Phase I and pharmacologic study of 7- and 21-day continuous etoposide infusion in patients with advanced cancer

 Purpose. This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. Methods. A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses from 30 to 75 mg/m² per day, and a second group of 37 patients a 21-day infusion (schedule B) every 28 days at doses from 18 to 40 mg/m² per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prior chemotherapy. Etoposide concentrations at steady state (Css) and other pharmacokinetic parameters (plasma clearance, CLp; area under the curve, AUC) were determined during the first treatment cycle. Correlation coefficients were calculated to measure the relationship between variables. Results. Myelosuppression was the major toxicity, and was associated with three deaths. The maximum tolerated dose due to neutropenia was 75 mg/m² per day for schedule A and 40 mg/m² per day for schedule B. There was significant interpatient pharmacokinetic variability in both infusional schedules. Even though etoposide dose levels did not significantly correlate with plasma levels, the Css was ≥1 μg/ml in the majority of the patients. A significant correlation between AUC and neutrophil absolute decrease was noted only in schedule B (r=0.56,  P=0.003). There were several marginal relationships in schedule B: PS versus Css (r=0.31,  P=0.058), PS versus AUC (r=−0.38; P= 0.058) and age versus CLp (r=−0.31, P=0.057). Conclusion. Overall, significant correlations were found for several hematologic variables and etoposide dose levels, but not with the Css values. One major problem with the application of pharmacodynamic models to predict hematologic toxicity in clinical practice is the presence of significant interpatient variability. Received: 3 April 1995/Accepted: 6 December 1995     

A pharmacogically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer

 Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m²) and vinblastine (4 mg/m²) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml^-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml^-1 min. Received: 9 May 1994/Accepted: 16 August 1994     

Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine

 Purpose: Preclinical studies were performed to examine the interaction of the hypoxic cell toxin tirapazamine (TPZ), a benzotriazine di-N-oxide, with several chemotherapeutic agents, including carboplatin, cyclophosphamide, doxorubicin, etoposide, 5-fluorouracil (5-FU), taxol, and navelbine. Methods: The modification by TPZ of the antitumor drug activity and the effect of schedule were determined with an in vivo/in vitro clonogenic assay using well-established RIF-1 murine tumors transplanted into C3H mice. Results: Additive, or greater than additive, tumor cell killing was observed when TPZ was combined with carboplatin, cyclophosphamide, doxorubicin, etoposide, 5-FU and taxol. With the exception of 5-FU there were only small, or no, enhancements of the systemic toxicities of the drugs by TPZ. The greatest enhancement of antitumor activity was with carboplatin, with the maximum effectiveness when TPZ was given 2–3 h before the carboplatin. The activity of cyclophosphamide, doxorubicin, etoposide and taxol were most enhanced when TPZ was given 24 h before the drug. Additional investigations with three-drug combination treatments using cisplatin and TPZ with either etoposide or navelbine indicated a substantial therapeutic gain from the addition of TPZ. Conclusions: The data for each of the drugs tested in combination with TPZ, with the exception of 5-FU, indicate that potential clinical benefit may be obtained from therapies combining TPZ with conventional chemotherapy. Received: 6 March 1996 / Accepted: 30 June 1996     

Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors

 Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m² infused over 2 h on days 1 and 2, and G-CSF 5 μg/kg per day starting on day 3 until WBC was ≥10 000/μl. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (C_pmax) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T_1/2α of 2.09±0.61 h, and T_1/2β of 5.83±1.71 h. An AUC as high as 1768.50 μg.h/ml was observed at a dose of 1200 mg/m². The total body clearance (TBC) showed an overall mean of 15.72±4.25 ml/min per m², and mean volume of distribution (V_Dss) of 5.64±1.06 l/m². The mean residual time (MRT) for etoposide was 6.24±1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related C_pmax and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high- dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important C_pmax and AUCs, clearance, terminal T_1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration. Received: 18 July 1995/Accepted: 20 October 1995     

