A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen

Purpose: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. Methods: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model), in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin-thiotepa-cyclophosphamide combination). Results: The measured mean AUC in our population was 4.1 min · mg/ml (median 3.9, range 1.9–6.3, SD 1.0 min · mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min · mg/ml (median 4.2, range 2.4–8.4, SD 1.2 min · mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. Conclusion: Although easy and attractive to use, the Ghazal-Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations. Received: 15 April 1998 / Accepted: 3 September 1998     

Carboplatin pharmacokinetics in young children with brain tumors

 Purpose: The pharmacokinetic parameters and maximal tolerated systemic exposure were determined for carboplatin in young children given in combination with cyclophosphamide and etoposide. Patients and methods: Carboplatin was administered as part of a multiagent chemotherapy regimen to 21 pediatric patients less than 5 years of age with newly diagnosed, malignant central nervous system tumors. Patients received cyclophosphamide, 1.2 g/m², on day 1 and carboplatin on day 2 followed by etoposide, 100 mg/m², each day. Carboplatin doses were calculated to achieve a targeted area under the serum concentration versus time curve (TAUC) of 5, 6.5 or 8 mg/ml . min based on each patient’s measured glomerular filtration rate (GFR). Carboplatin pharmacokinetic parameters were determined after course 1 and then after every third course of therapy. Results: The median carboplatin clearance and GFR after course 1 were 118 and 98 ml/min per m², respectively. Targeted doses based on measured GFR reliably achieved the TAUC for carboplatin. The median (range) carboplatin clearance for four children less than 1 year of age was 76 (66–84) ml/min per m², significantly lower (P=0.05) than the value of 131 (80–158) ml/min per m² for children from 1 to 4 years of age. The mean carboplatin clearance declined by 23% in 12 patients studied from course 1 to course 4 of therapy. The decrease was greater than 20% (range 20–53%) in 7 of the 12 patients studied. Conclusion: Carboplatin clearance for children aged between 1 and 4 years at diagnosis is approximately 45% higher than previously reported for pediatric patients, but declines after four courses of therapy. For children less than 1 year of age, carboplatin clearance per square meter is approximately 40% lower than patients 1 to 4 years of age. There are corresponding differences in GFR that provide a plausible explanation for the age and therapy-related changes in carboplatin clearance. Toxicity was acceptable for patients treated at a TAUC of 6.5 mg/ml . min for carboplatin given with etoposide and cyclophosphamide. The average carboplatin dose required for this AUC was 767 mg/m². Received: 13 July 1995/Accepted: 18 December 1995     

A phase I study of carboplatin and etoposide administered in conjunction with dipyridamole, prochlorperazine and cyclosporine A

Purpose: In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. Methods: Patients received intravenous VP-16 (200 mg/m²) and CBDCA (300 mg/m²), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. Results: A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m² (range 0.8–1.5 l/h per m²), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml · min (range 2.4–4.8 mg/ml · min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 μM (range 0.5–2.2 μM) and 4.4 μM (range 1.3–5.9 μM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 μM (range 0.004–0.04 μM). The median CSA level at 24 h of 1450 μg/l (range 1075–1640 μg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. Conclusion: These results demonstrate that in vitro DR- reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16. Received: 2 September 1999 / Accepted: 25 April 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 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.     

Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK 611 A study by the AIO groups PHASE-I and APOH

 NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity. A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m² [maximum tolerated dose (MTD) 120 mg/m²] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parantheses): mean residence time (MRT) 16.5 (5.4– 42.3)h, terminal half-life 14.0 (8.2–30.5)h, volume of distribution at steady state (V_ss) 11.4 (7.9–18.1) l/m², and plasma clearance (Cl_p) 15.1 (3.6–36.4) ml min^-1 m ^-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 μg ml^-1 h. The mean AUC (±SD) increased with the dose from 78.7±3.7 μg ml^-1 h at 60 mg/m² up to 202.8±157.2 μg ml^-1 h at 120 mg/m². The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and 25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx. 99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUC_free. The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be investigated in further studies. Received: 8 May 1995/Accepted: 27 October 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     

