Dosage adjustment of fluconazole during continuous renal replacement therapy (CAVH, CVVH, CAVHD, CVVHD)

Continuous arterio-venous haemofiltration (CAVH), continuous veno-venous haemofiltration (CVVH), continuous arterio-venous haemodialysis (CAVHD) and continuous veno-venous haemodialysis (CVVHD) are increasingly used in patients with acute renal failure (ARF). The elimination rate of fluconazole varies considerably depending on the procedure used. (In Germany, fluconazole is approved for the treatment of life-threatening fungal infections caused by Candida spp. and Cryptococcus neoformans at a dosage of up to 800 mg day-1.) The elimination rate of fluconazole by CVVHD depends on the combined dialysate/ultrafiltrate flow rate, but is much higher than achieved with CVVH and intermittent dialysis, with a fluconazole clearance in patients with CVVHD 2 l h-1 exceeding the values of healthy persons. To achieve therapeutic plasma levels during continuous renal replacement therapy, the same loading dose as in patients without renal failure should be administered, followed by a maintenance dose that is adjusted for anuric patients by multiplying by a factor that takes into account the extracorporeal elimination of the absorbed dose (CAVH, CVVH x 2.2, ultrafiltrate flow 0.5 l h-1; CAVHD, CVVHD x 3.8, combined dialysate/ultrafiltrate flow 1.5 l h-1). Despite the broad therapeutic margin of fluconazole, drug monitoring is recommended to achieve therapeutic drug levels in life-threatening indications because there have been only a few investigations of this, all involving relatively low dosages (up to 200 mg day-1).     

Antimycotic drugs under continuous renal replacement therapy

In critically ill patients with acute renal failure and continuous renal replacement therapy (CRRT), the elimination of antimycotic agents is influenced by many factors; these include not only the nature and dose of the renal replacement therapy but also the properties of the medicine. High protein binding, a high molecular weight and little or no renal elimination even in subjects with normal renal function suggest that a substance is not eliminated by CRRT. This is the case with amphotericin B, caspofungin, itraconazole and voriconazole, but not with fluconazole. In the case of fluconazole, an increase in dose than that used in patients with normal renal function may be required according to the nature and dose of CRRT, because the clearance of fluconazole can be substantially higher under CRRT than in subjects with normal renal function. Daily doses of 800 mg or more may be necessary. As a result of the diverse influences on elimination in patients receiving CRRT, the determination of fluconazole through concentrations cannot be dispensed with, in order to avoid underdosing and a failure of the antimycotic therapy.     

Special pharmacokinetics of fluconazole in septic, obese and burn patients

Although there are many potential changes of pharmacokinetic parameters in patients with thermal injury, obesity or septicemia, data about the actual effect on pharmacokinetics and clinical efficacy of fluconazole are very limited. As current dosing recommendations are derived from healthy subjects and patients with normal weight, these recommendations may be inaccurate when applied to the patient populations mentioned above. Pharmacokinetic data of 14 patients with thermal injury were reviewed and revealed a shorter half life and more rapid clearance of fluconazole. In a subgroup of five patients, distribution volume was up to 2 times larger as usual with no relationship to creatinine clearance and degree of burns. In one extremely obese patient treated with fluconazole 1200 mg/day, the corresponding mean steady-state plasma concentration and AUC were decreased with an increase of fluconazole clearance possibly due to a larger volume of distribution. In patients with septicemia, fluconazole plasma levels appear to be highly variable. As a considerable number of these patients develops acute renal failure, renal replacement therapy may be indicated which may require substantial dosage modifications of fluconazole.     

