Leukemic cell and plasma daunomycin concentrations after bolus injection and 72 h infusion

Summary The effect of the duration of daunomycin (DNM) infusion on leukemic cell drug concentrations was evaluated. Cellular and plasma DNM concentrations were measured in 20 patients with acute non-lymphocytic leukemia. DNM 45 mg/m² was administered either as a bolus injection or as a 4-, 8- or 72-h constant-rate infusion during 3 consecutive days. Peak plasma DNM levels amounted to 227±116 ng/ml after bolus injection and were only 16±6 ng/ml after 72-h DNM infusions. Terminal plasma DNM half-lives were 14±4 h. Peak leukemic cell DNM concentrations at the 3rd day of administration were 16810±2580 ng/10⁹ cells (bolus injections) and 10310±5510 ng/10⁹ cells (72-h infusions). The areas under the cellular curve were similar and independent of the duration of the DNM infusion. Peak leukemic cell daunomycinol (DNMol) concentrations were respectively 3500 ± 1600 ng/10⁹ cells and 2850±1720 ng/10⁹ cells. Cellular DNM terminal half-life was 13±4 h. DNM concentrations in nucleated blood and bone marrow cells correlated well (r=0.93, n=26). Long-term infusion produced less severe side effects. Therapeutic efficacy was maintained during long-term infusion.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     

Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia: comparison of bolus administration and continuous infusion

The purpose of this study was to determine whether administration of doxorubicin (DOX) as a continuous infusion or a bolus injection resulted in similar leukemic cell drug concentration in patients with refractory chronic lymphocytic leukemia (CLL). This study was carried out on five patients with refractory CLL, with DOX administered either as a bolus injection (35 mg/m²; CHOP protocol) or as a constant-rate infusion for a period of 96 h (9 mg/m² per day; VAD protocol). The two types of drug administration were used alternatively with the same patient. Plasma and cellular DOX concentration were determined using high-performance liquid chromatography. Peak plasma DOX levels were higher after the bolus injection than after continuous administration (1509±80 ng/ml vs 11.6±1.8 ng/ml, respectively), whereas the plasma area under the curve (AUC) levels were similar. Maximum DOX cellular concentrations were 8629±2902 ng/10⁹ cells (bolus injection) and 2745±673 ng/10⁹ cells (96 h infusion). The cellular AUC after the bolus injection was 2.85 times greater than that observed after continuous administration. This difference was due to a higher cellular peak level followed by a relatively prolonged retention of the drug, with a loss of only 25% in the first 24 h following. These findings demonstrated that in CLL the cellular DOX exposure can be notably modified by the method of drug administration, with higher drug intracellular concentrations being achieved after bolus administration than with the infusion schedule.     

Influence of infusion time on unchanged cisplatin disposition in patients with ovarian cancer

Summary The disposition of unchanged cisplatin in ten patients with ovarian cancer receiving 2-h infusions of 100 mg/m² was compared with that of ten patients receiving 6-h infusions. A high-performance liquid chromatographic assay specific for the unchanged drug was used and all collected samples were rapidly processed. Patients were catheterized for urine collections. Cisplatin renal clearance was significantly lower after 6-hour infusions (52.8±16.2 ml/min per m²) than after 2-h infusions (87.1±38.2 ml/min per m²) (P=0.026). Total clearance was also lower and less variable, although not significantly, in patients receiving the longer infusion. No differences in nonrenal clearance, volume of distribution, or half-life were observed between the two groups. There was only a poor relationship between cisplatin renal clearance and creatinine clearance after 2-h (r ²=0.02; P=0.66) and 6-h infusions (r ²=0.18; P=0.23). A single cisplatin plasma level obtained at the end of the infusion proved to be a good predictor of total cisplatin clearance after both 2-h (r ²-0.70; P=0.0096) and 6-h infusions (r ²=0.97; P=0.0001). This level was not significantly related to the relatively small changes in creatinine clearance that occurred after three courses of treatment.This study was supported by grants from the National Health and Medical Research Council of Australia and the Anti-Cancer Foundation of the Universities of South Australia     

Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit

Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg·kg^–1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739±265 vs 100±10 ng·ml^–1) and doxorubicinol (78±3 vs 16±3 ng·ml^–1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92±0.9 vs 3.59±0.72 g·g^–1 tissue;P<0.001) and doxorubicinol (0.24±0.02 vs 0.09±0.01 g·g^–1 tissue;P<0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol.     