A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve

 The aim of this study was to develop and validate a simple and rapid method for the estimation of the area under the free carboplatin plasma concentration versus time curve (AUC). The relationship between the carboplatin AUC and the total plasma platinum (Pt) concentration 24 h after treatment was studied using data from 49 patients treated with 20–1600 mg/m² carboplatin as a 60–100 min infusion (median 60 min). The relationship was confirmed by the in vitro incubation of carboplatin in human plasma and prospectively validated in 13 ovarian cancer patients. Free carboplatin was separated by ultrafiltration (MW cut off 30,000), and free and total Pt measured by atomic absorption spectrophotometry. There was a linear relationship in vivo between the 24 h (median 24.4; range 16.3–27.3 h) total plasma Pt concentration (μM) and free carboplatin AUC (mg/ml.min): AUC=(24 h Pt+0.3)/0.82 (r ²=0.93, AUC median 5.8 (0.13–28)mg/ml.min, 24 h Pt median 4.4 (0.1–23) μM). A similar relationship was observed in vitro [AUC=(24 h Pt +0.1)/0.93 (r ²=0.98, AUC median 7.9 (2.0–17) mg/ml.min, 24 h Pt median 7.1 (1.8–15) μM)]. The relationship derived from the in vivo data gave an unbiased and reasonably accurate estimate of the measured carboplatin AUC in 13 patients (AUC=5.1–8.7 mg/ml.min, GFR=59–129 ml/min, infusion time 30–45 min, 24 h sampling time 22.9–24.5 h), giving a percentage mean error of −4.2% and root mean squared percentage error of 11.5%. These results show that the analysis of a single blood sample taken 24 h after carboplatin administration can be used to produce an unbiased and reasonably accurate measure of the free carboplatin AUC. Unlike published limited sampling strategies, this method is not complicated by the need to accurately control the duration of the carboplatin infusion or the time at which the sample is taken. Received: 13 January 1995/Accepted: 14 May 1995     

Pharmacokinetics of carboplatin administered with lobradimil to pediatric patients with brain tumors

Purpose To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors.Methods Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mgmin/ml per dose ×2 (2.5 mgmin/ml per dose ×2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m²)=target AUC (mgmin/ml) × [0.93 × GFR (ml/min/m²)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min lobradimil infusion (100–600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity.Results The median GFR was 65 ml/min/m² (range 38–95 ml/min/m²) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m²/day (124–235 and 179–360 mg/m²/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2–131%). The median carboplatin AUCs at the 2.5 and 3.5 mgmin/ml target AUCs were 3.4 and 4.8 mgmin/ml (2.51–5.8 and 3.9–7.7 mgmin/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r²=0.14).Conclusions Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.     

Poor correlation between body surface area and glomerular filtration rate

Purpose: The aim of this study was to determine the correlation between body surface area (BSA) and glomerular filtration rate (GFR) measured by Tc-99m DTPA clearance in adult patients with cancer. Methods: GFR was determined by Tc-99m DTPA clearance in adult patients with cancer. Height and actual body weight were measured. Ideal body weight was calculated. BSA was calculated using the Du Bois and Du Bois linear method using both actual and ideal body weight. Results: Included in the study were 122 patients. The mean GFR measured by Tc-99m DTPA clearance was 87 ml/min (range 30–174 ml/min). The mean BSA (actual weight) was 1.76 m² (median 1.73 m², range 1.31–2.58 m²). The mean BSA (ideal body weight) was 1.63 m² (median 1.63 m², range 1.20–2.00 m²). The overall correlation between BSA (actual weight) and GFR in this adult population was r=0.24, and the 95% confidence interval was 0.06–0.4. The correlation between BSA (ideal body weight) and GFR was r=0.22. The correlation between BSA and GFR excluding patients with a BSA <1.5 m² or >2.0 m² was 0.12. When patients with GFR <50 ml/min or >100 ml/min were excluded, the correlation with BSA was 0.07. The correlations between GFR and height, actual weight and ideal weight were 0.22, 0.21 and 0.22, respectively. Conclusions: This study demonstrated a poor correlation between GFR determined by Tc-99m DTPA clearance and BSA calculated using the Du Bois and Du Bois linear method. The 95% confidence interval for the correlation between BSA and GFR was 0.06–0.4 indicating that a strong applicable clinical correlation is very unlikely. Received: 3 February 2000 / Accepted: 17 July 2000     

