Busulfan disposition and hepatic veno-occlusive disease in children undergoing bone marrow transplantation

Hepatic veno-occlusive disease (HVOD) is a frequent life-threatening toxicity in patients undergoing bone marrow transplantation (BMT) after the administration of a high-dose busulfan-containing regimen. Recent studies have shown that the morbidity and mortality of HVOD may be reduced in adults by pharmacologically guided dose adjustment of busulfan. We analyzed the pharmacodynamic relationship between busulfan disposition and HVOD in 61 children (median age, 5.9 years) with malignant disease. Busulfan, given at a dose ranging from 16 mg/kg to 600 mg/m², was combined with one or two other alkylating agents (cyclophosphamide, melphalan, thiotepa). Only 3 patients received the standard busulfan/cyclophosphamide (BUCY) regimen. A total of 24 patients (40%) developed HVOD, which resolved in all cases. A pharmacokinetics study confirmed the previously reported wide interpatient variability in busulfan disposition but did not reveal any significant alteration in children with HVOD. The mean area under the concentration-time curve (AUC) after the first dose of busulfan was higher in patients with HVOD (6,811±2,943 ng h ml^–1) than in patients without HVOD (5,760±1,891 ng h ml^–1;P=0.10). This difference reflects the higher dose of busulfan given to patients with HVOD. No toxic level could be defined and, moreover, none of the toxic levels identified in adults were relevant. The high incidence of HVOD in children given 600 mg/m² busulfan may be linked to the use of more intensive than usual high-dose chemotherapy regimens and/or drug interactions. Before the prospective evaluation of busulfan dose adjustment in children, further studies are required to demonstrate firmly the existence of a pharmacodynamic relationship in terms of toxicity and allogeneic engraftment, especially when busulfan is combined with cyclophosphamide. The maximal tolerated and minimal effective AUCs in children undergoing BMT are likely to depend mainly upon the disease, the nature of the combined high-dose regimen, and the type of bone marrow transplant.     

Dosing of thioTEPA for myeloablative therapy

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

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.     

Population pharmacokinetics of oral busulfan in children

Purpose To characterize the population pharmacokinetics of oral busulfan in 48 children including pooled data from three transplantation centres with the aim of estimating the variability in the kinetics of busulfan and to identify covariates that could be used for dose calculation.Methods A total of 508 plasma samples from 250 administrations (mean 9 samples per patient over 4 days of treatment) were collected from 48 children receiving busulfan orally every 6 h. The dosing varied between 13 and 20 mg/kg with seven patients receiving a dose of 600 mg/m². The busulfan formulations administered varied considerably. They included 2-mg tablets (Myleran), gelatine capsules, crushed tablets suspended in water and suspension for administration via nasogastric tube. Samples were analysed for busulfan either by HPLC using postcolumn photolysis or by LC-MS. Plasma concentration-time data were analysed by population pharmacokinetic modelling using NONMEM.Results Busulfan kinetics were best described by a one-compartment model (subroutine ADVAN 2 TRANS 2). Residual variability was modelled using a combined additive and proportional error model. The influence of different covariates on the pharmacokinetic parameters was tested. The best results were obtained by inclusion of body surface area (BSA) as a covariate for clearance (Cl/F) and volume of distribution (V/F). The final population estimates were: Cl/F 4.13 l/h per m² ±26%, V/F 21.3 l/m² ±31% and ka 1.31 h^–1 ±110% (population mean ± interindividual variability, IIV). Variability in one patient during the 4 days of treatment (interoccasion variability, IOV) for Cl/F (10%) and V/F (19%) were calculated to be less than interindividual variability, fulfilling the condition for individualization of busulfan dosage regimens.Conclusions In our paediatric population, BSA, not body weight, is the best predictor of Cl/F and V/F. Our final estimations reflect the wide interpatient variability after oral administration of busulfan with an IIV for ka of 110%.     

