Disposition of conjugate-bound and free doxorubicin in tumor-bearing mice following administration of a BR96-doxorubicin immunoconjugate (BMS 182248)

Purpose: The chimeric BR96–doxorubicin (DOX) immunoconjugate, BMS 182248, has induced remissions and cures of human lung adenocarcinoma (L2987) implanted in athymic mice. The purpose of this study was to evaluate the biodistribution of DOX after BMS 182248 administration to tumor-bearing mice and to evaluate the ability of BMS 182248 to target DOX to tumors. Methods: For this evaluation, L2987-implanted mice were given BMS 182248 (5 mg DOX/kg; three doses 4 days apart) and the levels of both conjugate-bound and free DOX in plasma, tumor, liver and heart were determined. Results: Conjugate-bound DOX comprised the majority of plasma DOX, with relatively low levels of free DOX present. From plasma, conjugate-bound DOX distributed to the tissues examined with the order of concentration (per gram of tissue) being tumor > liver > heart. Free DOX was also detected in liver and heart, but at concentrations lower than those present after an equivalent DOX dose (5 mg/kg; three doses 4 days apart). The total exposure of heart to free DOX after BMS 182248 administration was about one- quarter of that found after the administration of DOX alone. The elimination kinetics of both conjugate-bound and free DOX from heart and liver after BMS 182248 administration paralleled those observed from plasma, indicating that equilibrium had been attained between these nontumor tissues and plasma. The elimination kinetics of both entities from tumors, however, were different from those from plasma, liver and heart. BMS 182248 produced sustained levels of both conjugate-bound and free DOX which were present throughout the experiment. This suggested that, in contrast to normal tissues, tumor tissue retention of BMS 182248 by antigen-promoted binding had occurred and that the kinetics of free DOX in the tumors were controlled by the rate of release of DOX from tumor-associated BMS 182248. As a result of this retention, the tumor concentrations of free DOX after BMS 182248 administration exceeded those produced by i.v. administration of DOX at the same dose, a finding consistent with the greater antitumor activity of BMS 182248 relative to DOX. BMS 182248 also liberated DOX upon incubation with rat liver lysosomes and was accumulated by L2987 cells in culture, with the subsequent intracellular release of DOX. Conclusions: BMS 182248 effectively delivered DOX to L2987 xenografts implanted in athymic mice and produced higher and more prolonged tumor concentrations of free DOX than the administration of DOX alone. Following BMS 182248 administration, normal tissues (liver and heart) were exposed to lower overall concentrations of free DOX than were produced by administration of an equivalent DOX dose. Received: 18 June 1996 / Accepted: 27 November 1996     

Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in rats

 Purpose: β-L-Dioxolane-cytidine (OddC), a novel L-nucleoside analog with potent cytotoxicity in vitro, appears to be a promising candidate for anticancer therapy. In this study, a high performance liquid chromatography (HPLC) analytical method was developed and the preclinical pharmacokinetics of OddC were characterized in rats. Methods: Adult male Sprague Dawley rats were given 10, 25, or 50 mg/kg of OddC both intravenously and orally with a 6-day washout period between doses. Each rat received one dosage level of OddC and the route of administration was assessed by a randomized crossover design. Plasma and urine concentrations were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis. Results: Following intravenous administration, the plasma concentrations of OddC declined rapidly in a biexponential manner with a terminal phase half-life of 1.65±1.12 h (mean±SD). Mean total, renal, and nonrenal clearances were 1.38±0.62, 0.30±0.14, and 1.08±0.59 l/h per kg. Approximately 22% of the administered dose was excreted unchanged in the urine. Thus, nonrenal clearance was the predominant route of elimination of OddC. The steady-state volume of distribution averaged 1.42±0.66 l/kg, indicating intracellular distribution of OddC. The nucleoside analog was slowly absorbed after oral administration and bioavailability varied greatly between individual rats, averaging 41±27% when calculated from urinary excretion data and 37±25% when calculated from plasma OddC concentration data. Conclusion: The pharmacokinetics of OddC in rats were linear over the dose range studied. Received: 3 May 1996 / Accepted: 5 September 1996     

Plasma pharmacokinetics,bioavailability, and tissue distribution in CD2F1 mice of halomon,an antitumor halogenated monoterpene isolated from the red algae Portieria hornemannii