Steady-state plasma concentrations and effects of taxol for a 250 mg/m2 dose in combination with granulocyte-colony stimulating factor in patients with ovarian cancer

Taxol, a natural product initially isolated from the stem bark of the western yewTaxus brevifolia, is undergoing phase II and III evaluation due to its reported activity against a variety of tumors. Previous studies have described correlations between plasma concentrations and toxicity when taxol is given (a) at lower doses, (b) for shorter infusion times, and (c) without granulocyte-colonystimulating factor. Because the 24-h infusion schedule is most commonly used in current clinical trials, we attempted to correlate steady-state plasma concentrations of taxol achieved with a 24-h continuous i.v. infusion with toxicities and responses. Plasma samples from 48 refractory ovarian cancer patients were obtained 1–2 h prior to the end of the first taxol infusion. Taxol concentrations were measured by high-performance liquid chromatography (HPLC). Interpatient variation of taxol plasma concentrations was small (mean±SD, 0.85±0.21 M. Total taxol body clearance was 256±72 ml min^–1m^–2 (mean±SD). Taxol plasma protein binding was 88.4%±1.3% (mean±SD,n=9). Grade 3–4 hematologic toxicity, mainly leukopenia, occurred in 92% of the patients. The leukopenia was transient and did not warrant a reduction in the dose of taxol. Grade 3–4 nonhematologic toxicity occurred in 8% of the patients. No severe hypersensitivity reaction or grade 3–4 neurotoxicity was observed. Correlations of plasma concentrations and toxicities were not feasible due to the high frequency of hematologic effects and the low frequency of nonhematologic toxicity. The low degree of interpatient variation in plasma concentrations hindered the development of correlations with response.     

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     

Infusion-rate independent cellular adriamycin concentrations and cytotoxicity to human bone marrow clonogenic cells (CFU-GM)

The effect of adriamycin (ADM) infusion-rate on cellular ADM concentrations and on clonogenicity of human haematopoietic cells was studied in vivo and in vitro. In patients an ADM dose of 30 mg m-2 was administered as a bolus injection, or as a 4 h or a 24 h infusion. In vitro the effect of ADM on clonogenic cell growth was determined after exposure during 5 min, 2 h and 24 h of human bone marrow cells to increasing ADM concentrations. ADM showed rapid intracellular accumulation, to levels 100-fold the plasma concentration in vivo or the incubation medium concentration in the in vitro experiments. After a bolus injection or 5 min exposure only approximately 10% of the cellular peak ADM was retained after elimination of the drug from the plasma or the incubation medium. Ninety percent of the ADM was apparently 'loosely' bound. After 4 h and 24 h constant-rate infusions and also after 2 h and 24 h incubations in vitro, the cells accumulated ADM gradually, and the subsequent washing-out of the cellular ADM was substantially less, most of the ADM being 'tightly' bound. Despite these different patterns of uptake and retention after in vivo short- and long-lasting infusion of the same total dose, the 'tightly-bound' cellular ADM concentrations were the same. Moreover, comparable cellular ADM concentrations, retained after efflux of the 'loosely-bound' cellular ADM fraction were equally cytotoxic to normal human clonogenic cells. Short-lasting cellular peak ADM concentrations which occur after a bolus injection or after short exposure to high ADM concentrations are not essential for the cytotoxic effect, in contrast to the retained, 'tightly-bound' cellular ADM levels.     

