Clinical pharmacology of vinzolidine

Summary Vinzolidine (VZL), a new semisynthetic vinca alkaloid, was studied by using ³H-labeled VZL administered PO in four patients. At single doses from 1.5 to 36.5 mg/m² (0.034–0.919 mg/kg) radioactivity was rapidly absorbed with a half-life of absorption of 1 h and a peak at 4 h. Plasma decay of radiolabel followed a biphasic pattern with an alpha half-life of 10.48 h and a beta half-life of 172 h. The apparent plasma clearance was dose-dependent.The total radiolabel recovered was 52.9%±11.4% of the administered label, with 90% in the feces.HPLC analysis revealed that in all extracted plasma, urine, and feces the predominant material was unchanged VZL. Several metabolites were observed but not identified.Presented in part at the 75th Annual Meeting of the American Association for Cancer Research, May 19, 1984, Toronto, Canada, and at the 2nd International Conference on Malignant Lymphoma, Current Status and Prospects, June 19, 1984, Lugano, SwitzerlandSupported by Eli Lilly & Co., and The Don Monti Memorial Research Foundation     

Intratumoral measurement and plasma pharmacokinetics of intravenously administered Melphalan

Summary In a human case of plasmacytoma we studied plasma and tumor concentrations of melphalan given intravenously. Intratumoral concentration of melphalan was similar to plasma concentration 60 min after the end of infusion.     

Therapy of autochthonous skin cancers in mice with intravenously injected liposomes containing muramyltripeptide

Liposomes containing the immunomodulator muramyltripeptide phosphatidylethanolamine (MTP-PE) or free saline were injected i.v. into BALB/c mice with autochthonous skin cancers induced by chronic exposure to ultraviolet irradiation. Treatment with liposomes containing MTP-PE produced significant retardation in the growth of the primary autochthonous skin cancers and significantly prolonged survival of the treated mice as compared with the saline-treated controls. Since ultraviolet-irradiated mice have a defect in immunological recognition of their autochthonous tumors, the therapeutic effects of liposomes containing MTP-PE are very encouraging. These results suggest that liposomes containing MTP-PE could be used for the treatment of patients with skin cancer or other malignant diseases.     

荷瘤小鼠静脉注射洛铂和顺铂后药物浓度的变化规律

目的研究洛铂和顺铂在小鼠血浆、肾脏和肿瘤内的药物浓度随时间变化的规律,为放疗增敏提供实验数据。方法 70只C57BL/6近交系Lewis肺癌荷瘤小鼠随机分组,按10mg药物/kg体重经尾静脉分别给小鼠注射药物（洛铂或顺铂）,给药后在0.5、2、4、24、48、72、96 h分别将小鼠处死获取血液和组织标本（肿瘤和肾脏）,应用ICP-MS方法测定标本铂含量。结果洛铂和顺铂的血浆药时曲线均符合三室模型,半衰期分别为51.139h和35.583h,洛铂在血浆中的清除速率大于顺铂[0.532L/（h.kg）对0.192 L/（h·kg）];洛铂和顺铂在肿瘤组织的浓度均在给药后迅速达到最大[（2.79±0.35）μg/g对（4.78±1.11）μg/g],然后迅速下降,在4 h后分别降至0.99±0.21μg/g和3.39±0.55μg/g,在96 h肿瘤中仍有药物存在,浓度分别为0.23±0.05μg/g和1.41±0.71μg/g。肿瘤药物浓度与血浆药物浓度呈对数相关,Rsq分别为0.948和0.837。结论洛铂和顺铂在小鼠体内静脉给药后半衰期长,肿瘤内药物浓度在给药后很快达到最大,在4 h降至平台期,96 h仍有药物存在,顺铂在肿瘤内的浓度高于洛铂;洛铂在小鼠体内的清除速率快于顺铂;可以通过检测血浆中的洛铂和顺铂浓度来估算肿瘤内的药物浓度。     

Plasma and cerebrospinal fluid pharmacokinetics of intravenously administered ABT-751 in non-human primates

