Clinical pharmacokinetics of 3-deazaguanine

Summary 3-Deazaguanine (3DG), an antipurine antimetabolite, has recently completed a phase I clinical trial at this Institute. The drug was given on a dailyx5 schedule by i.v. infusion over 0.25–2.16 h. The pharmacokinetics of 3DG during 16 courses were studied in 12 patients at doses of 200–800 mg/m². 3DG in plasma was measured by an isocratic reverse-phase high-performance liquid chromatographic (HPLC) procedure carried out on IBM phenyl columns at 40° C using 10mM phosphate buffer (pH 7) as the mobile phase and detection at 300 nm. Plasma decay of 3DG was biexponential in all patients. The AUC correlated linearly with dose at 200–600 mg/m² but deviated from linearity at doses>600 mg/m². The drug was cleared rapidly from plasma; at doses of 200–600 mg/m², the mean plasma clearance was 61.64±9.97 l/h and the mean terminal-phase elimination half-life was 1.6±0.6 h. The steady-state volume of distribution (98.8±29.1 l) and distribution coefficient (1.24±0.39 l/kg) indicated extensive tissue distribution for the drug. No statistically significant difference was observed between the pharmacokinetics of 3DG on day 1 and that on day 4 as evaluated in three patients for whom complete plasma data were available on both days.     

Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics

 A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of ≥110 mg/m² per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m² per day. Hypertriglyceridemia was dose-limiting at 269 mg/m² per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of ≥0.5 μg/ml (1.7 μM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m², although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response. Received: 7 January 1996 / Accepted: 24 June 1996     

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     

Pharmacokinetics of 7-con-O-methylnogarol in patients with solid tumors

Summary The pharmacokinetics of 7-con-O-methylnogarol were investigated by HPLC assay with fluorometric detection in nine cancer patients with normal hepatic and renal function, after a 2-h infusion of 160 or 200 mg/m². The drug disappeared from plasma biexponentially with a mean elimination half-life of 38±3 h; the mean apparent volume of distribution and the plasma clearance were 805±91 l/m² and 14±2 l/h per m². Within 48 h of administration, urinary excretion of the drug and its metabolite 7-con-O-methyl-N-demethylnogarol accounted for 2%–15% and 0.1%–6% of the dose, respectively. Neither 7-con-O-methylnogarol nor its N-demethyl derivative was conjugated with glucuronic acid or sulfate in detectable amounts.     

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.     

Phase I and pharmacokinetic study of weekly oral therapy withvinorelbine in patients with advanced breast cancer (ABC)

Background:A phase I dose-escalation study of a newformulation of oral vinorelbine was conducted to determine the maximumtolerated dose (MTD) of a once weekly regimen and preliminarypharmacokinetic profile in patients with advanced breast cancer (ABC).Twenty-six patients were treated at dose levels ranging from 60 to 100mg/m²/week. Pharmacokinetics was assessed during the firstadministration. Patients and methods:All patients hadhistologically confirmed locally advanced or metastatic breast cancerand had received no more than two prior chemotherapy regimens forABC. Results:The MTD was 100 mg/m²/weekdue to the occurrence of dose-limiting neutropenia, nausea/vomitingand constipation in five of six patients. Toxicities at 80mg/m²/week were manageable, neutropenia being the maintoxicity (grade 3–4 seen in 10 of 13 patients). Nausea, vomitingand diarrhoea were common but rarely severe. Vinorelbine was rapidlyabsorbed with maximum blood concentration (C_max) of 103.8± 41.6 ng·ml^–1 observed 1.2 ± 0.8hours (T_max) after administration of 80 mg/m².Pharmacokinetic exposure increased linearly with dose. Area under theconcentration-time curve (AUC) and concentration measured 24 hours afterdrug intake (C_24h) were significantly correlated withdepletion of neutrophils. Objective tumour responses were reported in 6of the 14 evaluable patients treated at doses 80mg/m²/week. Conclusion:The safety profile oforal vinorelbine appears comparable to that of intravenous dosing. Therecommended phase II dose is 80 mg/m²/week and requiresregular monitoring of neutrophil counts.     