A phase I trial of carboplatin and etoposide for elderly (≥75 year-old) patients with small-cell lung cancer

Purpose: The combination of carboplatin and etoposide is currently considered the most appropriate regimen for treating elderly patients with small-cell lung cancer (SCLC). Previous reports on elderly patients, 70 years or older, found that the recommended dose was close to that of younger patients. Then, we conducted a phase I study of carboplatin and etoposide in elderly patients, 75 years or older, with SCLC. This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Methods: Twenty-six patients fulfilling the eligibility criteria, chemotherapy-naive, performance status (PS) of 0–2, age ≥75, and adequate organ functions were enrolled. Patients’ characteristics were: male/female=21/5; PS 0/1/2=9/11/6; median age (range)=78 (75–82); and limited/extensive stage=16/10. The patients intravenously received carboplatin with a target AUC of 4 or 5 mg min/ml (Chatelut formula) on day 1 and etoposide at 80–120 mg/m² on days 1, 2 and 3. Therapy was repeated four times in every 4 weeks. Results: The MTD of carboplatin/etoposide was AUC=5/80, 4/110, and 4/120. The DLTs were thrombocytopenia, neutropenia, leukopenia, and febrile neutropenia. Overall, grade 4 thrombocytopenia, neutropenia (≥4 days), leukopenia (≥4 days), and febrile neutropenia occurred in 27, 20, 7, and 13% of cases at MTD levels, respectively, and 0% at other levels. Twenty of 26 patients showed objective responses (2CR, 18PR; RR=77%). Conclusion: A dose of carboplatin of AUC=4 and etoposide of 100 mg/m² was recommended in this regimen.The authors indicated no potential conflicts of interest.     

Pharmacokinetics of carboplatin administered in combination with the bradykinin agonist Cereport (RMP-7) for the treatment of brain tumours

Introduction: Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood–brain barrier (BBB). In order to investigate the pharmacokinetics of carboplatin in combination with Cereport, we performed pharmacological studies in conjunction with early clinical trials. Methods: Pharmacokinetic samples were collected from eight patients in a phase I study (Cereport 100–300 ng/kg) and ten patients in a phase II study (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were compared with respect to the dose of Cereport and with historical controls. Results: Cereport combined with carboplatin was well-tolerated, with mild haematological toxicities consistent with the target area under the concentration–time curve (AUC) of 7 mg/ml*min. Although the clearance of carboplatin was within the range reported for this drug alone, the addition of Cereport resulted in a higher than expected carboplatin AUC. This effect was related to the dose of Cereport in the phase I study (AUC values 104–133% of target, Spearman rank correlation coefficient=0.71, P < 0.001). The higher than expected AUC value was confirmed in the phase II study (AUC values 106–189% of target). Conclusions: Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation. Received: 12 April 1999 / Accepted: 9 September 1999     

Phase II trial of a 2-h infusion of gemcitabine plus carboplatin as first-line chemotherapy for advanced non-small-cell lung cancer

Purpose: To evaluate the efficacy and safety of the combination of using gemcitabine as a rate infusion of 10 mg/m² per min with carboplatin in front-line chemonaive patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Fifty-four chemonaive patients with stage IIIB or IV NSCLC have been included, 44 males and 10 females, with a median age 63 years (range 19–75). Thirty-two (59%) patients had adenocarcinoma, 13 (24%) squamous cell, 1 (2%) large cell carcinoma and 8 (15%) others. Eight (15%) had stage IIIB and 46 (85%) stage IV. Treatment was consisted of 1,200 mg/m² gemcitabine given as a 2-h continuous infusion (10 mg/m² per min) on days 1 and 8 of each cycle an AUC 5 carboplatin as on day 1, repeating each cycle for every 21 days. A total of 223 chemotherapy cycles were administered, with a median of four cycles per patient (range 1–6), and 15 (28%) patients received all six cycles. Results: Of the 54 patients enrolled, all were evaluated for toxicity and 51 assessed for response. The overall response rate was 41% (95% confidence interval, 28–57%) with complete and partial responses of 4 and 37%, respectively. The median time to disease progression was 5.0 months (95% CI, 3.7–6.3 months), and median overall survival time was 11.5 months (95% CI, 9.9–13.1 months). One-year survival was 42%. The main grade 3–4 toxicity (according to the WHO scale) consisted of neutropenia (56%) and thrombocytopenia (57%). Patients were required platelet transfusion in 27 cycles (12%) and hematopoietic growth factors support care in 56 (25%) cycles. No bleeding episodes were recorded. Grade 3 nausea/vomiting occurred in 6% and grade 1–2 skin rash occurred in 43%. Conclusions: Prolonged gemcitabine infusion combined with carboplatin is manageable and tolerated, and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment.     