Purpose ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on β-tubulin and inhibits microtubule polymerization. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of ABT-751, after a short intravenous infusion, were evaluated in a non-human primate (Macaca mulatta) model that is highly predictive of the CSF penetration of drugs in humans. Materials and methods Plasma and CSF samples were collected over 24 h after 7.5 mg/kg (150 mg/m²) ABT-751 infused over 0.25–0.70 h, and ABT-751 concentrations in plasma and CSF were quantified using a validated HPLC-MS/MS assay. Pharmacokinetic parameters in plasma and CSF were derived using non-compartmental methods. Results and conclusion Plasma disappearance was bi-exponential with a terminal half-life of 13 h. The mean ± SD clearance was 100 ± 18 ml/min m², the mean ± SD volume of distribution at steady state was 1.3 ± 0.5 l/kg, and the mean ± SD mean residence time was 4.6 ± 1.8 h. The mean ± SD peak ABT-751 concentration in CSF was 0.26 ± 0.08 μM, and the mean ± SD CSF half-life of 1.3 ± 0.3 h. CSF penetration was limited (mean ± SD AUC_CSF:AUC_plasma, 1.1 ± 0.3%) relative to total (protein-bound + free) plasma drug concentrations, but the CSF concentrations approximated the estimated free drug concentrations in plasma.     

Fate of intravenously injected human tumor cells in the lung of nude mice following whole-body X-irradiation

X-irradiation administered to nude mice and the ensuing pulmonary metastasis of injected human tumor cells were investigated. When human tumor cells (5 X 10(5)) were injected into the tail vein of male adult nude mice 5 days after 3 Gy whole-body X-irradiation, the incidence of pulmonary metastasis was more frequent in the irradiated mice than in the nonirradiated controls. Platelet aggregation and fibrin deposition around the tumor cells were present in the capillaries of the lung in the irradiated mice while prominent neutrophilic infiltration was noted around the tumor cells in the nonirradiated controls. Fibrinolytic activity of the lung was decreased in the irradiated mice, while serum fibrinogen level was increased after irradiation. Natural killer cell activity was decreased after irradiation. We conclude from this study that increase in serum fibrinogen levels and decrease in fibrinolytic activity of the lung, as a target organ, together with decreased infiltration of neutrophils, may be related to the trapping and lodgement of tumor cells when nude mice are subjected to irradiation.     

Near infrared fluorescence-guided real-time endoscopic detection of peritoneal ovarian cancer nodules using intravenously injected indocyanine green

Near infrared fluorescence-guidance can be used for the detection of small cancer metastases and can aid in the endoscopic management of cancer. Indocyanine green (ICG) is a Food and Drug Administration (FDA)-approved fluorescence agent. Through non-specific interactions with serum proteins, ICG achieves enhanced permeability and retention (EPR) effects. Yet, ICG demonstrates rapid clearance from the circulation. Therefore, ICG may be an ideal contrast agent for real-time fluorescence imaging of tumors. To evaluate the usefulness of real-time dual fluorescence and white light endoscopic optical imaging to detect tumor implants using the contrast agent ICG, fluorescence-guided laparoscopic procedures were performed in mouse models of peritoneally disseminated ovarian cancers. Animals were administered intravenous ICG or a control contrast agent, IR800-conjugated to albumin. The ability to detect small ovarian cancer implants was then compared. Using the dual view microendoscope, ICG clearly enabled visualization of peritoneal ovarian cancer metastatic nodules derived from SHIN3 and OVCAR5 cells at 6 and 24 hr after injection with significantly higher tumor-to-background ratio than the control agent, IR800-albumin (p < 0.001). In conclusion, ICG has the desirable properties of having both EPR effects and rapid clearance for the real-time endoscopic detection of tiny ovarian cancer peritoneal implants compared to a control macromolecular agent with theoretically better EPR effects but longer circulatory retention. Given that ICG is already FDA-approved and has a long track record of human use, this method could be easily translated to the clinic as a robust tool for fluorescence-guided endoscopic procedures for the management and treatment of cancer.     

Local distribution and concentration of intravenously injected 131I-9.2.27 monoclonal antibody in human malignant melanoma

Regional measurements of 131I-9.2.27 distribution in human melanoma tumors were obtained using quantitative autoradiography. Tumors were removed from patients 72-96 h after they had received an i.v. injection of 9.15 mCi (100 mg) of 131I-9.2.27. The autoradiographic images showed that the radioactivity reaching the tumor was heterogeneously distributed. Areas of relative high and low uptake were selected in each tumor. Regions of high activity contained from 51 to 1371 nCi/g, while areas with low uptake had radioactivity ranging from 12 to 487 nCi/g. The reliability of the autoradiographic measurements was demonstrated by the strong positive correlation with direct tissue sample counting (r = 0.994 P less than 0.001). Since comparative immunocytochemistry showed a homogeneous and diffuse staining of target antigen on viable tumor cells, variability of monoclonal antibody uptake within individual tumors was not primarily due to heterogeneity of antigen expression in these cases. However, antigen levels accounted for some of the variation from tumor to tumor. When immunoperoxidase staining was repeated on adjacent sections without the addition of 9.2.27, it confirmed the nonuniform distribution of monoclonal antibody found at autoradiography. Thus, quantitative autoradiography gives information about the distribution and the local concentration of radioactive antibody in tumors allowing calculation of the radiation dose delivered to small regions within tumors.     