Cerebrospinal fluid pharmacokinetics of carboplatin in children with brain tumors

Summary The pharmacokinetics of carboplatin in cerebrospinal fluid (CSF) and plasma was studied in five children with brain tumors (four medulloblastomas and one ependimoblastoma) who underwent preirradiation treatment with carboplatin. Carboplatin pharmacokinetics was studied following the administration of 600 mg/m² as a 1-h infusion. Four children were treated a few weeks after surgery, whereas one child with an unresectable tumor was treated prior to surgery. All patients had a ventricular-peritoneal CSF shunt connected to a subcutaneous reservoir. Total platinum and free carboplatin were measured. The mean AUC values for free carboplatin in CSF and plasma were 2.29±1.20 and 8.18±1.27 mg ml^–1 min, respectively. The mean ratio of CSF AUC to plasma AUC was 0.28 (range, 0.17–0.46). Both plasma peak levels and AUC values showed limited interpatient variability. On the other hand, carboplatin levels in CSF showed substantial interpatient variability, with a>5-fold difference in peak levels and a 3-fold difference in AUC values being recorded. The interpatient difference in CSF pharmacokinetics may have been related at least in part to the different anatomical alterations induced by the surgical procedures or by the presence of a large tumor mass. In the four evaluable patients exhibiting macroscopic residual tumor, we observed one complete remission (CR) and two partial remissions (PR) following two cycles that consisted of two doses of 600 mg/m² carboplatin given on 2 consecutive days (total dose, 1200 mg/m²) and were separated by a l-month interval. These results may give some indication as to the optimal dose and schedule for carboplatin administration in the treatment of primitive neuroectodermic tumors (PNET).This work was partially supported by the AIRC     

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.     

A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m² per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m², three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m², two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 M. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m² per day.     

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.     

Carboplatin and cisplatin pharmacokinetics after intrapleural combination treatment in patients with malignant pleural effusion

Background: Cisplatin (DDP) and carboplatin (CBDCA) are two of the mosteffective drugs in a locoregional approach. Since simultaneous combinedtreatment with intrapleural DDP and CBDCA has not been reported in humans, weinvestigated its use in patients with malignant effusions, focusing onpharmacokinetics.Patients and methods: The pharmacokinetics of DDP and CBDCA were studiedin 10 patients with malignant pleural effusion treated intrapleurally with acombination of DDP (60 mg/m²) and CBDCA (270mg/m²) and in additional patients who received the same dosesof drugs administered intravenously as single agents or in combination.Platinum (Pt) species originating from DDP (metabolites plus unchanged DDP)and intact CBDCA in plasma and pleural fluid ultrafiltrates were measured bymeans of high performance liquid chromatography and atomic absorptionspectrometry.Results: Both in the plasma and pleural fluid, the total levels of free Ptrepresented the additive result of the individual concentrations of CBDCA andPt-species derived from DDP. After intrapleural combination, highpleural-plasma ratios of the peak concentrations and AUCs were observed bothfor CBDCA and DDP-derived Pt species, highlighting a distinct localpharmacological advantage. However, the Pt species originating from DDP wereabsorbed more rapidly from the pleural cavity than CBDCA (K_a= 86 × 10^-3 vs. 37 ×10^-3 min^-1, P < 0.05).Intrapleural combination of CBDCA and DDP produced therapeutic plasma levelsof reactive (free) DDP species and increased the extent of their residencetime (MRT) compared with single intravenous DDP treatment [peak concentration:1.1 ± 0.1 (SD) vs. 1.6 ± 0.2 µg/ml; MRT: 5.2 ± 1.9vs. 0.5 ± 0.06 h]. Furthermore, the plasma AUC of free CBDCA afterintrapleural combined treatment (2.1 ± 0.5 mg/ml × min) wassimilar to that after intravenous administration of CBDCA alone (2.1 ±0.2 mg/ml × min). The intrapleural treatment was well tolerated by allpatients. Toxicity consisted of mild nausea and vomiting (grade 1–2according to the WHO scale) in four patients. Myelosuppression (grade1–2) was remarkable only in two heavily pretreated patients. No evidenceof recurrence of the pleural effusion was observed in six patients (completeresponse), while an asymptomatic minimal fluid reaccumulation not requiringdrainage (partial response) was observed in four patients.Conclusions: The pharmacologic results seem to exclude a pharmacokineticinteraction between CBDCA and DDP and suggest that a dose of CBDCA 2-foldhigher than that used in this study associated intrapleurally with 60mg/m² DDP could induce an acceptable and predictablemyelosuppresion.     