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

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

Clinical pharmacokinetics of carboplatin in children

The present study was undertaken to evaluate in children the plasma pharmacokinetics of free carboplatin given at different doses and schedules and to evaluate the inter- and intrapatient variability and the possible influence of schedule on drug exposure. A total of 35 children (age range, 1–17 years) with malignant tumors were studied. All patients had normal renal function (creatinine clearance corrected for surface body area, above 70 ml min^–1 m^–2; range, 71–151 ml min^–1 m^–2) and none had renal involvement by malignancy. Carboplatin was given at the following doses and schedules: 175, 400, 500, and 600 mg/m² given as a 1-h infusion; 1,200 mg/m² divided into equal doses and infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m² given as a 5-day continuous infusion. A total of 57 courses were studied. Carboplatin levels in plasma ultrafiltrate (UF) samples were measured both by high-performance liquid chromatography and by atomic absorption spectrophotometry. Following a 1-h infusion, carboplatin free plasma levels decayed biphasically; the disappearance half-lives, total body clearance, and apparent volume of distribution were similar for different doses. In children with normal renal function as defined by creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we found at each dose studied a limited interpatient variability of the peak plasma concentration (C_max) and the area under the concentration-time curve (AUC) and a linear correlation between the dose and both C_max (r=0.95) and AUC (r=0.97). The mean value ± SD for the dose-normalized AUC was 13±2 min m² l^–1 (n=57). The administration schedule does not seem to influence drug exposure, since prolonged i.v. infusion or bolus administration of 1,200 mg/m² achieved a similar AUC (13.78±2.90 and 15.05±1.44 mg ml^–1 min, respectively). In the nine children studied during subsequent courses a limited interpatient variability was observed and no correlation (r=0.035) was found between AUC and subsequent courses by a multivariate analysis of dose, AUC, and course number. The pharmacokinetic parameters were similar to those previously reported in adults; however, a weak correlation (r=0.52,P=0.03) between carboplatin total body clearance and creatinine clearance varying within the normal range was observed. A dosing formula appears unnecessary in children with normal renal function since a generally well-predictable free carboplatin AUC is achieved following a given dose.Supported by the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.)     

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     

Effect of a low-protein diet on doxorubicin pharmacokinetics in the rabbit

Summary Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enchanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low- protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8–12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1,n=15; group 2,n=14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48±3 vs 59±4 ml min^–1 kg^–1;P<0.05), prolonged the terminal climination half-life (28±2 vs 22±2 h;P<0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722±122 vs 1405±71 ng h ml^–1;P<0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-portein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52±5 vs 40±2 h;P<0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.Supported by the Department of Veterans Affairs and the American Heart Foundation     

Bleomycin pharmacokinetics in man

Summary Bleomycin plasma decay kinetics and urinary excretion were studied in nine patients after IV bolus injections of 13.7 to 19.9 U/M². Radio-immunoassay was used to measure bleomycin in plasma and urine samples. The resulting plasma concentration versus time data for each patient and the combined data obtained from all patients were fitted to a multiexponential equation using a nonlinear regression computer program. Pharmacokinetic parameters derived from the mean of all individual patient parameters and the composite of all plasma decay data were similar. Bleomycin initial and terminal plasma half-lives and volume of distribution for all plasma decay data from eight patients with normal serum creatinies were 24.4±4.0 min, 237.5±8.5 min, and 17.3±1.5 L/M², respectively. Mean 24-h urinary excretion accounted for 44.8±12.6% of the dose in seven patients who had normal serum creatinine values and complete urine collections. The total body clearance and renal clearance in these seven patients averaged 50.5±4.1 ml/min/M² and 23.0±1.9 ml/min/M², respectively. One patient with a serum creatinine of 1.5 mg% (normal 0.7 to 1.3 mg%) who was given 15.6 U/M² had a terminal plasma halflife of 624 min, a volume of distribution of 36.3 L/M², and 24-h urinary excretion of 11.6% of the dose. We conclude that bleomycin after intravenous bolus injection has a relatively short terminal phase plasma halflife and relatively large urinary elimination.     

