Pharmacokinetics of Sodium Borocaptate: A Critical Assessment of Dosing Paradigms for Boron Neutron Capture Therapy

The pharmacokinetics of sodium borocaptate (BSH), a drug that has been used clinically for boron neutron capture therapy (BNCT) of malignant brain tumors, have been characterized by measuring boron concentrations by direct current plasma-atomic emission spectroscopy (DCP-AES) in a group of 23 patients with high-grade gliomas. The disposition of BSH following intravenous (i.v.) infusion, which was determined by measuring plasma boron concentrations by DCP-AES, was consistent with a three-compartment open model with zero-order input and first-order elimination from the central compartment. Boron disposition was linear over the dose range of 26.5–88.2mg BSH/kg body weight (b.w.), corresponding to 15–50mg boron/kg b.w. Mean total body boron plasma clearance was 14.4±3.5ml/min and the harmonic mean half-lives (range) were 0.6 (0.3–3.7), 6.5 (4.8–10.1) and 77.8 (49.6–172.0)h for the ,, and disposition phases, respectively. Using an empirically determined plasma:blood boron concentration ratio of 1.3±0.2, the calculated total body boron blood clearance was 18.5±4.5ml/min. In order to develop a model for selecting the optimum dosing paradigm, a pharmacokinetic correlation was established between the boron content of normal brain, solid tumor, and infiltrating tumor to the shallow tissue pharmacokinetic compartment (C₂). Based on our model, it was concluded that although multiple i.v. infusions of BSH might increase absolute tumor boron concentrations, they will not improve the tumor:plasma boron concentration ratios over those attainable by a single i.v. infusion. The results from our study are confirmatory of those previously reported by others when blood sampling has been carried out for a sufficient period of time to adequately characterize the pharmacokinetics.     

Tissue Uptake of BSH in Patients with Glioblastoma in the EORTC 11961 Phase I BNCT Trial

Purpose: The uptake of the boron compound Na₂B₁₂H₁₀-SH (BSH) in tumor and normal tissues was investigated in the frame of the EORTC phase I trial Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility (protocol 11961).Methods and Materials: The boron concentration in blood, tumor, normal brain, dura, muscle, skin and bone was detected using inductively coupled plasma-atomic emission spectroscopy in 13 evaluable patients. In a first group of 10 patients 100mg BSH/kg bodyweight (BW) were administered; a second group of 3 patients received 22.9mg BSH/kg BW. The toxicity due to BSH was evaluated.Results: The average boron concentration in the tumor was 19.9±9.1ppm (1 standard deviation (SD)) in the high dose group and 9.8±3.3ppm in the low dose group, the tumor/blood ratios were 0.6±0.2 and 0.9±0.2, respectively. The highest boron uptake has been detected in the dura, very low uptake was found in the bone, the cerebro-spinal fluid and especially in the brain (brain/blood ratio 0.2±0.02 and 0.4±0.2). No toxicity was detected except flush-like symptoms in 2 cases during a BSH infusion at a much higher speed than prescribed.Conclusion: BSH proved to be safe for clinical application at a dose of 100mg BSH/kg infused and at a dose rate of 1mg/kg/min. The study underlines the importance of a further investigation of BSH uptake in order to obtain enough data for significant statistical analysis. The boron concentration in blood seems to be a quite reliable parameter to predict the boron concentration in other tissues.     

Pharmacokinetics of sodium borocaptate: a critical assessment of dosing paradigms for boron neutron capture therapy