 The purpose of the present study was to define the plasma pharmacokinetics, bioavailability, and tissue distribution in mice of halomon, a halogenated monoterpene from Portieria hornemanii that is active in vitro against brain-, renal-, and colon-cancer cell lines. Halomon formulated in cremophor : ethanol : 0.154 M NaCl (1 : 1 : 6, by vol.) was injected i.v. at 20, 60, 90, or 135 mg/kg into female CD₂F₁ mice. Doses of 135 mg/kg were also given i.p., s.c., and by enteral gavage to female CD₂F₁ mice and i.v. to male CD₂F₁ mice. Plasma halomon concentrations were measured with a gas-chromatography system using electron-capture detection. Halomon concentrations were also determined in the brains, hearts, lungs, livers, kidneys, spleens, skeletal muscles, fat, red blood cells, and, if present, testes of mice given 135 mg/kg i.v. Halomon plasma pharmacokinetics were well fit by a two-compartment, open linear model and were linear between 20 and 135 mg/kg. Population estimates of parameters describing halomon plasma pharmacokinetics in female CD₂F₁ mice were developed with a standard two-stage technique and also by simultaneous modeling of data from 20-, 60-, 90-, and 135-mg/kg i.v. studies in female mice. Halomon bioavailability was 45%, 47%, and 4% after i.p., s.c., and enteral dosing, respectively. Urinary excretion of the parent compound was minimal. Halomon was distributed widely to all tissues studied but was concentrated and persisted in fat. Halomon concentrations measured in the brain were comparable with concomitant concentrations detected in plasma and most other tissues. These data and models are helpful in the simulation and evaluation of conditions produced by preclinical screening and toxicology studies. Received: 18 February 1996/Accepted: 13 June 1996     

Enhanced adriamycin—induced delayed gastrointestinal radiosensitivity in tumor-bearing mice

Intestinal proliferative activity in BDF, mice bearing the Lewis lung tumor (LL_ca/BDF₁) was markedly depressed with increasing tumor burden. When compared with non-tumor-bearing mice (BDF₁), integrated cell production over 7 days was reduced to 56% in animals with small (400 mm³) tumors and to 30% in animals with large (2500 mm³) tumors. Gastrointestinal radiosensitivity was measured by proliferative compensatory response kinetics to a radiation dose of 600 rad. The presence of tumor (mean tumor volume = 859 ± 209 mm³) delayed the jejunal response to radiation by 24 hr and reduced the integrated cell production from 136% in BDF₁ mice to 119% in the LL_ca/BDF₁ mice. While the presence of tumor did not alter the temporal response of the colonic epithelium to radiation, the compensatory peak was reduced from 248% (BDF₁) to 200% (LL_ca/BDF₁). Adriamycin (Adr; 10 mg/kg) given 60 days prior to radiation failed to enhance the jejunal radiosensitivity in BDF₁ mice. However, when tumor-bearing LL_ca/BDF₁ mice were treated under an identical dose and time configuration, the jejunal response to 600 rad was significantly impaired: proliferative peaks were reduced from 182 to 115% ; integrated cell production was reduced from 119 to 72%. In the colon of tumor-bearing mice, pretreatment with AdR reduced the proliferative compensatory peak from the subsequent radiation dose to 120% of pretreatment levels.     

Influence of age on toremifene pharmacokinetics

Toremifene pharmacokinetics were compared in ten healthy young men (< 33 years) and elderly women (< 65 years). A single oral 120-mg dose of toremifene was given after an overnight fast and blood samples were collected over 28 days. Serum levels of the parent drug and the metabolites were determined; appropriate pharmacokinetic parameters were calculated and statistically evaluated. Toremifene peak concentrations (average 640 ng/ml) were achieved at 3.5 h. The area under the curve (AUC) and the apparent oral clearance were comparable in the young and elderly subjects. The half-life was prolonged (4.2 versus 7.2 days) and the apparent volume of distribution was increased (457 versus 627 l) in the elderly. The peak concentration of the main metabolite N-demethyltoremifene was lower (159 versus 233 ng/ml) and the half-life was prolonged (8.3 versus 19.1 days) in the elderly subjects, but the AUC values were comparable. The results suggest that toremifene is distributed more widely in the elderly but that its clearance is unaffected by age. It is concluded that the dosage requirement of the drug is unlikely to differ between young and elderly subjects. Received: 16 June 1996 / Accepted: 15 December 1996     