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     

Plasma concentrations of polysorbate 80 measured in patients following administration of docetaxel or etoposide

 Docetaxel (Taxotere, Rhone-Poulenc Rorer) and etoposide are water-insoluble drugs formulated with polysorbate 80 for intravenous administration. We have previously reported that surfactants, including polysorbate 80 and Cremophor EL, can reverse the multidrug resistance (MDR) phenotype in an experimental system and that plasma Cremophor EL concentrations measured following a 3-h infusion of paclitaxel were ≥1 μl/ml, sufficient to modulate MDR in vitro. The purpose of this study was to measure polysorbate 80 plasma concentrations in patients following intravenous administration of etoposide or docetaxel using a bioassay in which MDR-expressing cells are incubated with daunorubicin (DNR) plus 50/50 growth medium/plasma and equilibrium intracellular DNR fluorescence is measured by flow cytometry. In vitro experiments show maximal reversal of MDR at concentrations of 1.0–2.0 μl/ml and 50% reversal at 0.2–0.3 μl/ml. Patients received docetaxel at 75 mg/m² (five patients) or 100 mg/m² (four patients) (total dose 125–178 mg, containing 3.12–4.45 ml polysorbate 80) over 60 min. The median end-infusion polysorbate 80 concentration was 0.1 μl/ml (range 0.07–0.41 μl/ml). Only one patient had a level of >0.2 μl/ml. Five patients received intravenous etoposide at 120 mg/m² over 45–120 min (total dose 180–250 mg, containing 0.67–0.93 ml polysorbate 80). In the end-infusion plasma sample, polysorbate 80 was not detectable (<0.06 μl/ml) in any patient. Plasma polysorbate 80 levels following an intravenous infusion of 120 mg/m² etoposide or of docetaxel at doses used in Phase II trials, are insufficient to show modulation of MDR in vitro. Received: 21 July 1996 / Accepted: 4 November 1996     

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     

Quantitative relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-time curve (AUC) as the major toxicodynamic determinant in vivo

 Purpose: The major pharmacokinetic parameters of unchanged cisplatin (CDDP) related to nephrotoxicity were evaluated in rats in vivo using a pharmacodynamic model. Methods: CDDP was administered according to various dosing schedules (single bolus, intermittent bolus, or continuous infusion). Unchanged CDDP in plasma and urine was quantified using high-performance liquid chromatography (HPLC). The pharmacokinetics were assessed by model-independent methods. The relationship between pharmacokinetics and BUN levels was evaluated using a sigmoid maximum response (E_max) model. Results: Unchanged CDDP showed linear pharmacokinetics after single bolus injections of 1 to 5 mg/kg CDDP. Nephrotoxicity was ameliorated following intermittent bolus injection (1 mg/kg per day for 5 days) and continuous infusions (over 2 and 3 h) of the same CDDP doses (5 mg/kg), although these dosing schedules did not change the area under the concentration-time curve (AUC), total clearance (Clt), urinary excretion of unchanged CDDP or kidney platinum levels significantly. The maximum BUN level, as a nephrotoxicity marker, showed dose-related increases after single bolus injection of 1 to 5 mg/kg CDDP and after 3-h infusion of 5 to 25 mg/kg. The pharmacodynamic relationship between the maximum BUN level and C_max and between the maximum BUN level and AUC were apparently different between single bolus injection and 3-h infusion. The maximum BUN level was related to the AUC calculated by plasma concentrations of unchanged CDDP greater than the threshold level (AUC_>Cmin), a relationship most successfully described by the signoid E_max model, regardless of CDDP dose and schedule. The plasma threshold level of unchanged CDDP was determined as 0.9 μgPt/ml in rats. Conclusions: The present results substantiated the importance of C×T (AUC) value as an indicator of CDDP-induced nephrotoxicity in vivo as well as of tumor cell-killing effect of CDDP in vitro. The AUC_>Cmin of unchanged CDDP was found to be an important pharmacokinetic parameter predicting CDDP nephrotoxicity. Received: 12 February 1996 / Accepted: 5 September 1996     