Unchanged pharmacokinetics of etoposide given by intra-arterial hepatic infusion as compared with i.v. infusion

 We investigated the pharmacokinetics of etoposide given to a patient suffering from multifocal liver metastases from an unknown primary tumor. The drug was given either by i.v. infusion or by hepatic arterial infusion (HAI). The calculated pharmacokinetic parameters (mean values ± SD) were similar after i.v. infusion and HAI, viz., 6.4±0.7 versus 6.5±0.2 h for the terminal elimination half-life (t _1/2β), 98.5±1.3 versus 101.3±5.9 mg l^-1 h for the area under the plasma concentration-time curve (AUC), 21.2±0.3 versus 20.6±1.2 ml min^-1 m^-2 for clearance (Cl), 17.7±1.9 versus 18.1±2.6 mg/l for the peak concentration, and 11.7±1.3 versus 11.6±1.0 l/m² for the volume of distribution (V _d ), respectively. We therefore conclude that administration of etoposide by HAI does not result in a significantly higher liver extraction. Hepatic extraction of etoposide is determined by the fraction of non-protein-bound (free) drug present. The lack of a difference between the two administration routes suggests that under in vivo conditions the equilibrium between free and bound drug is established before the drug reaches the hepatic arterioles. Consequently, administration by HAI does not lead to an increased exposure of the tumor in the liver to free (active) etoposide. Furthermore, the overall exposure of the liver to total (bound + free) etoposide is increased only from about 100 to 120 mg l^-1 h. These results do not favor the use of this more complex route of drug administration in the treatment of (metastatic) cancer located in the liver. Received: 5 November 1995/Accepted: 17 January 1996     

The effect of treatment with high dose melphalan,cisplatin or carboplatin on levels of glutathione in plasma,erythrocytes, mononuclear cells and urine

 Glutathione (GSH) has been implicated as an important factor in the detoxification of many electrophilic xenobiotics, including agents used in cytotoxic chemotherapy. Maintenance of high levels of GSH in normal tissues is believed to be important in the prevention of drug-induced toxicity. Previous studies have indicated that exposure of cells to some toxic electrophiles both in vitro and in vivo can cause a temporary decrease in intracellular levels of GSH. In this paper we report that in a series of 22 children and young adults treated with high dose melphalan (ten courses studied, all 200 mg/m²), cisplatin (eight courses, 80–104 mg/m²) or carboplatin (seven courses, 507–750 mg/m²) there was no significant alteration in the level of plasma, erythrocyte or urine GSH in the period immediately following drug administration. Fluctuations in the level of GSH in mononuclear cells were observed in some patients but did not follow any consistent pattern and were similar to those observed in a series of nine normal adult controls over the same time course. These results suggest that for melphalan, cisplatin and carboplatin, drug-GSH adduct formation is insufficient to cause a measurable decrease in intracellular GSH levels in normal peripheral haematopoietic cells during the course of treatment. Received: 6 October 1994/Accepted: 22 May 1995     

Pharmacokinetics of the hypoxic cell cytotoxic agent tirapazamine and its major bioreductive metabolites in mice and humans: retrospective analysis of a pharmacokinetically guided dose-escalation strategy in a phase I trial

 Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold; firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine, and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD₁₀ to the LD₅₀. The AUC at the LD₁₀ (2932 μg ml^-1min) was used to determine a target AUC value of 1173 μg ml^-1min (equivalent to 40% of the mouse LD₁₀ AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every 3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m²) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD₁₀ 294 mg/m², LD₅₀ 303 mg/m²). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic ptosis and conjunctivitis were observed at doses of >300 mg/m². The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma (t _1/2=36±0.65 min) occuring at the LD₁₀ dose of 294 mg/m². A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of 36–450 mg/m². Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m² and the MTD was 390 mg/m² for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m² (range 1035–1611 μg ml^-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at tolerable doses. Received: 27 May 1996 / Accepted: 30 September 1996     

A phase I study of prolonged ambulatory infusion carboplatin with oral etoposide showing activity in prostate cancer

Purpose: This phase I study aimed to establish the dose for phase II trials of a dose-intense outpatient regimen of ambulatory carboplatin and oral etoposide. Patients and Methods: Cohorts of three patients received escalating doses of carboplatin 15, 20, and 23 mg/m²/day as a 3-week continuous ambulatory infusion with oral etoposide initially at 50 mg/day. Patients entered had prostate, colon, head and neck, breast, unknown primary cancers and mesothelioma. Results: At 23 mg/m² of carboplatin, two patients had WHO grade 3 lethargy and myelosuppression, which were the dose-limiting toxicities. Six patients were entered at the dose recommended for phase II studies, carboplatin 20 mg/m²/day and etoposide 50 mg/day for 21 days repeated every 6 weeks. This was well tolerated except for one patient with multiple bone metastases from prostate cancer experiencing grade 4 myelosuppression and a single patient with grade 3 constipation. Seven patients with hormone-resistant prostate cancer were entered into the study, one at 15 mg/m², four at 20 mg/m² and two at 23 mg/m² of carboplatin, and received a median of four cycles of treatment. The only responses were seen in prostate cancer where there were two partial responses in patients with soft tissue predominant disease. Five patients who could be evaluated with initially elevated PSA exhibited falls of ≥50% after receiving the chemotherapy. All but one patient with prostate cancer experienced significant reduction in pain levels. The median time to progression of the patients with prostate cancer was 4 months. Conclusions: Ambulatory infusion carboplatin and oral etoposide is a tolerable dose- intense outpatient regimen which warrants further testing in phase II trials including hormone-resistant prostate cancer. Received: 13 March 2000 / Accepted: 26 May 2000     

Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae

Purpose: Carboplatin doses can be individualized using the formula of Calvert et al. (Calvert formula) dose (mg) = area under the plasma concentration versus time curve (AUC) · [glomerular filtration rate (GFR) + 25]. Creatinine clearance (Ccr), either measured by the 24-h method or calculated by the formula of Cockcroft and Gault [Cockcroft-Gault (CG) formula], is often substituted for the GFR. The CG formula is based on patient weight, age and sex, and the serum creatinine (Cr) concentration. Another method for predicting carboplatin clearance (CL) using patient characteristics has also been proposed by Chatelut et al. (Chatelut formula). This study was undertaken to evaluate the performance of the three formulae in predicting standard- and low-dose carboplatin pharmacokinetics. Methods: A total of 52 patients with advanced lung cancer were enrolled in this pharmacokinetic study; 37 received standard-dose carboplatin and 25 received low-dose carboplatin. The Cr concentration was measured using an enzymatic assay. The three formulae were used to predict carboplatin CL. The median absolute percent error (MAPE) for each formula was evaluated by comparing the calculated and observed CL. For comparison of AUCs, free platinum plasma concentrations were measured at intervals up to 24 h after carboplatin administration. AUCs were determined and compared with predicted values. Results: In the standard-dose carboplatin group, the MAPEs for the prediction of carboplatin CL from the 24-h Calvert, CG-Calvert and Chatelut formulae were 13%, 12% and 23%, respectively. In the low-dose carboplatin group, the corresponding MAPEs were 27%, 18% and 44%, respectively. Observed standard-dose carboplatin AUCs after aiming for target AUCs of 5 and 6 mg · min/ml using the Calvert formula based upon the 24-h Ccr were 5.3 ± 0.8 and 5.9 ± 0.8, respectively, indicating a small and acceptable bias compared with that predicted from the dosing formula. Conclusions: The pharmacokinetics of standard-dose carboplatin were accurately predicted by the Calvert formula based upon either 24-h or CG-calculated Ccr, but not by the Chatelut formula. Either CG-calculated or 24-h Ccr can be substituted for the GFR in the Calvert formula for the determination of individual doses. The poor predictability of the Chatelut formula found in this study might be the result of a differences in either the Cr assay or the patient population. Therefore, formulae which attempt to estimate GFR are not necessarily valid if either the Cr assay or the patient population is changed. Received: 23 July 1997 / Accepted: 16 December 1997     