Plasma and cerebrospinal fluid pharmacokinetics of cytosine arabinoside in dogs

Summary Cytosine arabinoside (ara-C) is a component of many protocols for the treatment of CNS (central nervous system) leukemia and lymphoma in humans and dogs. It is also used for the prophylaxis of CNS metastasis in acute lymphoblastic leukemia. Although ara-C enters the cerebrospinal fluid (CSF) of human cancer patients after i.v. administration, it is unclear whether a similar CNS distribution occurs in humans whose blood-brain barrier has not been compromised by invasive disease. No information on the penetration of ara-C into the CSF in dogs is available. We studied the plasma and CSF pharmacokinetics of 600 mg/m² ara-C in ten healthy male dogs after its administration as a rapid i.v. bolus (six dogs) or as a 12-h i.v. infusion (four dogs). Ara-C concentration in blood and CSF samples was determined by high-performance liquid chromatography (HPLC). After an i.v. bolus of ara-C, the mean plasma distribution half-life was 7.1±4.5 min and the mean elimination half-life was 69±28 min. The mean plasma clearance was 227±125 ml min^–1 m^–2. The peak concentration of ara-C in the CSF was 29±11 m, which occurred at 57±13 min after the ara-C bolus. The CSF elimination half-life was 113±26 min. During a 12-h infusion of ara-C (50 mg m^–2 h^–1), the plasma steady-state concentration was 14.1±4.2 m, the CSF steady-state concentration was 8.3±1.1 m, and the CSF: plasma ratio was 0.62±0.14. The plasma eleimination half-life was 64±19 min and the plasma clearance was 214±69 ml min^–1 m^–2. The CSF elimination half-life was 165±28 min. No clinically significant toxicity was observed over a 21-day period following drug administration in either of the treatment groups. Our data indicate that ara-C crosses the blood-brain barrier in normal dogs and that i.v. administration of this drug has potential as a treatment modality for neoplasia involving the CNS.Supported by the Canine Disease Research Fund and in part by the Elsa U. Pardee Foundation     

Cardiac troponin T as an indicator of reduced left ventricular contractility in experimental anthracycline-induced cardiomyopathy

Purpose Cardiac troponin T (cTnT) plasma concentration is considered a useful marker of anthracycline-induced cardiomyopathy. In this study we used daunorubicin-treated Chinchilla rabbits as a model to investigate the relationship between left ventricular contractility and cTnT plasma concentrations.Methods Two groups of animals were used: a control group (n=8) received i.v. saline, and an experimental group (n=11) received daunorubicin (3 mg/kg, i.v.). The substances were administered once weekly for 10 weeks, and 5–7 days after the last administration, left ventricular cardiac contractility (dP/dt_max) was invasively measured as a contractility index and blood was sampled for cTnT concentration determination (Elecsys Troponin T STAT immunoassay).Results Cardiac contractility was significantly lower in seven surviving daunorubicin-treated animals than in control animals (745.7±69.3 vs 1393.4±25.5 kPa/s; P<0.001), while cTnT plasma concentrations were significantly increased (medians 0.278 vs 0.000 ng/ml; P<0.001). When the dP/dt_max values of individual daunorubicin-treated animals were plotted against the corresponding cTnT plasma concentrations, a close negative linear correlation was found (R=–0.910; P<0.005; regression equation: dP/dt_max=–1861*cTnT+1234).Conclusions This study suggests that determination of cTnT plasma levels, which is simple and inexpensive, could be used in anthracycline-treated patients for left ventricular systolic function assessment and contractility estimation.     

Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit

Summary Doxorubicin is metabolized extensively to doxorubicinol by the ubiquitous aldoketoreductase enzymes. The extent of conversion to this alcohol metabolite is important since doxorubicinol may be the major contributor to cardiotoxicity. Aldoketoreductases are inhibited in vitro by phenytoin. The present study was conducted to examine the effect of phenytoin on doxorubicin pharmacokinetics. Doxorubicin single-dose pharmacokinetic studies were performed in 10 New Zealand White rabbits after pretreatment with phenytoin or phenytoin vehicle (control) infusions in crossover fashion with 4–6 weeks between studies. Infusions were commenced 16 h before and during the course of the doxorubicin pharmacokinetic studies. Phenytoin infusion was guided by plasma phenytoin estimation to maintain total plasma concentrations between 20 and 30 g/ml. Following doxorubicin 5 mg/kg by i.v. bolus, blood samples were obtained at intervals over 32 h. Plasma doxorubicin and doxorubicinol concentrations were measured by HPLC. The mean plasma phenytoin concentrations ranged from 17.4 to 33.9 g/ml. Phenytoin infusion did not alter doxorubicin pharmacokinetics. The elimination half-life and volume of distribution were almost identical to control. Clearance of doxorubicin during phenytoin administration (60.9±5.8 ml/min per kg, mean±SE) was similar to that during vehicle infusion (67.5±5.4 ml/min per kg). Phenytoin administration was associated with a significant decrease in doxorubicinol elimination half-life from 41.0±4.8 to 25.6±2.8 h. The area under the plasma concentration/time curve (AUC) for doxorubicinol decreased significantly from 666.8±100.4 to 491.5±65.7 n.h.ml^-1. These data suggest that phenytoin at clinically relevant concentrations does not alter the conversion of doxorubicin to doxorubicinol in the rabbit. The reduction in the AUC for doxorubicinol caused by phenytoin appears to be due to an increased rate of doxorubicinol elimination. Phenytoin or similar agents may have the effect of modifying doxorubicinol plasma concentrations by induction of doxorubicinol metabolism rather than by inhibition of aldoketoreductase enzymes.     

Pharmacokinetic and pharmacodynamic studies with 4′-epi-doxorubicin in nasopharyngeal carcinoma patients

Summary The plasma pharmacokinetic profile of 4-epidoxorubicin (epirubicin) was investigated in 28 patients with nasopharyngeal carcinoma (NPC) after single i.v. rapid infusions. All patients had normal liver and renal functions. Plasma concentrations of the parent compound were specifically determined by a high-performance liquid chromatographic (HPLC) method, with UV detection at 254 nm. Plasma levels of the compound were fitted to a three-compartment open model; a triexponential decrease in plasma concentrations with a long terminal plasma halflife (44.8±21.2 h) was observed in 27 patients. The respective mean (±SD) serum concentration at 72 h and the AUC, plasma clearance, and terminal elimination rate constant in complete responders were 7.67±1.98 ng/ml, 4,002±3,080 ng· h/ml, 26.6±12.9 l/h·m², and 0.009±0.007 l/h, whereas those in nonresponders were 4.96±1.8 ng/ml, 1,88±652.8 ng·h/ml, 44.4±15 l/h·m², and 0.017±0.006 l/h, respectively; these differences were significant (P(0.05). Epirubicin produced a 52% response rate, including 6 patients with a complete response, 8 with a partial response, 11 with no change, and 2 with progressive disease. No relationship could be found between the various pharmacokinetic parameters and either leukopenia, age, or sex. These observations strongly suggest that plasma clearance may be one of the determining factors affecting the response or nonresponse of NPC patients to epirubicin, and a dose adjustment according to plasma clearance would probably increase the response rate.     

Prolonged response to a single androgen suppression phase in a subpopulation of prostate cancer patients