Combination chemotherapy of carboplatin and gemcitabine against solid tumors: a phase I trial

Background. Some trials have suggested that the combination of gemcitabine and platinum compounds can have a synergistic effect on several solid tumors, but, at present, the data concerning carboplatin-gemcitabine combinations are not sufficient to allow the planning of phase II trials. The present phase I trial was planned to define the maximum tolerated dose and the dose-limiting toxicity of a carboplatin-gemcitabine combination. Methods. Thirty-two patients with advanced, pretreated solid tumors were treated with carboplatin on day 1 and gemcitabine on days 1, 8, and 15 every 28 days. The starting doses of carboplatin and gemcitabine were 3.5 mg/ml per min (area under the curve; AUC), and 600 mg/m², respectively. The doses of the two agents were alternately increased to 4, 4.5, and 5 mg/ml per min and to 800 and 960 mg/m², respectively. At each dose level, three patients were initially enrolled. If one of them experienced grade IV hematological toxicity or grade III–IV nonhematological toxicity (with the exception of alopecia), an additional three patients were enrolled at the same dose level. If two or more patients experienced grade IV hematological toxicity or grade III–IV non-hematological toxicity (with the exception of alopecia), the maximum tolerated dose was considered to have been reached, and the dose below this was recommended for further studies. All patients were evaluated weekly for toxicity and after every two courses of chemotherapy for response. Results. Dose-limiting toxicity was hematological, and the maximum tolerated doses were 4.5 mg/ml per min for carboplatin and 800 mg/m² for gemcitabine. The activity of the carboplatin/gemcitabine combination was encouraging, with a 21.9% response rate (7/32), three complete disease regressions, and a median time to progression of 30 weeks. The gemcitabine doses of day 15 or days 8 and 15 were omitted for hematological toxicity in 57 (50%) and 17 (14.9%) courses of chemotherapy, while no courses of chemotherapy were delayed for grade III–IV hematological or nonhematological toxicity. Conclusion. The maximum tolerated doses suggested by this trial are lower than those in other similar phase I trials, but they are consistent with those reported by most of the trials investigating gemcitabine either in combination with cisplatin or in heavily pretreated patients. Carboplatin 4.5 mg/ml per min on day 1 plus gemcitabine 800 mg/m² on days 1, 8, and 15 every 28 days may represent a promising schedule for further phase II trials. Received: January 29, 2001 / Accepted: September 13, 2001     

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     

Difference in CDDP penetration into CSF between selective intraarterial chemotherapy in patients with malignant glioma and intravenous or intracarotid administration in patients with metastatic brain tumor