Summary The pharmacokinetics of sodium borocaptate (BSH), a drug that has been used clinically for boron neutron capture therapy (BNCT) of malignant brain tumors, have been characterized by measuring boron concentrations by direct current plasma-atomic emission spectroscopy (DCP-AES) in a group of 23 patients with high-grade gliomas. The disposition of BSH following intravenous (i.v.) infusion, which was determined by measuring plasma boron concentrations by DCP-AES, was consistent with a three-compartment open model with zero-order input and first-order elimination from the central compartment. Boron disposition was linear over the dose range of 26.5–88.2 mg BSH/kg body weight (b.w.), corresponding to 15–50 mg boron/kg b.w. Mean total body boron plasma clearance was 14.4 ± 3.5 ml/min and the harmonic mean half-lives (range) were 0.6 (0.3–3.7), 6.5 (4.8–10.1) and 77.8 (49.6–172.0) h for theα, β, andγ disposition phases, respectively. Using an empirically determined plasma: blood boron concentration ratio of 1.3 ± 0.2, the calculated total body boron blood clearance was 18.5 ± 4.5 ml/min. In order to develop a model for selecting the optimum dosing paradigm, a pharmacokinetic correlation was established between the boron content of normal brain, solid tumor, and infiltrating tumor to the shallow tissue pharmacokinetic compartment (C₂). Based on our model, it was concluded that although multiple i.v. infusions of BSH might increase absolute tumor boron concentrations, they will not improve the tumor: plasma boron concentration ratios over those attainable by a single i.v. infusion. The results from our study are confirmatory of those previously reported by others when blood sampling has been carried out for a sufficient period of time to adequately characterize the pharmacokinetics.     

Pharmacokinetics of acridine-4-carboxamide in the rat,with extrapolation to humans

Summary The pharmacokinetics ofN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) were investigated in rats after i. v. administration of 18, 55 and 81 mol/kg [³H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (±SD) model-independent pharmacokinetic parameters were; clearance (Cl), 5.3±1.1 1 h^–1 kg^–1; steady-state volume of distribution (Vss), 7.8±3.0 l/kg; mean residence time (MRT), 1.5±0.4 h; and terminal elimination half-life (t _1/2Z), 2.1±0.7 h (n=10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1–8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05–0.10; 95% confidence limits) 1 h^–1 kg^–1 and a V_ss value of 0.63 (range, 0.2–1.1) l/kg for total drug concentrations in humans.     

Tissue uptake of BSH in patients with glioblastoma in the EORTC 11961 phase I BNCT trial

Summary Purpose: The uptake of the boron compound Na₂B₁₂H₁₀-SH (BSH) in tumor and normal tissues was investigated in the frame of the EORTC phase I trial ‘Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility’ (protocol 11961). Methods and Materials: The boron concentration in blood, tumor, normal brain, dura, muscle, skin and bone was detected using inductively coupled plasma-atomic emission spectroscopy in 13 evaluable patients. In a first group of 10 patients 100 mg BSH/kg bodyweight (BW) were administered; a second group of 3 patients received 22.9 mg BSH/kg BW. The toxicity due to BSH was evaluated. Results: The average boron concentration in the tumor was 19.9 ± 9.1 ppm (1 standard deviation (SD)) in the high dose group and 9.8 ± 3.3 ppm in the low dose group, the tumor/blood ratios were 0.6 ± 0.2 and 0.9 ± 0.2, respectively. The highest boron uptake has been detected in the dura, very low uptake was found in the bone, the cerebro-spinal fluid and especially in the brain (brain/blood ratio 0.2 ± 0.02 and 0.4 ± 0.2). No toxicity was detected except flush-like symptoms in 2 cases during a BSH infusion at a much higher speed than prescribed. Conclusion: BSH proved to be safe for clinical application at a dose of 100 mg BSH/kg infused and at a dose rate of 1 mg/kg/min. The study underlines the importance of a further investigation of BSH uptake in order to obtain enough data for significant statistical analysis. The boron concentration in blood seems to be a quite reliable parameter to predict the boron concentration in other tissues.     