CVVH联合血液灌流治疗多发性骨髓瘤合并急性肾损伤的疗效观察

目的:观察连续性静脉-静脉血液滤过(continuous veno-venous hemofiltration，CVVH)联合血液灌流(hemoperfusion，HP)对多发性骨髓瘤（multiple myeloma，MM）合并急性肾损伤（acute kidney injury，AKI）患者的治疗效果。方法:选取本院2017年5月至2018年5月收治的MM合并AKI患者68例纳入研究，按照随机数字表法分成两组，每组各34例，对照组给予硼替佐米、马法兰和泼尼松化疗治疗，观察组在对照组基础上采用CVVH联合HP治疗，观察并比较两组患者的治疗效果，治疗前后肾功能损伤及其相关指标的变化。结果:观察组治疗总有效率为82.35%，明显高于对照组的55.88%（P＜0.05）；治疗后，两组患者的BUN、SCr、β2-MG及CysC水平均较治疗前下降（P＜0.05），且观察组患者各指标较对照组下降更显著（P＜0.05）；治疗后，两组的M 蛋白水平和骨髓瘤细胞百分比均较治疗前显著降低，血红蛋白水平均较治疗前显著升高（P＜0.05），且观察组较对照组改善更显著（P＜0.05）；治疗后，两组患者的不良反应发生率比较差异无统计学意义（P＞0.05）。结论:CVVH联合HP能够提高MM合并AKI患者的治疗效果，减轻肾功能损伤，安全性良好。     

Pharmacokinetics of ethylenediaminemalonatoplatinum(II) (JM-40) during phase I trial

Pharmacokinetics of the cis-platin analog ethylenediaminemalonatoplatinum(II) (JM-410) was studied in 28 cycles of 19 patients during the phase I study of this drug. The drug was administered intravenously by short-term (10-60 min) infusion. Doses ranged from 20 to 1,200mg m-2. JM-40 was determined in plasma ultrafiltrate and urine by HPLC. Platinum (Pt) concentrations were determined in plasma, plasma ultrafiltrate, urine and red blood cells by atomic absorption spectrometry up to 5 days after administration of the drug. Ultrafilterable Pt could be determined up to 45 days after the infusion in one patient sampled over such a long period. Pharmacokinetics of JM-40 showed a linear behaviour. The final half-life of total Pt in plasma was 4.1 +/- 0.9 days. The disposition of JM-40 was similar to that of ultrafilterable Pt in respect to t1/2 alpha (10 and 13 min), t1/2 beta (44 and 57 min), volumes of distribution Vc (11 and 121) and Vss (17 and 201), systemic clearance (256 and 223 ml min-1), renal clearance (69 and 73 ml min-1) and metabolic clearance (183 and 154 ml min-1). During the first 6 h 27 +/- 9% of the administered dose was excreted as JM-40. Cumulative platinum excretion in the urine amounted to 29 +/- 13% and 60 +/- 13% over the first 6 h, 24 h and 5 days, respectively. The uptake of platinum in red blood cells was limited, comprising only 0.24 +/- 0.12% of the administered dose. Although JM-40 and carboplatin are structurally closely related, pharmocokinetics and toxicity of JM-40 were more similar to cis-platin than to carboplatin.     

Pharmacokinetics of oxaliplatin in humans

Oxaliplatin is a novel platinum complex used for the treatment of metastatic colorectal carcinoma. The pharmacokinetics of the free fraction of oxaliplatin in blood were evaluated in 10 patients given 85 mg/m² of oxaliplatin using an infusion time of 2 h. Blood samples were collected during and after the infusion and immediately placed on ice. The samples were ultrafiltrated centripetally and the concentration of oxaliplatin in the ultrafiltrate was determined by liquid chromatography in combination with postcolumn derivatization. The in vitro degradation rate was determined in blood from the patients taken immediately before drug administration. The maximal blood concentration (C _max) and terminal half-life (t _1/2) were 1.44±0.20 (SD) μg/mL and 14.1 min (range: 10.2–24.5), respectively. The area under the blood concentration time curve (AUC), clearance (CL), and distribution volume (V _ss) were (means±SD) 161±22 μg min/mL, 32.1±4.2 L/h/m², and 0.26±0.06 L/kg, respectively. There was a significant correlation between the clearance of oxaliplatin in the patients and the degradation rate in whole blood (r=0.746; p=0.017). Oxaliplatin has a short elimination half-life, which is in a sharp contrast to previously reported elimination half-lives obtained by analysis of the platinum content in plasma and ultrafiltrate. The correlation between in vivo and in vitro data suggests that the degradation in whole blood plays a role for the elimination of the drug.     