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

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

Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats

The purpose of this study was to examine the effect of tamoxifen pretreatment on the metabolism and pharmacokinetics of doxorubicin. We tested the hypothesis that the pretreatment would counteract the side effects of doxorubicin and modify the disposition of the drug. The concentration-time profiles of doxorubicin in plasma and blood cells were determined in conjunction with the cumulative amount of renal and hepatobiliary elimination of unchanged drug and metabolites following a 10-day tamoxifen pretreatment at a dose of 1 mg/kg per day. Furthermore, under the same experimental protocol the serum concentration-time profile of endothelin was determined as a biomarker of toxicity. Methods: Female Sprague Dawley rats (225–275 g), pretreated orally for 10 days with corn oil or tamoxifen in corn oil (1 mg/kg per day), received ¹⁴C-doxorubicin (specific activity 0.4 μCi/mg, 10 mg/kg) intravenously. Plasma, blood cells, bile and urine were collected periodically and analyzed for doxorubicin and its metabolites. Four other groups of animals received the same pretreatment and non-labeled doxorubicin. Their serum samples were analyzed for endothelin. Two additional groups were also used to examine the effect of tamoxifen on the in vitro metabolism of doxorubicin by the cytosolic enzyme aldo-keto reductase. Results: Tamoxifen pretreatment reduced the total protein of the cytosolic fraction by 50% and reduced the formation of doxorubicinol both in vitro and in vivo. The pretreatment resulted in a notable increase in the area under plasma and blood cells concentration-time curves of doxorubicin and a significant reduction in mean residence time, apparent volume of distribution and serum endothelin levels. Conclusions: We attributed the increase in the area under the curves of plasma and blood cells following tamoxifen pretreatment to a reduction in the uptake of doxorubicin by peripheral tissues. This conclusion was consistent with the reduction in the volume of distribution of plasma, mean residence time and higher availability of the parent compound for excretion. An interesting observation was that the increase in concentration of doxorubicin in plasma was not concomitant with an increase in concentration of doxorubicinol. The levels of this toxic metabolite and its corresponding biliary rate constant were reduced by approximately 50%. The results demonstrate that tamoxifen, in addition to being a modulator of P-glycoprotein and counteracting the effects of doxorubicin at the cellular level, also alters the metabolic profile of doxorubicin either by inhibiting the formation of the toxic metabolite doxorubicinol or by reducing the enzyme responsible for the biotransformation. The change in metabolism may well be a contributing factor to reduction of serum endothelin levels. Received: 2 September 1999 / Accepted: 14 April 2000     

Plasma pharmacokinetics and urinary excretion of the polyamine analogue 1, 19-bis(ethylamino)-5, 10, 15-triazanonadecane in CD2F1 mice

 The pharmacokinetics of 1, 19-bis(ethylamino)-5, 10, 15-triazanonadecane (BE-4-4-4-4) were determined in CD₂F₁ female mice after administration of i.v. bolus doses of 20 mg/kg (approximately the dose lethal to 10% of the study animals, ∼LD₁₀) as well as 15, 10, and 5 mg/kg and after s.c., i.p., or p.o. doses of 20 mg/kg. BE-4-4-4-4 in plasma and urine was derivatized with dansyl chloride and measured by gradient high-performance liquid chromatography (HPLC) with fluorescence detection. Data were modeled by noncompartmental and compartmental methods. The declines observed in plasma BE-4-4-4-4 concentrations after i.v. delivery of 20, 15, 10, and 5 mg/kg were modeled simultaneously using an interval of 2000 min between doses and were best approximated by a two-compartment, open, linear model. The time courses of plasma BE-4-4-4-4 concentrations after i.p. and s.c. delivery were fit best by a two-compartment, open, linear model with first-order absorption. Peak plasma concentrations of BE-4-4-4-4 measured following an i.v. dose of 20 mg/kg ranged between 30 and 33 μg/ml, the terminal elimination half-life was 94 min, and the volume of distribution (V_dss) was 850 ml/kg. The plasma pharmacokinetics of BE-4-4-4-4 were linear with dose. BE-4-4-4-4 (0.5 and 2.0 μM) in mouse plasma was approximately 67% protein-bound. Bioavailabilities after i.p., s.c., and p.o. delivery were 40%, 50%, and approximately 3%, respectively. Urinary excretion of parent BE-4-4-4-4 in the first 24 h after dosing accounted for less than 30% of the delivered dose. As BE-4-4-4-4 proceeds toward and undergoes clinical evaluation, the data and analytical method presented herein should prove useful in formulating a dose-escalation strategy and, possibly, evaluating toxicities encountered. Received: 25 November 1994/Accepted: 25 August 1995     

