase II studies, and to analyze the pharmacokinetics of KW-2170. A secondary purpose was to assess tumor response to KW-2170.Experimental design KW-2170 was given as a 30-min i.v. infusion every 4 weeks. Doses were escalated from 1.0 mg/m² according to a modified Fibonacci method.Results A total of 45 cycles of KW-2170 were delivered to 41 patients at doses ranging from 1.0 to 53.0 mg/m². The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m² and in two of two patients treated at 53.0 mg/m²; therefore, the MTD was 53.0 mg/m². Although no patients showed a complete response (CR) or partial response (PR), 15 patients were evaluated as having freedom from progression at the 1-month time-point, with two demonstrating slight tumor shrinkage in their metastatic lesions. None of the patients experienced significant cardiotoxicity. The plasma concentration of KW-2170 declined in a triphasic manner. The half-life, total clearance (CL_tot) and volume of distribution (V_dss) were nearly constant and independent of dose, and showed a relatively small interpatient variability. A linear relationship was observed between dose and maximum plasma concentration (C_max) and area under the concentration–time curve (AUC_0–). In addition, there was a good correlation between neutropenia and AUC_0–. This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxidative metabolites were observed in the patients plasma and urine.Conclusions The primary DLT of KW-2170 in this study was neutropenia, with a MTD of 53 mg/m². A significant linear relationship was observed between neutropenia and AUC_0–. We estimate the recommended dose for phase II studies to be 41.0 mg/m².