Pharmacokinetics and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide after i.v. administration in the mouse

Summary The pharmacokinetics, tissue distribution and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide(AC) were studied after i.v. administration to mice. Over the dose range of 9–121 mol/kg (3–40 mg/kg), AC displayed linear kinetics with the following model-independent parameters: clearance (C), 21.0±1.9 l h^–1 kg^–1; steady-state volume of distribution (V_ss), 11.8±1.4 l/kg; and mean residence time (MRT), 0.56±0.02 h. The plasma concentration-time profiles for AC fitted a two-compartment model with the following parameters:C _c, 19.4±2.3 l h^–1 kg^–1; V_c, 7.08±1.06 l/kg;t _1/2 13.1±3.5 min; andt _1/2Z, 1.60±0.65 h. AC displayed moderately high binding in healthy mouse plasma, giving a free fraction of 15.9%–25.3% over the drug concentration range of 1–561 M. After the i.v. administration of 30 mol/kg [³H]-AC, high radioactivity concentrations were observed in all tissues (especially the brain and kidney), showing a hight _1/2c value (37–59 h). At 2 min (first blood collection), the AC concentration as measured by high-performance liquid chromatography (HPLC) comprised 61% of the plasma radioactivity concentration (expressed as AC equivalents/l). By 48 h, 73% of the dose had been eliminated, with 26% and 47% of the delivered drug being excreted by the urinary and faecal routes, respectively; <1% of the total dose was excreted as unchanged AC in the urine. At least five distinct radiochemical peaks were distinguishable by HPLC analysis of plasma extracts, with some similar peaks appearing in urine. The 121-mol/kg dose was well tolerated by mice, with sedation being the only obvious side effect and no significant alterations in blood biochemistry or haematological parameters being recorded. After receiving a dose of 152 mol/kg, all mice experienced clonic seizures for 2 min (with one death occuring) followed by a period of sedation that lasted for up to 2h. No leucopenia occurred, but some mild anaemia was noted. There was no significant change in blood biochemistry. A further 20% increase in the i.v. dose (to 182 mol/kg) resulted in mortality, with death occurring within 2 min of AC administration.Supported by the Auckland Medical Research Foundation and the Cancer Society of New Zealand     

Pharmacokinetics and boron uptake of BSH (Na2B12H11SH) in patients with intracranial tumors

We evaluated retrospectively the pharmacokinetics and boron uptakeof BSH (mercaptoundecahydrododecarborate) for Boron Neutron Capture Therapy(BNCT) in 123 patients undergoing craniotomy for intracranialtumors. The pharmacokinetics revealed that BSH could moveeasily from blood to the peripheral organs; itwas retained there and elimination was very slow.BSH after intra-arterial infusion (IA) was found tomove into the peripheral organs more easily thanafter intra-venous (IV) infusion.In patients with malignant glioma, the average valuesof boron concentration in tumor and the tumorto blood ratio (T/B ratio) after IA infusionwere 26.8 ± 19.5 g/g (range, 6.1–104.7 g/g)and 1.77 ± 1.30 (range, 0.47–6.65) respectively. Onthe other hand, after IV infusion the valueswere 20.9 ± 12.2 g/g (range, 7.0–39.7 g/g)and 1.30 ± 0.65 (range, 0.61–2.94) respectively. Thedifferences are not statistically significant. Boron uptake inmalignant glioma was about three times higher thanlow grade glioma. We found a good correlationbetween boron uptake and time interval from BSHinfusion, and 15–20 hours after BSH infusion theboron concentration in tumor was above 20 g/g¹⁰B in 69% of the malignant glioma patients;T/B ratio was above one in 75%, andabove two in 44% of them.We recommend intra-venous infusion of BSH clinically sinceit is safer, and results in sufficient boronconcentration in tumor, and the planned irradiation mightbe optimal around 15–20 hours after the BSHinfusion for treating malignant glioma.     