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 effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy

A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m² per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m² per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m² (range 77–1804 ml/min per m²) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were <1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients. Received: 29 January 1997 / Accepted: 9 May 1997     

Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative

 NK611 is a novel water-soluble podophyllotoxin derivative that has comparable antitumour activity but higher potency and better bioavailability in animals as compared with etoposide. The primary objectives of this study were to determine, after both oral and intravenous administration in the same patient, the bioavailability and the pharmacokinetic profile of NK611. Secondary objectives involved evaluation of the toxicity and the antitumor activity. Patients were randomly assigned to receive oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg/m² on day 1, when pharmacokinetic studies were performed. A daily oral dose of 20 mg/m² was then given from day 4 through day 7 for respective total doses of 85, 90, and 100 mg/m². NK611 and its metabolites were determined in plasma and urine by two different high-performance liquid chromatography (HPLC) methods with UV detection. A total of 21 adult patients entered the study and received the complete first cycle and at least the 1st day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the plasma decay curve of NK611 followed a two-exponential model, and after oral administration it declined monoexponentially in most cases. At all dose levels, bioavailability values were around 100%. At concentrations between 10 and 20 mg/m² after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma clearance, and volume of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to the dose. The urinary excretion of NK611 corresponded to 10–15% of the dose after administration by both routes, whereas that of N-demethyl NK611 and its picroform was highly variable. The features of neutropenia were comparable with those noted for etoposide involving a high degree of interpatient variability and recovery within 1 month after treatment. A daily dose of 20 mg/m² for 5 consecutive days every 4 weeks is the recommended regimen for phase II studies in patients who have never been treated or have undergone previous chemotherapy only once. Received: 26 November 1995: Accepted: 27 March 1996     

Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma

Summary The pharmacokinetics of carboplatin and etoposide were studied in four testicular teratoma patients receiving four courses each of combination chemotherapy consisting of etoposide (120 mg/m² daily×3), bleomycin (30 mg weekly) and carboplatin. The carboplatin dose was calculated so as to achieve a constant area under the plasma concentration vs time curve (AUC) of 4.5 mg carboplatin/ml x min by using the formula: dose=4.5×(GFR+25), where GFR is the absolute glomerular filtration rate measured by ⁵¹Cr-EDTA clearance. Carboplatin was given on either day 1 or day 2 of each course and pharmacokinetic studies were carried out in each patient on two courses. Etoposide pharmacokinetics were also studied on two separate courses in each patient on the day on which carboplatin was given and on a day when etoposide was given alone. The pharmacokinetics of carboplatin were the same on both the first and second courses, on which studies were carried out with overall mean ± SD values (n=8) of 4.8±0.6 mg/ml x min, 94±21 min, 129±21 min, 20.1±5.41, 155±33 ml/min and 102±24 ml/min for the AUC, beta-phase half-life (t_1/2), mean residence time (MRT), volume of distribution (Vd) and total body (TCLR) and renal clearances (RCLR), respectively. The renal clearance of carboplatin was not significantly different from the GFR (132±32 ml/min). Etoposide pharmacokinetics were also the same on the two courses studied, with overall mean values ±SD (n=8) of: AUC=5.1±0.9 mg/ml x min, t_1/2=40±9 min, t_1/2=257±21 min, MRT=292±25 min, Vd=13.3±1.31, TCLR=46±9 ml/min and RCLR=17.6±6.3 ml/min when the drug was given alone and AUC=5.3±0.6 mg/ml x min, t_1/2=34±6 min, t_1/2=242±25 min, MRT=292±25 min, Vd=12.5±1.81, TCLR=43±6 ml/min and RCLR=13.4±3.5 ml/min when it was given in combination with carboplatin. Thus, the equation used to determine the carboplatin accurately predicted the AUC observed and the pharmacokinetics of etoposide were not altered by concurrent carboplatin administration. The therapeutic efficacy and toxicity of the carboplatin-etoposidebleomycin combination will be compared to those of cisplatin, etoposide and bleomycin in a randomised trial.     