Effect of renal dysfunction in dogs on the disposition and marrow toxicity of melphalan.

The effect of renal failure on melphalan pharmacology and toxicity has been poorly understood. Such information is of interest because melphalan is the most commonly used anticancer drug in the treatment of multiple myeloma, which is frequently associated with renal failure. We have studied the disposition and marrow toxicity of parenteral melphalan in dogs before and after induction of renal failure with subtotal nephrectomy. The surgical procedure decreased the creatinine clearance by an average of 62% (P = 0.001). The lowest neutrophil counts following i.v. melphalan (1 mg/kg) averaged 4.9 x 10(3)/mm3 pre-nephrectomy and 0.9 x 10(3)/mm3 post-nephrectomy, respectively (P = 0.002). The mean lowest recorded platelet counts after melphalan (1 mg/kg) were 115 x 10(3)/mm3 in the pre-nephrectomized dogs, and 9.7 x 10(3/mm3 in those who had been nephrectomized (P = 0.002). Following nephrectomy, i.v. melphalan''s terminal-phase plasma half-life and renal clearance were both raised (P = 0.02) to 75% over pre-nephrectomy values. These studies show that i.v. melphalan-induced myelosuppression is markedly increased and its plasma elimination and renal clearance significantly decreased in the presence of renal dysfunction in dogs. These data suggest that parenteral melphalan''s starting dose be decreased by at least 50% when used in myeloma patients with renal failure.     

Clinical pharmacokinetics of oxaliplatin: a critical review.

Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O'] platinum; Eloxatine) is a novel platinum coordination complex used for the treatment of metastatic colorectal carcinoma in combination with fluoropyrimidines. The objective of this review is to integrate the key data from multiple studies into a single, comprehensive overview of oxaliplatin disposition in cancer patients. The pharmacokinetics (PKs) of unbound platinum in plasma ultrafiltrate after oxaliplatin administration was triphasic, characterized by a short initial distribution phase and a long terminal elimination phase (t1/2, 252-273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m2 every 3 weeks or 85 mg/m2 every 2 weeks. Interpatient and intrapatient variability in platinum exposure (area under the curve(0-48)) is moderate to low (33 and 5% respectively). In the blood, platinum binds irreversibly to plasma proteins (predominantly serum albumin) and erythrocytes. Accumulation of platinum in blood cells is not considered to be clinically significant. Platinum is rapidly cleared from plasma by covalent binding to tissues and renal elimination. Urinary excretion (53.8 +/- 9.1%) was the predominant route of platinum elimination, with fecal excretion accounting for only 2.1 +/- 1.9% of the administered dose 5 days postadministration. Tissue binding and renal elimination contribute equally to the clearance of ultrafilterable platinum from plasma. Renal clearance of platinum significantly correlated with glomerular filtration rate, indicating that glomerular filtration is the principal mechanism of platinum elimination by the kidneys. Clearance of ultrafilterable platinum is lower in patients with moderate renal impairment; however, no marked increase in drug toxicity was reported. The effect of severe renal impairment on platinum clearance and toxicity is currently unknown. Covariates such as age, sex, and hepatic impairment had no significant effect on the clearance of ultrafilterable platinum, and dose adjustment due to these variables is not required. Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation and is not subjected to CYP450-mediated metabolism. Up to 17 platinum-containing products have been observed in plasma ultrafiltrate samples from patients. These include several proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo-diaminocyclohexane platinum complexes, along with several other noncytotoxic products. Oxaliplatin does not inhibit CYP450 isoenzymes in vitro. Platinum was not displaced from plasma proteins by a variety of concomitant medications tested in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and irinothecan have been observed. These results indicate that the additive/synergistic antitumor activity observed with these agents is not due to major alterations in drug exposure, and the enhanced efficacy is likely to be mechanistically based. Together, these PK, biotransformation, drug-drug interaction analyses and studies in special patient populations provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition observed in patients.     