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.     

Phase I and pharmacokinetic trial of liposome-encapsulated doxorubicin

A total of 21 patients with advanced cancer were entered into a phase I study to determine the maximum tolerable dose (MTD) of liposome-encapsulated doxorubicin (LED) given weekly for 3 consecutive weeks at doses of 20, 30, or 37.5 mg/m² per week. For a comparison of the pharmacokinetic behavior of LED with that of standard-formulation doxorubicin, 13 patients received a dose of standard-formulation doxorubicin 2 weeks prior to the first dose of LED. All doses were given by 1-h infusion through a central vein. Toxicity was evaluated in 22 courses delivered to 17 patients. The MTD with this schedule was 30 mg/m² per week×3. The single patient treated at 37.5 mg/m² weekly could not complete the entire course due to myelosuppression. At the dose of 30 mg/m² per week, three of eight patients had grade 3 leukopenia. Other toxicities included mild to moderate thrombocytopenia, nausea, vomiting, fever, alopecia, diarrhea, fatigue, stomatitis, and infection. At the dose of 30 mg/m² per week, the total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 8.75±8.80 M h (mean±SD) and 3.07±1.45 M, respectively, after LED administration. The total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 3.92±2.47 M h and 2.75±2.70 M, respectively, after the infusion of standard-formulation doxorubicin. The total body clearance of doxorubicin was 18.42±11.23 l/h after the infusion of LED and 31.21±15.48 l/h after the infusion of standard-formulation doxorubicin. The mean elimination half-lives of doxorubicin were similar: 8.65±5.16 h for LED and 7.46±5.16 h for standard-formulation doxorubicin. Interpatient variability in pharmacokinetic parameters as demonstrated by the percentage of coefficients of variation was 33%–105%. There was no relationship between the percentage of WBC decrease or the duration of WBC suppression and the total doxorubicin or doxorubicinol AUC. There was no correlation between the duration of leukopenia and drug exposure as reflected by the AUC of liposome-associated doxorubicin. LED can be given in doses similar to those of standard-formulation doxorubicin and produces acute toxicities similar to those caused by standard doxorubicin.Abbreviations MTD maximum tolerable dose - LED liposome-encapsulated doxorubicin - AUC area under the plasma concentration x time curve - WBC white blood cell count - PLT platelet count - ECOG Eastern Cooperative Oncology Group - EKG electrocardiogram - MUGA multigated nuclide scan - CLTB total body clearance - PC phosphatidylcholine: PG, phosphatidylglycerol - PEG-DSPE polyethylene glycol conjugated to distearoyl phosphatidylethanolamine - HSPC hydrogenated soy phosphatidylcholine - chol cholesterol This work was supported by DHHS, NCl NO-l-CM 07 303 and by a Career Development Award from the American Cancer Society (to B. A. C.)     

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     

Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma

Background: In clinical trials in the USA, IDEC-C2B8 (a mouse-humanchimeric anti-CD20 monoclonal antibody) has demonstrated high response rateswith only mild toxic effects in relapsed B-cell lymphoma at a dose of fourweekly 375 mg/m² infusions. The aim of the present trial wasto determine whether or not this dose is practically applicable to Japanesepatients with relapsed B-cell lymphoma with respect to safety,pharmacokinetics and efficacy.Patients and methods: Patients with relapsed CD20+ B-cell lymphomareceived intravenous infusions of IDEC-C2B8 once a week for four weeks. Atotal of 12 patients (four at 250 mg/m² and eight at 375mg/m²) were enrolled.Results: All 11 eligible patients treated with either dose leveltolerated IDEC-C2B8 well. Commonly observed adverse drug reactions weregrades 1 or 2 non-hematologic toxicities during the infusion, consistingmostly of flu-like symptoms and skin reactions. All of the observedhematologic toxicities were of grade 3 or less, and transient. A rapid andsustained B-cell decrease in peripheral blood was observed, but noinfectious episodes were encountered. Human anti-mouse and anti-chimericantibodies were not detected. Of the 11 eligible patients (eight withfollicular, two with diffuse large-cell and one with mantle cell lymphoma),two showed a complete response and five showed a partial response, and allof the seven responders had lymphoma with follicular histology. Apharmacokinetic analysis showed that the elimination half-life (T1/2) ofIDEC-C2B8 was 445 ± 361 hours, and that the serum antibody levelsincreased in parallel with the course of infusions, and in most patients wasstill measurable at three months.Conclusions: The dose of four weekly 375 mg/m² infusionsof IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-celllymphoma. Further studies evaluating IDEC-C2B8 are warranted.     