Clinical pharmacokinetics of vindesine

Summary The pharmacokinetics of vindesine were investigated in five patients with advanced cancer who were receiving the drug. Following a rapid IV bolus dose, vindesine kinetics were described by a triphasic serum decay curve compatible with a three-compartment open mammillary model. Serum half-lives were 2 min, 50 min, and 24 h for the fast, middle, and slow phases, respectively. The volume of the central compartment approximated the plasma volume in all patients studied. Distribution occurred quickly into a superficial tissue compartment in fairly rapid equilibrium with the plasma compartment, and also into a deep tissue compartment with slower redistribution to the central compartment. The large apparent volume of distribution and long elimination half-live suggest extensive tissue sequestration or delayed excretion of the drug in man. The slightly increased serum half-life of vindesine compared with published results for vinblastine may account for the greater degree and longer duration of marrow suppression seen clinically with vindesine.     

Clinical pharmacokinetics of nitrosoureas

The pharmacokinetic characteristics of chloroethylnitrosourea anti-cancer agents are based on their high chemical reactivity and subsequent rapid breakdown in the plasma; and on a widespread tissue distribution due to the molecules' lipophilic properties. These physico-chemical properties explain the main problems that one may face during pharmacokinetic studies (assay method, isolation of high reactive intermediates) and that are related to the typical pharmacokinetic profile of these agents: rapid gastro-intestinal absorption, short half-life, widespread pulmonary and renal distribution, passage through the blood-brain barrier with levels within a therapeutic range, lipoprotein fixation, mainly hepatic and pulmonary metabolism, renal excretion. A drug interaction with phenobarbital has been described in the rat. The rational use of these compounds in cancer chemotherapy requires the optimisation of assay methods and a better understanding of their transformation pathways as well as their mechanism of action.     

Clinical pharmacokinetics of 3-deazaguanine

Summary 3-Deazaguanine (3DG), an antipurine antimetabolite, has recently completed a phase I clinical trial at this Institute. The drug was given on a dailyx5 schedule by i.v. infusion over 0.25–2.16 h. The pharmacokinetics of 3DG during 16 courses were studied in 12 patients at doses of 200–800 mg/m². 3DG in plasma was measured by an isocratic reverse-phase high-performance liquid chromatographic (HPLC) procedure carried out on IBM phenyl columns at 40° C using 10mM phosphate buffer (pH 7) as the mobile phase and detection at 300 nm. Plasma decay of 3DG was biexponential in all patients. The AUC correlated linearly with dose at 200–600 mg/m² but deviated from linearity at doses>600 mg/m². The drug was cleared rapidly from plasma; at doses of 200–600 mg/m², the mean plasma clearance was 61.64±9.97 l/h and the mean terminal-phase elimination half-life was 1.6±0.6 h. The steady-state volume of distribution (98.8±29.1 l) and distribution coefficient (1.24±0.39 l/kg) indicated extensive tissue distribution for the drug. No statistically significant difference was observed between the pharmacokinetics of 3DG on day 1 and that on day 4 as evaluated in three patients for whom complete plasma data were available on both days.     

Clinical pharmacokinetics of high-dose DTIC

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

Clinical pharmacokinetics of vinca alkaloids

Vinca alkaloids (VA) represent a family of closely related molecules, which includes vincristine (VCR), vinblastine (VLB), vindesine (VDS) and navelbine (NVB), a new synthetic VA presently in phase II clinical trial. Development of sensitive and specific analytical tools (polyclonal and monoclonal antibodies) enabled us to investigate the kinetic behavior of VDS and NVB after IV bolus or long term administration. Following IV bolus injection, the mean pharmacokinetic parameters are: total plasma clearance: 0.53 l/h-1kg-1, 0.72 l/h-1kg-1 and apparent elimination half-life: 23.2 h, 39.5 h for VDS and NVB, respectively. Chronic treatment reveals time- and dose-dependence relationships and detailed observations of individual kinetics demonstrate an important interindividual variability for both drugs. Renal excretion of VDS and NVB is low (from 5 to 12% of the total dose), suggesting the important role of the liver in their rapid elimination.