Effective clearance of Ara-U the major metabolite of cytosine arabinoside (Ara-C) by hemodialysis in a patient with lymphoma and end-stage renal failure

Purpose

We report that hemodialysis clears Ara-U from the blood after high-dose Ara-C treatment in a patient with lymphoma and end-stage renal failure.

Methods

The patient received two doses of Ara-C 1?g/m² 24?h apart and was hemodialyzed at about 6?h after each dose and subsequently as per her usual dialysis schedule. Multiple blood samples were collected after dosing. Blood and dialyzate were also collected from the dialysis circuit during a second identical treatment cycle. Ara-C and its metabolite Ara-U in plasma and dialyzate were measured chromatographically, and the data subjected to pharmacokinetic analysis.

Results

The distribution and elimination half-lives, steady-state volume of distribution and clearance values were 0.5?h, 7?h, 181 L and 307?l/h for Ara-C and 4.1?h, 34?h, 118 L and 2.64?l/h for Ara-U, respectively. The dialysis sessions immediately after the first and second doses cleared 39 and 52% (as Ara-U) of the respective Ara-C doses. Some 63% of Ara-U in plasma was extracted by dialysis. The patient showed no signs of neurotoxicity or other drug-related adverse effects.

Conclusion

Hemodialysis is very effective in clearing Ara-U from the plasma in renal failure, and this maneuver could easily be used routinely to prevent Ara-U accumulation and minimize adverse effects in patients with renal failure.     

Pharmacokinetics of dibromodulcitol in humans: a phase I study

A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed. Twenty-three patients with advanced neoplasms received DBD doses ranging from 600 to 1,800 mg/m2 body surface area (BSA). The dose-limiting toxicity was myelosuppression, with both significant granulocytopenia and thrombocytopenia occurring at dose levels of 1,500 to 1,800 mg/m2. The average pharmacokinetic parameters for DBD, calculated on the basis of a one-compartment model with first-order absorption and elimination, include the elimination constant, .005 +/- .002/min; absorption constant, .012 +/- .009/min; and an apparent volume of distribution, 1.03 +/- .4 L/kg. The area under the drug concentration curve (AUC) and the peak drug level (Cmax) were linearly related to the dose administered (P less than .001). The mean AUC was 18.7 +/- 6.1 mmol/L min, and the mean Cmax was 47.1 +/- 16.8 mumol/L when normalized to a DBD dose of 1 gm/m2. The elimination constant was significantly reduced in patients with abnormal hepatic function (P less than .01). The elimination constant was not correlated with renal function. The half-life of DBD in plasma (158 minutes) was considerably shorter than the four-to eight-hour half-life of total radioactivity in plasma measured by previous investigators following the administration of radiolabeled DBD.     