Phase I and pharmacokinetic study of tiazofurin (NSC 286193) administered by 5-day continuous infusion

Summary A phase I and pharmacokinetic study of tiazofurin (NSC 286193), a C-nucleoside that inhibits IMP dehydrogenase, has been completed. The drug was administered by continuous infusion over 5 days. The maximum tolerated dose was 1650 mg/m² per day, neurological toxicity being the dose-limiting factor. Gastrointestinal and hematological toxicity were mild. A definite relationship exists between dosage and steady-state levels. The plasma clearance was 29.13 (±SD 4.05) ml/min per m². No complete or partial remissions were demonstrated among the 18 patients treated at five dose levels between 550 mg/m² and 2200 mg/m² per day.     

Pharmacokinetics and tissue disposition of the biological response modifier BAY i 7433 (copovithane) in patients with cancer

Summary Copovithane is an uncharged, water-soluble, synthetic polymer with an average molecular weight of 5800 daltons. It demonstrates antitumor activity in vivo against a variety of tumors in animal models but is inactive in vitro. This agent has been found to have immunorestorative activity in man. In concert with its phase I clinical trial, copovithane concentrations were analyzed by HPLC in plasma, urine, and autopsy and in tumor biopsy specimens obtained from patients. Copovithane was cleared from plasma biphasically with a mean t_1/2 of 11.1±4 min and a t_1/2 of 246±78 min at the dose of 1 g/m², while the plasma half-lives increased to 57.7±12 and 718±149 for the alpha and beta phases, respectively, at the 10 g/m² dose, demonstrating clear, dose-dependent pharmacokinetics. There were no significant differences between dose 1 and dose 4 pharmacokinetics. The apparent volume of distribution (V_d) was 14.5±1. at the 1 g/m² dose and increased to 73 1. at the 33 g/m² dose. The calculated mean clearance rate for copovithane in plasma was between 2.4 and 5.4 mg/kg x min and did not appear to be dose-dependent. The urinary excretion of copovithane was approximately 5% of the administered dose over 120 h at the 1 g/m² dose and decreased to 1% at the 33 g/m² dose. In seven tumor biopsy samples, concentrations of drug in tumor varied from 1- to 1000-fold higher than that found in concurrent plasma samples. In three autopsy samples, the highest concentrations were found in kidney, intestine, and liver, in decreasing order. These studies show that copovithane exhibits dose-dependent changes in pharmacokinetics at doses between 1 and 33 g/m². However, copovithane does penetrate well to tumor tissues, achieving high tumor/plasma ratios. In addition, copovithane concentrations were highest in kidney tissue, which may be a site for potential organ toxicity.     

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     

Phase I study of an oral formulation of irinotecan administered daily for 14 days every 3 weeks in patients with advanced solid tumours

A phase I study was conducted with oral irinotecan given daily for 14 days every 3 weeks in 45 patients with solid tumours to establish the maximum tolerated dose (MTD), toxicity, preliminary antitumour response and pharmacokinetics. Irinotecan was administered orally as a powder-filled capsule at doses ranging from 7.5 to 40 mg/m² per day. Tumours were predominantly colorectal (30) together with 10 other gastrointestinal, 2 breast, 2 small cell lung and 1 ovarian. All but three patients had received prior chemotherapy. The median number of administered cycles was 3 (range 1–19). Gastrointestinal toxicities (grade 3 nausea, grade 3/4 vomiting and diarrhoea) and one incidence of grade 3 asthenia were dose limiting. There were no grade 3/4 haematological toxicities. The MTD was 30 mg/m² per day. There were two documented partial responses, one in a patient with cancer of the small intestine and the other in a patient with colon cancer. Stable disease was seen in 16 patients (35.5%). Peak concentrations of irinotecan and metabolite SN-38 were reached within 2.0–2.4 h. The metabolic ratio of SN-38 AUC to irinotecan AUC was 0.17±0.10 (mean±SD). The dose recommended for phase II studies is 30 mg/m² per day administered daily for 14 days every 3 weeks.     

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.