Boron neutron capture therapy for glioblastoma multiforme using p-boronophenylalanine and epithermal neutrons: Trial design and early clinical results

A Phase I/II clinical trial of boron neutroncapture therapy (BNCT) for glioblastoma multiforme is underwayusing the amino acid analog p-boronophenylalanine (BPA) andthe epithermal neutron beam at the Brookhaven MedicalResearch Reactor. Biodistribution studies were carried out in18 patients at the time of craniotomy usingan i.v. infusion of BPA, solubilized as afructose complex (BPA-F). There were no toxic effectsrelated to the BPA-F administration at doses of130, 170, 210, or 250 mg BPA/kg bodyweight. The tumor/blood, brain/blood and scalp/blood boron concentrationratios were approximately 3.5:1, 1:1 and 1.5:1, respectively.Ten patients have received BNCT following 2-hr infusionsof 250 mg BPA/kg body weight. The averageboron concentration in the blood during the irradiationwas 13.0 ± 1.5 g ¹⁰B/g. The prescribedmaximum dose to normal brain (1 cm³ volume)was 10.5 photon-equivalent Gy (Gy-Eq). Estimated maximum andminimum doses (mean ± sd, n=10)to the tumor volume were 52.6 ± 4.9Gy-Eq (range: 64.4–47.6) and 25.2 ± 4.2 Gy-Eq(range: 32.3–20.0), respectively). The estimated minimum dose tothe target volume (tumor + 2 cm margin)was 12.3 ± 2.7 Gy-Eq (range: 16.2–7.8). Therewere no adverse effects on normal brain. Thescalp showed mild erythema, followed by epilation inthe 8 cm diameter field. Four patients developedrecurrent tumor, apparently in the lower dose (deeper)regions of the target volume, at post-BNCT intervalsof 7, 5, 3.5 and 3 months, respectively.The remaining patients have had less than 4months of post-BNCT follow-up. BNCT, at this startingdose level, appears safe. Plans are underway tobegin the dose escalation phase of this protocol.     

Pharmacokinetics of mitomycin C in non-oat cell carcinoma of the lung

Summary The disposition kinetics of the cancer chemotherapeutic agent mitomycin C have been studied in six male patients receiving mitomycin C in combination with cisplatin and vinblastine for non-oat cell carcinoma of the lung. Following rapid IV administration of mitomycin C (10 mg/m²), serum concentration-time course data were biexponential, with biologic half-lives of 46.2 ± 12.1 min (mean ± SD). Pharmacokinetic analysis of data by the CSTRIP and NONLIN digital computer programs generated parameters which suggested extensive distribution (V_area=656.8±169.8 ml·kg^–1, mean ±SD) and, as reported for other alkylating agents, rapid elimination (total body clearance=10.3 ± 3.2 ml · kg^–1 · min^–1, mean ± SD). Interpatient variations in pharmacokinetic parameters were relatively small, suggesting that close monitoring of mitomycin C therapy might be unnecessary in patients with normal renal and hepatic function.     

Clinical pharmacokinetics of high-dose DTIC

Summary The pharmacokinetics of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC, dacarbazine) given at a dose of 850–1,980 mg/m² as a 10- to 30-min infusion was studied in cancer patients, and the plasma concentration-time curves were adjusted to a two-compartment model, with a meant _1/2 value of 0.17 h (range, 0.1–0.26 h) and a meant _1/2 value of 2 h (range, 1.5–2.7 h) being found. The mean volume of the central compartment (V_c) and the apparent volume of distribution (V_B) were 0.42 l kg^–1 (range, 0.24–0.54 l kg^–1) and 1.49 l kg^–1 (range, 0.88–1.74 l kg^–1), respectively. The mean total body clearance of DTIC was 0.58 l kg^–1 h^–1 (range, 0.26–0.82 l kg^–1 h^–1), and the mean renal clearance was 0.28 l kg^–1 h^–1 (range, 0.17–0.49 l kg^–1 h^–1). Unchanged DTIC recovered from urine within 24 h varied from 11% to 63% of the delivered dose, with an inverse correlation being found between the DTIC dose and the amount excreted. The metabolite aminoimidazole carboxamide (AICA) was detectable in plasma from the start of DTIC infusion, and its concentration-time curve showed a monophasic decay, exhibiting a meant _1/2 value of 3.25 h (range, 1.77–5.82 h). Mean AICA renal clearance was 0.15 l kg^–1 h^–1 (range, 0.05–0.32 l kg^–1 h^–1). The amount of AICA excreted in urine increased with increasing DTIC dose and varied from 1.2% to 13.6% of the delivered DTIC dose. Both DTIC distribution and disposition and AICA production and renal excretion seemed to be limited after high DTIC doses as compared with the pharmacokinetics of low-dose DTIC. Nonlinear pharmacokinetics for highdose DTIC could not be clearly excluded.This work was supported in part by CAICYT grant 1182     