Background:In an intermittent androgen suppression therapy (IAS)trial we observed regular cycles of tumor suppression and regrowth in themajority of patients (17 ± 2.6 month), with a subpopulation of patients(14 of 72) exhibiting a prolonged response of 28 ± 7 month (range18–64+ month) to the first eight-month androgen suppression cycle. Purpose:To compare clinical data and laboratory tests(testosterone, prostate-specific antigen, and tissue polypeptide-specificantigen) of matched IAS patients showing either regular treatment cycles(n= 16) or prolonged response (n= 14). Results:Periods of androgen suppression resulted in reversiblereduction of serum testosterone (<1 nmol/l), PSA (<1 ng/ml) indicatingpartial growth arrest and apoptotic regression of the tumors. The long-termresponse subgroup showed significantly lower mean values of tumor gradings,of pretreatment PSA values (11.36 ± 4.54 vs. 47.5 ± 12.4 ng/mlPSA), of PSA nadirs during androgen suppression (0.5 vs. 1 ng/ml PSA), and ofoverall testosterone values (3.9 ± 1.14 vs. 6.6 ± 1.18 mmol/lpretreatment) associated with low TPS values. Conclusions:Patients exhibiting prolonged response to a singlecycle of androgen suppression during IAS are characterized by a lower tumorburden, slow growing and less agressive tumors, lower testosterone serumconcentrations and lower absolute PSA nadirs during androgen suppressioncompared to a matched control group of short-term responders.     

Uridine pharmacokinetics in cancer patients

Summary The availability of uridine can alter the sensitivity of tumor cells to antimetabolites such as N-phosphonacetyl-l-aspartic acid (PALA) and acivicin by virtue of the cell's ability to salvage preformed metabolites from its environment. We investigated the pharmacokinetics of physiologically relevant amounts of uridine in cancer patients in a pilot study to further our understanding of uridine metabolism in the human body. Four cancer patients, two males and two females, were given an i.v. bolus of a trace amount of radiolabeled uridine. The nucleoside disappeared from the plasma in a triphasic manner, with initial half-lives of 0.57±0.28 and 1.79±0.62 min and a terminal half-life of 17.5±7.3 min. The volume of distribution was 481±70 ml/kg, and the plasma uridine clearance was calculated to be 1.70±0.42 l/min. Simultaneous plasma and bone marrow uridine concentrations were measured in a separate group of seven healthy volunteers. The uridine concentration in plasma was 2.32±0.58 M, and that in the bone marrow plasma was 10.44±5.06 M. These results suggest a very rapid turnover of uridine in the plasma when the nucleoside is present at physiologic concentrations, and that there is a locally high concentration of uridine available for salvage in the bone marrow.Supported by grants CA 23334 and CA 23100 from the NCI and a grant from Boehringer Ingelheim Ltd. Presented as an abstract at the American Association for Cancer Research Meeting in Los Angeles, CA, May 7–10, 1986. This research is conducted in part by the Clayton Foundation for Research, California Division. Dr. Howell is a Clayton Foundation Investigator     

A phase I trial of high-dose continuous-infusion hydroxyurea

Hydroxyurea inhibits ribonucleotide reductase, resulting in depletion of intracellular deoxynucleotide pools and inhibition of DNA repair. It has been used in a variety of malignancies and is usually given orally. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuous infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximum tolerated, doses (MTD) of intravenous hydroxyurea given as a 24-or 48-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m² following a bolus of 1,690 mg/m², and the mean (±SD) plasma steady-state concentration was 1.93±0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m² following a bolus of 2,197 mg/m² and the mean steady-state level was 1.43±0.31 mM. The doselimiting toxicity on both schedules was marrow suppression manifesting as, neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing clearance with increasing dose, implying that drug elimination is saturable. Pharmacodynamic analysis showed a slight correlation between steady-state plasma levels and the degree of marrow suppression.This work was supported in part by grants 5T32-CA-09307, P30-A-14236-18, and 5-R01-CA45529 from the National Institutes of Health and the National Cancer Institute and by the P.B. Cohen Memorial Fund     

Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10^–3 M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016±143 mol/l. The mean dose delivered was 13.2±2 g/m². The clearance was 49.1±11.7 ml min^–1 m^–2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with at _1/2 of 2.66±0.82 h and at _1/2 of 15.69±8.63 h. The volume of distribution was 0.32±0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%–21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. Thet _1/2 and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P<0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significantly different from those of the group of nonsensitive patients.