Disposition of total and unbound etoposide following high-dose therapy

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

Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics

The pharmacokinetics of high-dose busulphan was studied in 17 patients during conditioning prior to bone marrow transplantation using deuterium-labeled busulphan (d₈-BU). About 50% of busulphan doses 1 and 16 was replaced with d₈-BU. Patients were treated with phenytoin or diazepam as prophylactic anticonvulsant therapy. Patients who received phenytoin demonstrated significantly higher clearance (mean ±SD, 3.32±0.99 ml min^–1 kg^–1), a lower area under the concentration-time curve (AUC, 5,412±1,534 ng h ml^–1; corrected for dose/kilogram) and a shorter elimination half-life (3.03±0.57 h) for the last dose of d₈-BU (dose 16) as compared with the first dose (2.80±0.78 ml min^–1 kg^–1, 6,475±2,223 ng h ml^–1 and 3.94±1.10 h, respectively). No difference in the above-mentioned pharmacokinetic parameters was seen in patients treated with diazepam. Moreover, a continuous decrease in the steady-state level of busulphan was observed in four of seven patients in the phenytoin-treated group, whereas in the diazepam group, such a decrease was seen in only one of eight patients. We conclude that phenytoin used as prophylactic anticonvulsant therapy alters busulphan pharmacokinetics and, most probably, its pharmacodynamics. For adequate prophylactic therapy, anticonvulsants with fewer enzyme-inductive properties than phenytoin should be used.Abbreviations AML acute myelocytic leukaemia - ALL acute lymphocytic leukaemia - MDS myelodysplastic syndrome - ABMT autologous bone marrow transplantation - BMT allogeneic bone marrow transplantation This work was supported by a grant from the Swedish Cancer Society (2805-B90-01X)     

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     

Continuous vincristine infusion as part of a high dose chemoradiotherapy regimen: drug kinetics and toxicity

Summary A 5-day continuous infusion of vincristine (VCR; total dose 4 mg/m²) has been given as part of a high-dose chemoradiotherapy regimen with bone marrow transplantation. Evidence of neurotoxicity, such as weakness, paraesthesia and intestinal hypomotility, was evaluated prospectively in nine patients. Five patients had advanced neuroblastoma and four, relapsed sarcomas, and all had responded to initial conventional-dose therapy. VCR was combined with high-dose melphalan (180 mg/m²) and fractionated total-body irradiation. Plasma concentrations of VCR were measured by radioimmunoassay during and up to 24 h after the infusion. Serum and urine electrolytes and liver function tests were measured during VCR treatment and at regular intervals thereafter. VCR concentration at 1 h ranged from 1.8 to 10.9 (median 6.6) ng/ml, and a steady state was achieved by 13–30 h (median 16 h). Levels above 1 ng/ml were maintained throughout the 5-day period with a mean steady-state concentration of 1.7 ng/ml (range 1.3–2.15). After cessation of the infusion, serum concentrations fell to below 0.25 ng/ml within 24 h. Abdominal pain occurred in one patient, but neither constipation nor ileus was seen. In two patients severe muscle pain occurred in the lower limbs towards the end of the infusion. Significant electrolyte problems did not occur and, in particular, there was no evidence of inappropriate ADH secretion. Transient increases in liver enzymes were common but bilirubin was not elevated during the period of monitoring. This regimen allows a two-fold escalation in the dose of VCR to be administered, producing sustained high serum drug levels without major toxicity.     

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.     

Low dose oral administration of 4-demethoxy-daunorubicin (idarubicin) in advanced cancer patients

Summary Data relating to 4-demethoxydaunorubicin (DMDR) pharmacokinetics after oral administration (10–15 mg/m² per day for 3 days) were collected in a total of 12 patients with advanced breast cancer and melanoma.Drug absorption took place in the first 2–4 h after administration. Plasma levels of the reduced metabolite DMDRol were higher than those of the parent compound: Peak levels were 4–10 ng/ml for DMDR and 15–40 ng/ml for DMDRol. The dose-corrected area under the timeconcentration curve (AUC) was consequently higher for DMDRol (12.3–74.7, mean 32.6 vs 2.4–7.4, mean 4.6 ng/ml.mg for DMDR).Apparent plasma terminal half-lives after the last dose administered were in the range of 13–36 (mean 23.7) h for DMDR and 30–81 (mean 58.9) h for DMDRol.Drug and the reduced metabolite accumulated in the blood cells; the ratio of AUC (blood) to AUC (plasma) was 1.40–3.75 (mean 2.80) for DMDR and 1.29–3.50 (mean 2.16) for DMDRol.The biliary excretion of the drug and of the fluorescent metabolites was studied in two additional patients with extrahepatic obstruction and percutaneous biliary drainage. In the first 7 days of therapy, biliary excretion (DMDR + DMDRol) accounted for 3.7%–4% of the administered dose.In contrast to our observations with doxorubicin and epirubicin, urinary excretion seems very likely to be more important for this drug than biliary excretion. In these patients urinary excretions were 2.2, 2.9 times (for DMDR) and 1.2, 3.4 times (for DMDRol) the biliary excretion.Supported in part by contract CNR, n.84.00710.44 (Progetto Finalizzato Oncologia, Italian National Council of Research)     