Pharmacokinetic study of BSH and BPA in simultaneous use for BNCT

Summary In order to improve the effectiveness of boron neutron capture therapy (BNCT) for malignant gliomas, we examined the optimization of the administration of boron compounds in brain tumor animal model. We analyzed the concentration of boron atoms in intracranial C6 glioma -bearing rats using inductively coupled plasma atomic emission spectrometry. Each tumor-bearing rat received one of two different amounts of sodium borocaptate (BSH) and/or 500 mg/kg of boronophenylalanine (BPA) via intraperitoneal injection. We compared the boron concentrations of the tumor, the contralateral normal brain and the blood in rats of 3 different treatment groups (BSH alone, BPA alone and a combination of both BSH and BPA). Our results show that the tumor boron concentration increased much more than 30 μg/g by the coadministration of both compounds. Additionally, the blood boron concentration remained below 30 μg/g and the boron concentration in the normal brain was low (mean 4.7±1.1 μg/g). Even in comparison with the administration of BPA alone, coadministration of BPA and BSH shows an improved tumor/normal brain ratio of boron concentrations.     

Optimal timing of neutron irradiation for boron neutron capture therapy after intravenous infusion of sodium borocaptate in patients with glioblastoma

PURPOSE: A cooperative study in Europe and Japan was conducted to determine the pharmacokinetics and boron uptake of sodium borocaptate (BSH: Na(2)B(12)H(11)SH), which has been introduced clinically as a boron carrier for boron neutron capture therapy in patients with glioblastoma. METHODS AND MATERIALS: Data from 56 patients with glioblastoma who received BSH intravenous infusion were retrospectively reviewed. The pharmacokinetics were evaluated in 50 patients, and boron uptake was investigated in 47 patients. Patients received BSH doses between 12 and 100 mg/kg of body weight. For the evaluation, the infused boron dose was scaled linearly to 100 mg/kg BSH. RESULTS: In BSH pharmacokinetics, the average value for total body clearance, distribution volume of steady state, and mean residence time was 3.6 +/- 1.5 L/h, 223.3 +/- 160.7 L, and 68.0 +/- 52.5 h, respectively. The average values of the boron concentration in tumor adjusted to 100 mg/kg BSH, the boron concentration in blood adjusted to 100 mg/kg BSH, and the tumor/blood boron concentration ratio were 37.1 +/- 35.8 ppm, 35.2 +/- 41.8 ppm, and 1.53 +/- 1.43, respectively. A good correlation was found between the logarithmic value of T(adj) and the interval from BSH infusion to tumor tissue sampling. About 12-19 h after infusion, the actual values for T(adj) and tumor/blood boron concentration ratio were 46.2 +/- 36.0 ppm and 1.70 +/- 1.06, respectively. The dose ratio between tumor and healthy tissue peaked in the same interval. CONCLUSION: For boron neutron capture therapy using BSH administered by intravenous infusion, this work confirms that neutron irradiation is optimal around 12-19 h after the infusion is started.     