Intrasubject variation in children of ifosfamide pharmacokinetics and metabolism during repeated administration

 The aim of this study was to investigate intrasubject variability in ifosfamide (IFO) pharmacokinetics and metabolism which may influence clinical effect, since the pharmacology of this drug is dependent on metabolism. A group of 11 patients (ages 1–16 years) were studied on at least two occasions. IFO, 9 gm^-2, was administered as a continuous infusion over 72 h. Plasma and urine samples were collected and concentrations of IFO and its metabolites were determined. Comparisons were made between courses in the same subject, allowing for differences in age and prior IFO treatment. There was a wide variation in drug (twofold) and metabolite (up to tenfold) AUCs between courses in the same patient. Although some patients did show an increase in clearance between courses (up to threefold), there was no significant consistent change in overall pharmacokinetics among the different courses studied in the same patient. There was a significant decrease (up to 63%) in the AUC of the inactive metabolite 3-dechloroethylifosfamide (3-DCI) in later courses compared with the first course studied (P=0.032, paired t-test). This was matched by an increase in the AUC of the total dechloroethylated metabolites with course (P=0.015, paired t-test). None of the other metabolites measured showed any consistent change in plasma or urine levels between courses. Overall, the AUC of parent drug correlated with age (r ²=0.86, P=0.011), and postinfusion half-life correlated with plasma bilirubin (r ²=0.89, P=0.007). This study demonstrated large and seemingly unpredictable intrasubject variability in IFO pharmacokinetics and metabolism during repeated administrations. Investigations relating the clinical effects of IFO to pharmacokinetics and metabolism must take this variation into account. Received: 13 January 1995/Accepted: 9 October 1995     

Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics: allometric scaling of animal data,pharmacokinetics and toxicodynamics of 5-fluorouracil in humans

 The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihy-dropyrimidine dehydrogenase (DPD) inactivator, 5-ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. Method: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. Results: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL=0.47B^0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution (V_c) increased proportionately with body weight (V_c=0.58 B^0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h) or (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85 was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v. bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m² of 5-FU, respectively. Discussion: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose of 5-FU is needed in patients treated with 776C85. Received: 6 October 1995/Accepted: 28 May 1996     

A Phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumors

 Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m² per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m² per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m² per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (<1,000/μl) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Nonhematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37^°–40^°C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cp_ss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m² per day. Both the Cp_ss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m² per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m² per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies. Received: 14 March 1994/Accepted: 22 July 1994     

Cisplatin pharmacokinetics and pharmacodynamics in patients with squamous-cell carcinoma of the head/neck or esophagus

 The pharmacokinetics of total platinum (Pt) in plasma and cisplatin (CDDP)-DNA adducts in different cell types were described in ten patients with squamous-cell carcinoma of the head/neck or esophagus after their first cycle of chemotherapy containing a CDDP dose of 100 mg/m². Nephrotoxicity was studied in terms of urinary excretion of marker proteins (protein HC, IgG, and albumin). Pharmacodynamic relationships between pharmacokinetic parameters and toxicity were investigated. A population-based model with limited sampling was found feasible for producing pharmacokinetic information, in accordance with literature data. The kinetics of two normal cell types with different turnover (lymphocytes and buccal cells) appeared to have different kinetic profiles of CDDP-DNA adducts. Analysis of urinary excretion of marker proteins (protein HC, albumin, and IgG) showed that the nephrotoxicity was displayed first as tubular damage and later as impaired glomerular barrier function. There were indications that tubular nephrotoxicity may be predicted by pharmacokinetic parameters of plasma Pt. We found older patients to have a lower Pt clearance and more extensive early tubular damage. There was no correlation between CDDP-DNA adducts in normal cells and nephrotoxicity. Larger studies are warranted to define the pharmacokinetic window of CDDP. Limited sampling for analysis of CDDP pharmacokinetics may then be a possible avenue for individualizing the dose and, thus, improving the clinical use of the drug. Received: 5 November 1995/Accepted: 15 May 1996     

Age-related pharmacokinetics of daunorubicin and daunorubicinol following intravenous bolus daunorubicin administration in the rat