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

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

Cisplatin disposition in children and adolescents with cancer

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

A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy

Cancer is often associated with abnormal activation of coagulation leading to a prothrombotic state. Some chemotherapeutic agents used for cancer may induce thrombosis but their biological alterations in the hemostatic system are not yet well understood. This study evaluated alterations of coagulative and fibrinolytic parameters following chemotherapy.In plasma samples of 38 patients (median age: 49 years) receiving CMF (schedule 1–21 or 1–8) for Stage II breast cancer, we evaluated: PT, aPTT, antithrombin III (AT-III), protein C (PC), protein S (PS), thrombinantithrombin complex (TAT), prothrombin fragment F1 + 2 (F1 + 2), fibrinogen (Fbg), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI - 1) and D-dimer (D-D). PT, aPTT, and Fbg were determined with routine methods; AT-III, PC, and PS were measured with coagulative tests; PC and PS were also evaluated with immunoenzymatic methods. t-PA, PAI-1, D-D, TAT, and F 1 + 2 were measured with immunoenzymatic methods. All tests were performed immediately before starting therapy and after each cycle.A PC antigen decrease appeared soon after beginning therapy and lasted throughout chemotherapy. The lowest values were present after the first treatment both in the CMF 1–21 group (mean ± SD = 72.5 ± 10.8%) and in the CMF 1–8 group (mean ± SD = 77.2 ± 6.9%); PC activity was also decreased. PS antigen decreased after the first administration (mean ± SD = 73.3 ± 10% in CMF 1–21 group, and 72.5 ± 4.9% in CMF 1–8 group); PS activity also decreased. PAI-1 antigen levels increased (mean ± SD = 43.1 ± 20.4 ng/ml in the CMF 1–21 group, and 37.5 ± 12.2 ng/ml in CMF 1–8 group) lasting up to the last cycle.CMF provokes a trend toward hypercoagulability; this effect should be considered when chemotherapy is employed in advanced cancer patients at high risk for thrombosis, or in patients with other risk factors.C.R. is a recipient of a fellowship from the Italian Association for Cancer Research (A.I.R.C.)     

Proteinuria due to suboptimal hydration with high-dose methotrexate therapy

One of the major complications after high-dose methotrexate (HDMTX) infusions is renal damage. We investigated the occurrence of proteinuria after HDMTX administration in children with pediatric malignancies (acute lymphoid leukaemia, osteosarcoma Burkitt's lymphoma). In the period 1989–1990 we gave 52 HDMTX courses to 24 children. During this period, prehydration and extra urinary alkalisation were performed only if the urinary specific gravity was over 1010 or if the urinary pH fell below 7. Using this schedule the mean values obtained for protein extraction were: before the therapy, 0.12±0.03 g/m²; on day 1 after MTX treatment, 0.38±0.06 g/m²; and on day 2 after the MTX infusion, 0.39±0.11 g/m² (P<0.01). A significant increase in proteinuria (>0.2 g/m² post- vs pretreatment) was detectable in 54% of the patients. In the period 1991–1992 we modified the hydration-alkalisation schedule to include i. v. prehydration for 18–24 h at 3 l/m²/day with a 0.45% NaCl-5% glucose solution along with sodium bicarbonate and posthydration for 72 h with the same solution. On this protocol the mean values determined for the urinary protein content were all in the normal range (pretreatment, 0.03 g/m²/day; day 1, 0.05 g/m²/day; and day 2, 0.08 g/m²/day). These findings were significantly different from the previous results (P<0.05).     

Bayesian estimation of doxorubicin pharmacokinetic parameters

Summary Doxorubicin was given by brief i.v. infusion (doses ranging from 25 to 72 mg/m²) to 28 patients for 2–7 successive courses of chemotherapy (68 courses studied in all). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of doxorubicin. Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 19 patients and a total of 30 courses, which, when combined with 4 individual plasma concentrations of drug, led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 38 courses. The estimated parameters for the elimination phase (A₃/V₁ andt1/2 elimination) and the residual plasma level at 48 h as computed by Bayesian estimation on this reduced sub-optimal sampling protocol were compared with a maximal likelihood estimation of these parameters. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean errors were –0.0315×10^–4 l^–1 for A₃/V₁, 0.0839 h fort1/2 elimination, and –0.22 ng/ml forc _{(48 h)}. The precision of the prediction of these three parameters (0.304×10^–5 l^–1, 3.34 h, and 0.659 ng/ml, respectively) remained lower than the interindividual standard deviation (1.42×10^–4 l^–1, 14.9 h, and 4.54 ng/ml, respectively). This procedure enables the estimation of individual pharmacokinetic parameters for doxorubicin at minimal cost and minimal disturbance of the patient.     