Pharamacokinetic Modeling for Boronophenylalanine-fructose Mediated Neutron Capture Therapy: 10B Concentration Predictions and Dosimetric Consequences

A two-compartment open model has been developed for predicting ¹⁰B concentrations in blood following intravenous infusion of the L-p-boronophenylalanine-fructose complex in humans and derived from pharmacokinetic studies of 24 patients in Phase I clinical trials of boron neutron capture therapy. The ¹⁰B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of 32g/g (for infusion of 350mg/kg over 90min) followed by a biexponential disposition profile with harmonic mean half-lives of 0.32±0.08 and 8.2±2.7h, most likely due to redistribution and primarily renal elimination, respectively. The mean model rate constants k ₁₂, k ₂₁, and k ₁₀ are (mean ± SD) 0.0227±0.0064min^–1, 0.0099±0.0027min^–1, 0.0052±0.0016min^–1, respectively, and the central compartment volume of distribution V ₁ is 0.235±0.042L/kg. In anticipation of the initiation of clinical trials using an intense neutron beam with concomitantly short irradiations, the ability of this model to predict, in advance, the average blood ¹⁰B concentration during brief irradiations was simulated in a retrospective analysis of the pharmacokinetic data from these patients. The prediction error for blood boron concentration and its effect on simulated dose delivered for each irradiation field are reported for three different prediction strategies. In this simulation, error in delivered dose (or, equivalently, neutron fluence) for a given single irradiation field resulting from error in predicted blood ¹⁰B concentration was limited to less than 10%. In practice, lower dose errors can be achieved by delivering each field in two fractions (on two separate days) and by adjusting the second fraction's dose to offset error in the first.     

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.     

Subcellular Biodistribution of Sodium Borocaptate (BSH: Na2B12H11SH) in a Rat Glioma Model in Boron Neutron Capture Therapy

Mercaptoundecahydrododecaborate (Na₂B₁₂H₁₁SH, sodium borocaptate or BSH) has been used clinically as a boron compound for boron neutron capture therapy (BNCT) in patients with malignant glioma in Japan and Europe. Boron-10 is known to accumulate selectively only in brain tumor cells. This work was aimed to clarify the subcellular biodistribution of BSH in a rat glioma model using immunohistochemical approach.Wistar rats were used for this experiment. An intracerebral injection of 5.0 × 10⁶ C6 glioma cells was introduced into the region of cerebral hemisphere. Fifty milligrams of ¹⁰B/kg BSH was infused intravenously two weeks after implantation. Host rats were divided into six groups according to the sampling time: 1, 4, 8, 16, 24 and 48 h after the start of BSH infusion. Immunohistochemical study was carried out using anti-BSH antibody.Boron was already found in a whole cell 1 h after BSH infusion, and then seemed to collect in a cell nuclei around 8–16 h after infusion. It was still recognized in tumor cell 48 h after infusion.This study supports the following hypothesis on selective boron uptake in a tumor. BSH can pass through the disrupted blood–brain barrier (BBB) easily and can come in contact with tumor cells; there, BSH can bind on the extracellular surface of plasma membrane to choline residues. After binding to the plasma membrane, boron with choline residues may be internalized into the cell by endocytic pathways and eventually travel to cell nuclei, and then stay there for a long time.     

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)     

Pharmacokinetics of high-dose busulfan in children

Summary The pharmacokinetics of high-dose busulfan given orally at 1 mg/kg every 6 h over 4 days (total dose, 16 mg/kg) in combined chemotherapy followed by autologous bone marrow transplantation was studied in 12 children with a mean age of 7 years (range, 4–14 years). Busulfan levels in biological fluids were measured by a gas chromatographic assay with mass fragmentographic detection, using a deuterated analogue as the internal standard. In a high-dose regimen, busulfan followed one-compartment model kinetics with zero-order absorption. A mean maximal concentration of 803±228 ng/ml was achieved at 92–255 min after dosing. The mean elimination half-life was 2.33 h, and the mean total clearance was 119±54 ml/min per m², with an apparent distribution volume of 27.10±11.50 l/m². A mean trough level of 370 ng/ml was found throughout the 4 days of the chemotherapy course. There were no significant variations in pharmacokinetic parameters measured after the first and last doses. Busulfan was monitored in the CSF of nine children at 3.25–7 h after the last dose and was detected in all patients, with a mean CSF-to-plasma concentration ratio of 0.95 (range, 0.5–1.4).     

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

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

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     

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