Population pharmacokinetics of hydroxyurea in cancer patients

 The pharmacokinetics of hydroxyurea (HU) were investigated in cancer patients after intravenous infusion or oral administration. On the basis of the minimal value of the objective function (MVOF) and prior knowledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Michaelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform the nonlinear regression and provide estimates of the population parameters. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (V _max), 0.097 mmol h^-1 l^-1; Michaelis constant for HU elimination (K _M), 0.323 mmol/l; renal clearance (Cl _R), 90.8 ml/min; volume of distribution (V _d), 0.186×(body weight)+25.4 l; absorption rate constant (K _a), 2.92 h^-1; and availability to the systemic circulation (F), 0.792. The principal findings of the investigation are that HU undergoes nonlinear elim- ination in cancer patients and that HU is reasonably well absorbed following oral administration. Received: 13 July 1994/Accepted: 3 August 1994     

Preclinical pharmacology and antitumour activity of the novel sequence-selective DNA minor-groove cross-linking agent DSB-120

 We examined the in vitro cytotoxicity, antitumour activity and preclinical pharmacokinetics of the novel sequence-selective, bifunctional alkylating agent DSB-120, a synthetic pyrrolo[1, 4][2, 1-c]benzodiazepine dimer. DSB-120 was shown to be a potent cytotoxic agent in vitro against a panel of human colon carcinomas [50% growth-inhibitory concentration (IC₅₀) 42±7.9 nM, mean±SE, n=7] and two rodent tumours (L1210 and ADJ/PC6). Antitumour activity was assessed in the bifunctional alkylating-agent-sensitive murine plasmacytoma ADJ/PC6 using a variety of administration protocols. The maximal antitumour eff- ects were observed following a single i.v. dose but the therapeutic index was only 2.6. DSB-120 was less effective when given i.p. either singly or by a daily+5 schedule. After a single i.v. dose at the maximum tolerated dose (MTD, 5 mg kg⁻¹) the plasma elimination was biphasic, with a short distribution phase (t _1/2α 4 min) being followed by a longer elimination phase (t _1/3β 38 min). Peak plasma concentrations were 25 μg ml⁻¹, the clearance was 1.3 ml g⁻¹ h⁻¹ and the AUC_0-∞ was 230 μg ml⁻¹ min. Concentrations of DSB-120 in ADJ/PC6 tumours were very low, showing a peak of 0.4 μg g⁻¹at 5 min. The steady-state tumour/plasma ratio was about 5% and the AUC was only 2.5% of that occurring in the plasma. DSB-120 appeared to be unstable in vivo, with only 1% of an administered dose being recovered unchanged in 24-h urine samples. Plasma protein binding was extensive at 96.6%. In conclusion, the poor antitumour activity of DSB-120 may be a consequence of low tumour selectivity and drug uptake as a result of high protein binding and/or extensive drug metabolism in vivo. Received: 5 November 1995/Accepted: 30 January 1996     