A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission

Purpose: To prospectively determine the efficacy of repeated high-dose alkylating chemotherapy to salvage patients with germ-cell tumors who relapsed after adequate first-line chemotherapy.Patients and methods: Patients with germ-cell cancers relapsing from a first, second or third complete remission induced by chemotherapy were offered to participate in a Dutch national prospective trial with broad entry criteria. The salvage treatment began with a conventional dose of ifosfamide (4 g/m² on day 1) and etoposide (100 mg/m² on days 1, 2 and 3) followed by daily s.c. administration of G-CSF (10 µg/kg) until peripheral blood progenitor cells had been harvested. Immediately after bone marrow recovery, an intermediate dose chemotherapy course of carboplatin (target AUC: 10 mg · ml^–1 · min on day 1) and etoposide (500 mg/m² on days 1, 3 and 5) was given with G-CSF daily s.c. After bone marrow recovery, two subsequent courses of high-dose CTC chemotherapy were given, each containing cyclophosphamide (6 g/m²), thiotepa (480 mg/m²) and carboplatin (target AUC: 20 mg · ml^–1 · min). The high-dose chemotherapy was administered as 30–60-minute infusions, divided over 4 days and the stem-cell transplants were given 48–72 hours after the last chemotherapy infusion. Whenever possible, residual masses were resected at the end of treatment.Results: Thirty-five patients were treated between January 1994 and October 1997. The toxicity of the treatment was manageable. Second CTC courses were administered in 25 patients and were associated with hemorrhagic cystitis and veno-occlusive disease in 3 and 4 patients, respectively. One patient who had recently undergone a partial hepatectomy, died of veno-occlusive disease. At the time of analysis, the median follow-up of the surviving patients was 37 months (range 12–56 months). The median progression-free survival for all patients was 44 months, and the median overall survival has not been reached. According to the internationally accepted criteria for predicting the outcome of salvage chemotherapy in germ-cell cancer (Beyer et al. J Clin Oncol 1996; 14: 2638–45), 30 patients had good risk criteria. Of these, 29 received high-dose chemotherapy. Of this group, the salvage rate at two years was 65% (95% confidence interval: 49.5%–85.1%).Conclusions: Over half of the germ-cell cancer patients relapsing from a chemotherapy-induced complete remission can be salvaged by a treatment strategy that incorporates high-dose chemotherapy, even when treatment is given in a multi-center setting. These data confirm the international prognostic model proposed by Beyer et al. in a prospectively studied, independent patient group and provide further evidence that high-dose therapy has a role in the salvage setting of patients with germ-cell cancer.     

Renal clearance of methotrexate in man during high-dose oral and intravenous infusion therapy

Summary The renal excretion and clearance of methotrexate (MTX) following high-dose (800 mg) therapy followed by folinic acid rescue was studied in 12 patients (2 female, 10 male): the mean age was 49.3±5.5 (SE), weight 68.6±3.9 (SE) and body surface area 1.8±0.1 m². Plasma and urine were collected over 154 h at intervals of 2–24 h, and the collection times, volume, and pH of urine samples recorded. Total MTX concentrations in urine and plasma were measured by the highly specific competitive protein-binding assay method. Plasma and urinary creatinine levels were measured on an SMA-12 autoanalyser. The renal clearance of MTX was calculated for each urine collection period. Following oral administration, clearance values during the first 6 h were high at 257±8.3 (ml/min), followed by a trough in clearance of 27.9±4.2 (ml/min) in the 20- to 30-h period. This was followed by a secondary rise of MTX renal clearance to 180.4±14.6 ml/min during the 68- to 84-h period and again to 84.9±17.1 ml/min between 84 and 112 h. In the last two periods it rose to 209±57.9 ml/min. Similar fluctuations were seen following IV administration. The changes in clearance were statistically significant at the P<0.005 level. It is suggested that high concentrations of MTX in the renal tubules result in inhibition of carrier protein synthesis, leading to a fall in active tubular secretion. When MTX concentrations fall the tubular cell recovers and a secondary rise in renal clearance occurs, leading to cyclical changes in MTX elimination.     