A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin

We have treated 14 cancer patients with liposome-encapsulated doxorubicin (LED) at doses of 30, 45, 60, and 90 mg/m2. Nausea and vomiting, phlebitis, and stomatitis were minimal or absent at each dose, but dose-limiting granulocytopenia occurred at 90 mg/m2. Thrombocytopenia and/or anemia also occurred in all patients treated at 60 or 90 mg/m2. Complete alopecia was seen in one of three cases at 60 mg/m2 and all cases at 90 mg/m2. No hepatic, renal, or other major organ toxicities were encountered. Clinical cardiac toxicity did not occur in any patient, but the cumulative doxorubicin doses in 13 cases were less than 400 mg/m2. The plasma elimination of LED out to 24 hours was analyzed in terms of a two-compartment model. Depending upon the dose and the infusion time, maximum plasma concentrations ranged from 2.6 mumol/L to 36.89 mumol/L and the area under the plasma concentration x time curve (AUC) values ranged from 1.86 mumol/L x h/L to 49.57 mumol x h/L. These values are significantly higher than those expected for free doxorubicin. Urinary excretion of LED was approximately 10% after 24 hours. Doxorubicinol and doxorubicinone appeared at low levels in plasma 12 to 24 hours after injection. LED pharmacokinetics differ from those of free drug by the higher plasma levels and AUC of doxorubicin achieved, and by the low conversion of LED to metabolites. Overall, LED was well tolerated and produced only moderate nausea and vomiting and little stomatitis at myelosuppressive doses. The study also suggested that LED produces less venous sclerosis than free doxorubicin, but this requires further clinical verification.     

Phase I-II study of interferon-gamma and eflornithine (DFMO) in patients with advanced renal cell carcinoma, malignant melanoma and colorectal carcinoma

Eflornithine (DFMO) and interferon-gamma (IFN-gamma) are known to exert synergistic activity on inhibition of ornithinedecarboxylase (ODC) in vitro and in experimental animal tumors thereby inhibiting tumor proliferation. In this study, we prospectively investigated therapeutic effects and side effects of a combination of DFMO and IFN-gamma in 15 patients with renal cell carcinoma (RCC), 9 with malignant melanoma (MM), and 9 with colorectal carcinoma (CRC). DEMO was given orally at a dose of 3x4 g/day during the first 2 weeks of each month; IFN-gamma was administered daily subcutaneously during the DFMO administration periods and every other day during the following 2 weeks. The starting dose of IFN-gamma was 30 mu g/m(2) in the first 5 patients and 60 mu g/m(2) in the next 28. IFN-gamma dose was doubled every 4 weeks to a maximum dose of 120 mu g/m(2) and 240 mu g/m(2), respectively. Therapy was applied for three months in cases with stable disease or partial remission. In 15 patients treatment was stopped after 3 to 11 weeks after initiation of therapy because of tumor progression (14 cases) or severe side effects (1 case). In one out of 15 patients with renal cell carcinoma a partial response was observed lasting 7 months, 5 patients showed stable disease, and 9 progressed. In patients with malignant melanoma and colorectal carcinoma, stable disease was observed in one patient and progressive disease in 8 patients per group. The most frequent side effects were fever and gastrointestinal disturbances observed in 26 patients each. The results of this study indicate that DFMO combined with IFN-gamma has no significant therapeutic activity in patients with advanced renal cell carcinoma, malignant melanoma, and colorectal carcinoma.     

A study to evaluate the pharmacokinetics of oral 5-fluorouracil and eniluracil after concurrent administration to patients with refractory solid tumours and varying degrees of renal impairment (FUMA1005)