 Platinum (Pt) levels in plasma and cerebrospinal fluid (CSF) in patients with malignant glioma were determined after initiation of selective intraarterial chemotherapy with a combination of VP-16 (etoposide) and CDDP (cisplatin), and were compared with the CSF Pt levels in patients with metastatic brain tumors after intravenous or intracarotid administration of VP-16 and CDDP. CSF Pt levels were also compared for various administration routes, doses, CSF sampling routes and blood–CSF barriers in metastatic brain tumor. Changes in the blood-CSF barrier to CDDP during treatment in a patient with meningeal lymphoma and in a patient recovering from surgical removal of a metastatic brain tumor were also examined by periodic administration of CDDP. All CSF samples were taken through Ommaya reservoirs placed in the anterior horn of the lateral ventricle or the postoperative cavity. The mean peak CSF/plasma total Pt ratio (T/T ratio) and the mean CSF total Pt/plasma ultrafiltrable Pt ratio (T/U ratio) were highest (15.0% and 24.4%, respectively) following selective intraarterial infusion of CDDP in patients with malignant glioma, followed by intravenous infusion in meningeal carcinomatosis (11.5% and 18.9%), intracarotid administration (5.4% and 8.7%) and intravenous infusion (60 mg/m² 2.5% and 100 mg/m² 2.9%; and 60 mg/m² 3.5% and 100 mg/m² 7.7%) in patients with the solid type of metastatic brain tumor. In CSF obtained from the postoperative cavity in cases of metastatic brain tumor, T/T and T/U ratios were extremely high (40.9% and 62.4%). However, the CSF Pt level even after selective intraarterial administration of CDDP in malignant glioma was 0.51–1.64 μg/ml total Pt and 0.43–1.08 μg/ml ultrafiltrable Pt. Even the CSF level obtained from the postoperative cavity was 1.0–4.7 μg/ml total Pt. These low levels of total and ultrafiltrable Pt are considered not to be cytotoxic to disseminated cells in the CSF space and to normal brain cells. As for changes in the blood–CSF barrier, repeated administration of CDDP showed that the rate of entry of Pt into the CSF decreased in parallel with improvements apparent on CT scans in the patient with meningeal lymphoma, and also showed that the blood–CSF barrier to Pt was gradually repaired after the metastatic brain tumor had been removed. Received: 20 June 1994/Accepted: 14 May 1995     

A limited sampling strategy for estimation of the cladribine plasma area under the concentration versus time curve after intermittent i.v. infusion,s.c. injection,and oral administration

 Cladribine is a newly developed antimetabolite with promising activity in lymphoproliferative disorders. Recent pharmacokinetics investigations have suggested that there is a relationship between its plasma area under the concentration versus time curve (AUC) and the degree of neutropenia posttreatment as well as the therapeutic outcome in hairy-cell leukemia. To enable a simple estimation of the plasma AUC, a limited sampling strategy was developed. Stepwise linear regression was used to determine which were the most important data points for estimation of the plasma AUC after 2-h i.v. infusion, s.c. injection (5 mg/m²), and oral administration (10 mg/m²) in 27 patients. The most important data points after i.v. infusion in 12 patients were 1, 4, and 24 h, in order of importance. The AUC could be estimated as 2.9081×C _1h ⁺5.1851×C _4h ⁺20.3265×C _24h .The accuracy and precision (mean value±SD for the determined/estimated AUC was 0.99±0.053) of the model could not be increased by the addition of more data points. A somewhat lower accuracy and precision (0.96± 0.089) was seen with the 2-, 4-, and 24-h data points. These were used to test the regression technique prospectively for the estimation of the AUC after i.v. administration in another set of 10 patients. The accuracy and precision of the estimation of the AUC was similar in this group (1.01±0.109). In all, 11 patients were treated orally (10 mg/m²) and 10 patients were treated by s.c. injection (5 mg/m²). The most important data points for estimation of the AUC were 2.5, 24, and 0.5 h after oral administration (AUC=0.8630×C _0.5 h+ 4.2337×C _2.5h ⁺45.4364×C _24h ) and 9, 1, and 16 h after s.c. injection (AUC=1.8821×C _1h +16.4256×C _9h ⁺ 25.4518×C _16h ). The accuracy and precision were 1.01±0.064 after oral dosing and 0.99±0.11 after s.c. injection. The derived mathematical models are reliable for estimation of the plasma AUC of cladribine after 2-h i.v. infusion, oral administration, and s.c. injection. Received: 8 October 1995/Accepted: 1 March 1996     

Relationship between calculated carboplatin area under the curve, using the Cockcroft-Calvert formula and the Chatelut formula, and thrombocytopenia induced by intraperitoneal carboplatin in combination with intravenous cyclophosphamide