Stereoselective pharmacokinetics of ifosfamide and its 2- and 3-N-dechloroethylated metabolites in female cancer patients

 The pharmacokinetics of the R and S enantiomers of ifosfamide (IFF) and of its 2- and 3-N-dechloroethylated metabolites (2-DCE-IFF and 3-DCE-IFF) were investigated in 14 cancer patients treated with a 3-h infusion of (R,S)-IFF (3 g/m²) with mesna uroprotection. An enantioselective gas chromatographic-mass spectrometric (GC-MS) assay was used to determine the concentrations in plasma and urine. The AUCs of (R)-IFF were significantly larger than those of (S)-IFF (2480±200 vs 1960±150 μM . h). The terminal half-lives (7.57±0.99 h) and mean residence times (11.17±1.10 h) of (R)-IFF were significantly longer than those of (S)-IFF, 6.03±0.82 h and 9.37±0.88 h, respectively. The mean volume of distribution at steady state of (R)-IFF (25.68±0.80 l/m²) was slightly smaller than that of (S)-IFF (27.35±0.89 l/m²). While the renal clearances of (R)-IFF and (S)-IFF were similar, the nonrenal clearance was significantly lower for (R)-IFF (30.20±2.70 vs 41.40±3.55 ml/m² per min) as was total clearance (41.52±2.90 vs 52.37±3.75 ml/m² per min). The AUC values for all of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF with 47% of the measured AUC accounted for by DCE from (S)-IFF compared to only 20% for (R)-IFF. Therefore, the enantioselective difference in IFF elimination can be partially explained by differences in N-dechloroethylation. Received: 13 December 1994/Accepted: 14 May 1995     

Inhibition of etoposide elimination in the isolated perfused rat liver by Cremophor EL and Tween 80

 Cremophor EL, a surfactant used in the clinical formulation of cyclosporine and paclitaxel, will reverse the multidrug resistance (MDR) phenotype in vitro. As other MDR modulators can alter the pharmacokinetics of cytotoxic drugs, the aim of this study was to examine the effect of Cremophor and another MDR-reversing surfactant, Tween 80, on the hepatic elimination and biliary excretion of etoposide. Using the isolated perfused rat-liver model with 80 ml recirculating perfusate containing 20% red blood cells and 4% bovine serum albumin, etoposide (1.6 mg) with and without Cremophor (800 or 80 mg) or Tween 80 (80 mg) was given into the perfusate reservoir, and perfusate and bile samples were collected for 3 h. Etoposide was measured by high-performance liquid chromatography (HPLC) and Cremophor was measured using a bioassay. Both surfactants changed the etoposide elimination profile from biphasic to monophasic. High-dose Cremophor increased the AUC (from 334±23 to 1540±490 μg min ml^-1, P<0.05) and decreased the total clearance (from 4.8±0.3 to 1.1±0.3 ml/min, P<0.05) and biliary clearance (from 2.6±1.1 to 0.5±0.2 ml/min, P<0.05) but decreased the elimination half-life (from 62±17 to 40±5 min, P<0.05) and volume of distribution (from 424±85 to 65±19 ml, P<0.05). Low-dose Cremophor and Tween 80 caused intermediate effects on these parameters that were statistically significant for total clearance, half-life, and volume of distribution. Cremophor had no adverse effect on liver function, whereas Tween 80 caused haemolysis and cholestasis. The initial high-dose Cremophor perfusate concentration was 0.8 mg/ml, which previous studies have shown to be clinically relevant and close to the optimal level for MDR reversal in vitro (1.0 mg/ml). Cremophor may be a clinically useful MDR modulator, but it may alter the pharmacokinetics of the cytotoxic drug. Received: 5 January 1995/Accepted: 25 August 1995