BACKGROUND: Eniluracil is an inactivator of dihydropyrimidine dehydrogenase, the first enzyme in the catabolic pathway of 5-fluorouracil (5-FU). Concurrent administration of oral eniluracil with oral 5-FU not only increases the bioavailability of 5-FU, owing to elimination of first-pass metabolism, but can change the route of elimination of 5-FU from hepatic metabolism to renal excretion. An open-label study was performed to determine the effect of renal impairment on the pharmacokinetics of 5-FU in the presence of eniluracil. METHODS: Enrolled in the study were 17 patients with refractory solid tumours (Karnofsky performance status >/=70%; age 31-74 years; 12 male, 5 female). The patients were separated into two groups based upon creatinine clearance (CLCr): group A had "normal" renal function arbitrarily defined as CLCr >/=50 ml/min ( n=8), and group B had moderate renal impairment, i.e. CLCr <50 ml/min ( n=9). Treatment was separated into test and treatment periods. During the test period all patients received eniluracil 50 mg orally on days 1-3 and 5-FU 10 mg/m(2) together with pharmacokinetic measurements. During the treatment period, all patients received eniluracil 50 mg orally on days 1-7 with 5-FU at a standard dose of 20 mg/m(2) for those in group A or a dose individualized according to the pharmacokinetic parameters in the test period for those in group B. RESULTS: The clearance of both eniluracil and 5-FU was decreased in patients with renal impairment compared to those with normal renal function. A linear relationship was observed between 5-FU CL/F and CLCr in patients with renal impairment, but not in those with normal renal function. 5-FU dose modification, on the basis of the test dose pharmacokinetic data for the patients with renal function impairment, accurately resulted in drug exposure in the potentially therapeutic range. Toxicity was not increased. CONCLUSIONS: Eniluracil increases the oral bioavailability of 5-FU and results in a switch from hepatic metabolism to renal elimination. A standard dose of this combination can be administered safely to patients with CLCr >50 ml/min. The combination can also be given to patients with renal impairment using a test dose and pharmacokinetic measurements to predict the appropriate dose of 5-FU. It is expected that sufficient information will be available from this and other studies to allow accurate prediction of the appropriate 5-FU dose modifications required in patients with renal impairment.     

High-dose ifosfamide,carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity

An autologous bone marrow transplant regimen of ifosfamide, carboplatin, and etoposide (ICE) has been developed as treatment for certain malignancies. At maximum tolerated doses renal insufficiency precludes dose escalation. The objective was to examine whether measurement of plasma drug levels early during treatment would provide warning of renal failure. Nine patients received a 96-h continuous infusion of ifosfamide 16000 mg/m², carboplatin 1600 mg/m², and etoposide 1200 mg/m². Pharmacokinetics, including drug levels and plasma concentration-time curves, of ifosfamide, ultrafiltrable platinum (uPt) and etoposide were analyzed and correlated with renal function. One of the nine patients developed anuric renal failure requiring hemodialysis. By 17 h from the start of infusion, this patient showed substantially higher drug levels of ifosfamide (200 vs mean 217 M) and uPt (19 vs mean 10M) than those patients with preserved renal function. The 95% confidence intervals suggested that a 16–22 h ifosfamide level >153 M and an uPt level >M predict the development of significant renal dysfunction. Although drug levels were substantially higher at 56 h, the serum creatinine did not yet reflect kidney injury. This study suggests that high plasma ifosfamide and uPt levels, analyzed early in the course of a 96-h infusion of high-dose ICE, provide warning of severe and potentially fatal renal injury. Since ICE has substantial activity in a number of malignancies, but significant renal morbidity, real-time pharmacokineticguided dosing may reduce treatment-related toxicity.Supported in part by US. Public Health Service Grants PO1-CA-38493 and CA-06516 and a grant from the Mathers Foundation. Drs. Ayash and Schwartz are recipients of a Career Development Award from the American Cancer Society     

Pediatric phase I trial and pharmacokinetic study of tiazofurin (NSC 286193)

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a new nucleoside antimetabolite, was evaluated in a phase I trial involving children with refractory cancers. The drug was administered i.v. as a 10-min infusion daily for 5 consecutive days repeated at 3-week intervals. The dose ranged from 550 to 3300 mg/sq m/day. Seventeen patients received 23 courses and were evaluable for toxicity. The maximally tolerated dose was 2200 mg/sq m/day. The major dose-limiting toxicities were nonhematological. Neurotoxicity, including headache, drowsiness, and irritability, was common and was the principal dose-limiting toxicity at the higher doses. Severe myalgias were also dose limiting in one patient. Other side effects were mild, reversible elevations in serum transaminases; nausea, vomiting, and diarrhea; mild hypertension; dysphagia; and exfoliative dermatitis of the hands and feet. Myelotoxicity was not significant. The pharmacokinetics of tiazofurin was studied in 16 patients. Plasma disappearance was triphasic with half-lives of 9.7 min, 1.6 h, and 5.5 h. Clearance was dose related, ranging from 120 ml/min/sq m at 550 mg/sq m/day to 70 ml/min/sq m at 3300 mg/sq m/day. The primary route of elimination was renal with 85% of the drug recoverable in the urine as the parent compound in the 24 h following administration.     