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion

Summary A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m² per day for 5 days and repeated every 21–28 days. The patient population had a median age of 55 years (range 38–76) and a median Karnofsky performance status of 80 (range 60–100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/l (range 100–4800) in 8 heavily pretreated patients treated at 350 mg/m² per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m² and had WBC nadirs of 800/l and 600l. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m² per day, nadir 85000/l). Neither hyponatremia nor symptomatic hypoosmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m² per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09–6.79 g/ml. Steady state was achieved in 14.5±5.9 h (mean ±SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t^1/2 of 5.3±3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543±150 g/ml h and reflected a cyclophosphamide total-body clearance (CL_TB) of 103±31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6–4.3 g/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3%±7.6% and 15.1%±2.0% of the administered daily dose, respectively. The t^1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m² as an i.v. bolus. The AUC of alkylating activity associated with the 5-day continuous infusion of cyclophosphamide is about three times greater than the AUC of alkylating activity calculated after a 1500-mg/m² bolus dose of cyclophosphamide. Daily urinary excretions of cyclophosphamide and alkylating activity associated with the 5-day continuous infusion schedule are similar to those reported after bolus doses of cyclophosphamide.     

Fluctuation of serum phenytoin concentrations during autologous bone marrow transplant for primary central nervous system tumors

Summary We reviewed our experience for adult patients receiving oral anticonvulsant therapy during high-dose chemotherapy and autologous bone marrow re-infusion for primary malignant tumors of the central nervous system. Nineteen patients received either iv carmustine (BCNU) 900–1050 mg/m² and 6120 cGy cranial irradiation (N = 10), iv carmustine 900–1050 mg/m2 and iv cisplatin 200 mg/m² (N = 8), or iv carmustine 600 mg/m², iv cisplatin 200 mg/m², and iv etoposide 2400 mg/m² (N = 1). Anticonvulsant therapy consisted of phenytoin alone (N = 8), phenobarbital alone (N = 4), carbamazepine alone (N = 2), phenytoin and carbamazepine (N = 2), carbamazepine and phenobarbital (N = 1), and no anticonvulsant therapy (N = 2). Serum anticonvulsant concentrations were monitored frequently and doses adjusted to keep values in the therapeutic range. While phenobarbital and carbamazepine doses remained relatively stable, all patients required increased doses of phenytoin anticonvulsant therapy after beginning chemotherapy (mean onset 3.7 days after initiation of chemotherapy). The increase in phenytoin dose ranged from 50% to 300% above baseline (mean 134%). By the time of discharge from the hospital (approximately 3–4 weeks after the start of chemotherapy) anticonvulsant dose was decreased to near pre-therapy levels. These swings coincided with the initiation of dexamethasone therapy for antiemetic effect and were more pronounced in patients also receiving cisplatin therapy. Due to close monitoring of serum phenytoin concentrations, no instances of toxicity due to excessive drug concentration, or seizures due to subtherapeutic doses, were noted in patients with primary CNS malignancies. Serum phenytoin concentrations fluctuate markedly during high-dose chemotherapy and must be analyzed frequently during the course of therapy.     

Cellular and plasma adriamycin concentrations in long-term infusion therapy of leukemia patients

Summary To determine whether long-term adriamycin (ADM) infusions resulted in cellular ADM concentrations at least comparable to those observed after bolus injections, ADM cellular and plasma concentrations were measured in 18 patients with leukemia. ADM was administered at 30 mg/m² per day for 3 days, either as bolus injections or as 4-, 8-, or 72-h infusions. Negligible accumulation of plasma ADM was observed. Peak plasma ADM concentrations after bolus injections were 1640±470 ng/ml (n=7). Maximum levels were 176±34 ng/ml during 4-h infusion (n=5); 85±50 ng/ml during 8-h infusion (n=4); and 47±5 ng/ml (n=2) after 72-h infusion. ADM concentrations in nucleated blood and bone marrow cells correlated well (r=0.82, n=47). ADM accumulated in leukemic cells up to 30–100 times the plasma concentrations. The shorter the administration time-span, the higher the peak leukemic cell concentration and the greater the loss of drug immediately after the end of the administration. The final cellular ADM half-life was approximately 85–110 h. After long-term infusion and bolus injection of the same dose, similar areas under the curve for plasma or leukemic blast cell ADM concentrations were attained. Since comparable therapeutic efficacy was observed in all regimens, the antileukemic effect appeared not to be related to the peak plasma concentrations, while acute toxicity phenomena decreased with increasing duration of the infusion. Long-term ADM infusion deserves more attention in the treatment of patients with anthracyclines.Supported by the Queen Wilhelmina Foundation (The Netherlands Cancer Foundation, grant SNUKC 82-7), The Ank van Vlissingen Foundation and The Maurits and Anna de Kock Foundation