Background. There is no standard formula to estimate doses for the intraperitoneal (IP) administration of carboplatin. We evaluated a combination of the Cockcroft and the Calvert (Cockcroft-Calvert) formula to determine the area under the curve (AUC) for IP carboplatin co-administered with intravenous (IV) cyclophosphamide (CPM). We also evaluated the correlation of carboplatin clearance determined by the Chatelut formula with carboplatin clearance determined by the Cockcroft-Calvert formula. Methods. We performed a retrospective study of the records of 149 treatments in 30 patients who received IP carboplatin and IV CPM for ovarian carcinoma. The glomerular filtration rate was calculated with the Cockcroft formula. Carboplatin doses were determined based on the body surface area. The Cockcroft-Calvert formula was used to calculate the AUC. The Chatelut formula was also used to calculate the clearance of carboplatin and the AUC. Results. The AUC calculated with the Cockcroft-Calvert formula was well correlated to the AUC calculated with the Chatelut formula (r ² = 0.965). During the first four courses of IP carboplatin combined with IV CPM (300–500mg/m²), the correlation between the percent decrease in platelet count and the calculated carboplatin AUC varied among methods: Cockcroft-Calvert formula AUC:r ² = 0.460; Chatelut formula AUC:r ² = 0.431; body surface area dose:r ² = 0.204; total dose:r ² = 0.143. Conclusion. To decrease patient platelet count by 67%, the optimal target AUC following IP administration of carboplatin in combination with 300–500mgCPM/m²IV was calculated as 6.5, using the Cockcroft-Calvert formula, and as 7.5, using the Chatelut formula. Considerable modification of the IP carboplatin dose is required after the fourth course. A prospective study is ongoing to confirm these results.     

Development and validation of a chiral high-performance liquid chromatography assay for rogletimide and rogletimide-N-oxide isomers in plasma

 The purpose of the present study was to develop and validate a stereo-specific high-performance liquid chromatography (HPLC) assay for rogletimide (Rog) and rogletimide-N-oxide (Nox) isomers in plasma. The assay was performed with a chiral cellulose-[4-methylbenzoate]ester column (Chiracel OJ). Optimal separation was achieved isocratically with a mobile phase consisting of n-hexane/anhydrous ethanol (65/35, v/v) at a flow rate of 0.9 ml/min, with the column being thermostated at +35°C (UV detection at 257 nm). Under these conditions, retention times were approximately 17, 28, 31 and 76 min for R-Rog, S-Rog, R-Nox and S-Nox, respectively. S-aminoglutethimide (S-Ag) served as the internal standard (retention time 70 min). An extraction procedure from plasma samples was developed on Bond Elut RP8 500-mg cartridges; conditioning was performed with 5 ml methanol and 5 ml water, after which 1 ml plasma that had previously been spiked with 5 μM S-Ag was applied. Washing was done with 6 ml water and elution, with 4 ml methanol. After evaporation to dryness, residues were dissolved in 400 μl anhydrous ethanol and 12–48 μl was injected onto the HPLC system. Blank plasma from healthy donors showed the random presence of a small interference eluting at the retention time of R-Rog, precluding the accurate quantification of R-Rog concentrations below 2.5 μM. Reproducibility assays demonstrated the need to use an internal standard. Taking into account the internal standard, at 2.5 μM the intra- and inter-assay coefficients of variation were 10.5% and 21.0% for R-Rog, 5.5% and 8.7% for S-Rog, 7.6% and 20.8% for R-Nox and 11.7% and 6.4% for S-Nox, respectively. The detection limit was 2.5 μM for R-Rog, 0.5 μM for S-Rog, 0.25 μM for R-Nox and 0.5 μM for S-Nox. Linearity was satisfactory at concentrations ranging from 2.5 to 10 μM for R-Rog, from 0.5 to 10 μM for S-Rog, from 0.25 to 2.5 μM for R-Nox and from 0.50 to 2.5 μM for S-Nox. This assay was applied to plasma obtained from rogletimide-treated breast cancer patients receiving conventional oral doses and demonstrated its feasibility with regard to sensitivity. The preliminary pharmacokinetic results reported herein suggest for the first time that both the R-Rog and S-Rog isomers are metabolized into rogletimide-N-oxide. Received: 26 July 1995/Accepted: 25 January 1996