Pharmacology of N,N-di(n-butyl)adriamycin-14-valerate in the rat

 Lipophilic N-alkylanthracyclines such as AD 198 (N-benzyladriamycin-14-valerate) or AD 201 [N,N-di-(n-propyl)adriamycin-14-valerate], which exert their cytotoxicity through mechanisms which are not yet fully defined, possess inherent abilities to circumvent multidrug resistance in vitro and in vivo, possibly through alterations in normal intracellular drug trafficking. As part of structure-activity studies with this class of agent, we have now examined the pharmacology of AD 202 [N,N-di(n-butyl)adriamycin-14-valerate], another analog possessing superior antitumor activity to doxorubicin in vivo and an ability to circumvent multidrug resistance in vitro. Following the administration of AD 202 (20 mg/kg, i.v.) to anesthetized rats, rapid drug distribution (T_1/2 5 min) was followed by more gradual elimination (T_1/2 3.6 h). Plasma clearance of AD 202 (224±63.6 ml/min per kg) and steady state volume of distribution (25.7±11.1 l/kg) were indicative of extensive tissue sequestration and/or a large degree of extra-hepatic metabolism. The parent drug predominated in plasma until 20 min, thereafter N,N-di(n-butyl)adriamycin became the principal circulating anthracycline. The systemic exposure to this biotransformation product (area under the plasma concentration-time curve from time zero to 480 min AUC_0-480 28 1672 ng ⋅ min/ml) was >tenfold higher than for the other detected plasma products (N-butyladriamycin-14-valerate, N-butyladriamycin, and three unidentified fluorescent signals; P1-3). Total urinary elimination over 8 h was limited (1.9% of dose), occurring predominantly as N,N-di(n-butyl)adriamycin (1.2% of dose), N-butyladriamycin (0.4% of dose), and their corresponding 13-carbinol metabolites (<0.1% of dose each). Low levels of adriamycin (ADR), aglycones and two unidentified products were also seen. Parental AD 202 was found in urine only up to 1 h. By contrast, hepatic elimination of parent drug was seen, albeit at low levels, through 8 h. Excretion by this route (22% of dose) occurred principally as N-butyladriamycin (8% of dose), N-butyladriamycinol (2.1% of dose) with lower levels of N,N-di(n-butyl)adriamycin (1.6% of dose), N,N-di(n-butyl)adriamycin (0.8% of dose), and aglycones (4.3% of dose, combined). Other products included ADR (1.1% of dose) and two unidentified signals (3.4% of dose, combined). The relatively poor mass balance in these studies is attributed to prolonged intracellular retention (elimination T_1/2 24.2 h) of N,N-di(n-butyl)adriamycin. Thus, in common with other N-alkylanthracyclines, the pharmacology of AD 202 is complex but its therapeutic properties clearly are not derived from an ADR prodrug effect. Significant differences continue to be noted as to the metabolic fate of congeners of this class of anthracycline analogs. Received: 19 September 1994/Accepted: 27 June 1995     

Single-dose pharmacokinetics of aztreonam in healthy volunteers and renal failure patients