 Age-related differences in pharmacokinetics may be important in determining altered anthracycline cardiotoxicity in the senescent rat and also in older humans. This study examined the effect of aging on daunorubicin pharmacokinetics in the Fischer 344 rat. Daunorubicin 7.5 mg/kg was administered i.v. to 6-and 24-month-old male Fischer 344 rats and plasma and tissue sampling was performed over 168 h for assay of daunorubicin and daunorubicinol concentrations by high-performance liquid chromatography. Systemic clearance of daunorubicin was decreased in older compared to younger animals (56±4 versus 202±17 ml min^-1 kg^-1; P<0.05). In addition, the area under the plasma daunorubicinol concentration/time curve was significantly increased in older rats. In the heart, the area under the concentration/time curve was significantly increased in senescence both in the case of daunorubicin (201±12 versus 86±4 μg h g^-1; P<0.05) and daunorubicinol (1347±118 versus 182±4 μg h g^-1; P<0.05). Furthermore, the peak mean concentrations of daunorubicin were increased in older compared to younger rats both in plasma (1078±82 versus 663±66 ng ml^-1; P<0.05) and in heart (27±1 versus 10±1 μg g^-1; P<0.05). This also was true for daunorubicinol in plasma (284±39 versus 168±27 ng ml^-1; P<0.05) and in myocardium (8.6±0.6 versus 2.4±0.2 μg g^-1; P<0.05). Following daunorubicin injection, the ratio of daunorubicinol to daunorubicin concentrations in tissues increased with time, particularly in plasma and heart in senescent rats. Thus, there are significant age-related changes in daunorubicin and daunorubicinol kinetics in the rat that could alter susceptibility to acute systemic toxicity and to chronic cardiotoxicity. Received: 22 December 1995 / Accepted: 30 July 1996     

Antitumor activity and pharmacokinetics of a morpholino-anthracycline derivative (KRN8602) against human breast carcinoma xenografts serially transplanted into nude mice

The antitumor activity and pharmacokinetics of (7R, 8S, 10S)-10-((3-deamino- 3-(4-morpholino)-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-8- ethyl- 7,8,9,10-tetrahydro-1,6,7,8,11-pentahydroxy-5,12-naphthacenedione hydrochloride (KRN8602) were evaluated using five human breast carcinoma xenografts in nude mice. The maximum non-toxic dose of KRN8602 was 2 mg/kg by q4d x 3 intraperitoneal and peroral administration. KRN8602 showed significant antitumor activity against MX-1, which is less sensitive to adriamycin, with the chemotherapeutic indices of 13.0 for po administration and 9.5 for ip injection. Although KRN8602 also inhibited the growth of T-61 significantly, the antitumor activity of this agent against the other three breast carcinoma xenografts was limited. To elucidate this discrepancy, pharmacokinetic analysis and MTT assay were conducted using the KRN8602-sensitive MX-1 and KRN8602-insensitive R-27. While no differences were observed in the area under the curve and the peak concentration of KRN8602 for each tumor, a difference in the sensitivity of the tumor strains was obvious in MTT assay. The efficacy of this agent seemed to depend on the sensitivity of each type of tumor cell rather than the concentration of agent in tumor tissues. If it were possible to select patients with sensitive tumor cells to this agent by the MTT assay, the phase II trial might be completed within a short period by reducing the number of studied patients.     

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     

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

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

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     

Effect of MX2, a new morpholino anthracycline, against experimental brain tumors

A new lipophilic morpholino anthracycline derivative, MX2, has an antitumor activity against a wide spectrum of experimental tumors. We examined the effect of MX2 against experimental brain tumors. At a low dose, MX2 exhibited strong growth inhibitory activity against human and rat glioma cells. The survival time of rats with meningeal carcinomatosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells was significantly prolonged by intravenous MX2. The growth of subcutaneously implanted glioma in rats was significantly retarded by intravenous MX2. These results suggest that MX2 warrants further experimental evaluation of its efficacy against malignant brain tumors including gliomas.     

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

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

Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients

 Purpose: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m²) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). Methods: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary β₂-microglobulin (BMG_p and BMG_u), urinary N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. Results: The maximum plasma concentration (C_max), maximum urinary excretion rate (dAe/dt_max), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t_1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m²) caused nephrotoxicity. The C_max of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. C_max was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. Conclusion: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the C_max or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 μg/ml in a standard continuous infusion schedule over 2 h and 4 h. Received: 2 May 1995/Accepted: 25 March 1996