The pharmacokinetics of aztreonam were studied in 6 healthy male volunteers and 12 male patients with various degrees of chronic renal failure after intravenous bolus injection of 1g of the drug. Serum pharmacokinetics of aztreonam were described by an open, two-compartment kinetic model. The serum levels of aztreonam exceeded the reported minimum inhibitory concentration (MIC)90 for Enterobacteriaceae for 8 hours and up to 24 hours, in healthy volunteers and renal failure patients, respectively. However, the serum levels of the drug exceeded the MIC50 for Pseudomonas aeruginosa for only 4 hours and 12 hours in healthy volunteers and patients, respectively. The half-life of elimination (t 1/2/beta) increased significantly (P less than 0.001) from 1.8 +/- 0.14 h in healthy volunteers and to 4.9 +/- 1.1 h in patients with renal failure. The total serum clearance of aztreonam decreased significantly (P less than 0.001) from 84.2 +/- 7.8 ml/h/kg in healthy volunteers to 30.2 + 9.2 ml/h/kg in patients with renal failure. A linear correlation (r = 0.971, P less than 0.001) was found between creatinine clearance and the total serum clearance of aztreonam. The AUC0-infinity increased significantly (P less than 0.001) from 137.5 +/- 12.2 micrograms/h/ml in healthy volunteers to 464 +/- 114.5 micrograms/h/ml in patients with renal failure.     

紫杉醇联合放射线照射对鼻咽癌细胞的放射增敏效应

目的探讨化疗药紫杉醇(PTX)联合放射线照射对鼻咽癌细胞的放射增敏作用。方法取指数生长期的CNE-I细胞,采用克隆形成分析法检测PTX的单药毒性,确定IC10、IC50和IC90剂量作为实验的药物浓度。分析照射前后PTX IC10、IC50和IC90浓度下作用24 h,照射剂量分别为0～10 Gy时对CNE-I细胞的放射增敏效应。采用流式细胞术分析不同浓度PTX作用0、2、6、12、18和24 h CNE-I细胞周期分布的变化。结果PTX对CNE-I细胞的IC10、IC50和IC90剂量分别为0.05、1.0和2.5 nmol/L。当小剂量照射前后,分别用0.05和1.0 nmoL/L PTX作用24 h,具有一定放射增敏作用。PTX浓度为2.5和10.0 nmol/L时,CNE-I细胞出现明显的G2/M期阻滞,高峰出现在18 h。结论在适当的结合序贯的基础上,PTX联合放射线照射对CNE-I细胞具有放射增敏效应,其增敏作用可能与PTX导致的细胞G2/M期阻滞相关。     

Single-Dose Pharmacokinetics of Aztreonam in Healthy Volunteers and Renal Failure Patients

Summary

The pharmacokinetics of aztreonam were studied in 6 healthy male volunteers and 12 male patients with various degrees of chronic renal failure after intravenous bolus injection of 1g of the drug. Serum pharmacokinetics of aztreonam were described by an open, two-compartment kinetic model. The serum levels of aztreonam exceeded the reported minimum inhibitory concentration (MIC)₉₀ for Enterobacteriaceae for 8 hours and up to 24 hours, in healthy volunteers and renal failure patients, respectively. However, the serum levels of the drug exceeded the MIC₅₀ for Pseudomonas aeruginosa for only 4 hours and 12 hours in healthy volunteers and patients, respectively. The half-life of elimination (t 1/2/β) increased significantly (P < 0.001) from 1.8 ± 0.14 h in healthy volunteers and to 4.9 ± 1.1 h in patients with renal failure. The total serum clearance of aztreonam decreased significantly (P< 0.001) from 84.2 ± 7.8 ml/h/kg in healthy volunteers to 30.2 + 9.2 ml/h/kg in patients with renal failure. Á linear correlation (r = 0.971, P< 0.001) was found between creatinine clearance and the total serum clearance of aztreonam. The AUC_0–∞ increased significantly (P< 0.001) from 137.5 ± 12.2 μg/h/ml in healthy volunteers to 464 ± 114.5 μg/h/ml in patients with renal failure.     

Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC)

Purpose

Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug–drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer.

Patients and methods

Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide.

Results

Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration.

Conclusions

Although there was no evidence of a clinically relevant pharmacological drug–drug interaction, the occurrence of dose-limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients.