Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours.

1. The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents. 2. Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24 h. Etoposide plasma concentration-time data was modelled using NONMEM® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V(d)) were determined by a nonlinear mixed effect model. 3. The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V(d)). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70 kg) values of CL and V(d) were 2.31 L/hr and 17.5 L, respectively. The CL and V(d) allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters. 4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V(d) increased with increasing weight similar to BSA.

A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs.

Optimization of the use of monoclonal antibodies (MAbs) as diagnostic tools and therapeutic agents in the treatment of cancer is aided by quantitative characterization of the transport and tissue disposition of these agents in whole animals. This characterization may be effectively achieved by the application of physiologically based pharmacokinetic (PBPK) models. The purpose of this study was to develop a PBPK model to characterize the biodistribution of the pancarcinoma MAb CC49 IgG in normal and neoplastic tissues of nude mice, and to further apply the model to predict the disposition of multivalent single chain Fv (scFv) constructs in mice. Since MAbs are macromolecules, their transport is membrane-limited and a two-pore formalism is employed to describe their extravasation. The influence of binding of IgG to the protective neonatal Fc receptor (FcRn) on its disposition is also accounted for in the model. The model successfully described (131)I-CC49 IgG concentrations in blood, tumor and various organs/tissues in mice. Sensitivity analysis revealed the rate of transcapillary transport to be a critical determinant of antibody penetration and localization in the tumor. The applicability of the model was tested by predicting the disposition of di- and tetravalent scFv constructs of CC49 in mice. The model gave reasonably good predictions of the disposition of the scFv constructs. Since the model employs physiological parameters, it can be used to scale-up mouse biodistribution data to predict antibody distribution in humans. Therefore, the clinical utility of the model was tested with data for (131)I-CC49 obtained in patients, by scaling up murine parameter values according to known empirical relationships. The model gave satisfactory predictions of CC49 disposition and tumor uptake in man.

Pharmacokinetic and biodistribution studies of a bone-targeting drug delivery system based on N-(2-hydroxypropyl)methacrylamide copolymers.

Osteotropicity of novel bone-targeted HPMA copolymer conjugates has been demonstrated previously with bone histomorphometric analysis. The pharmacokinetics and biodistribution of this delivery system were investigated in the current study with healthy young BALB/c mice. The 125I-labeled bone-targeted and control (nontargeted) HPMA copolymers were administered intravenously to mice, and their distribution to different organs and tissues was followed using gamma counter and single photon emission computed tomography (SPECT). Both the invasive and noninvasive data further confirmed that the incorporation of D-aspartic acid octapeptide (D-Asp8) as bone-targeting moiety could favorably deposit the HPMA copolymers to the entire skeleton, especially to the high bone turnover sites. To evaluate the influence of molecular weight, three fractions (Mw of 24, 46, and 96 kDa) of HPMA copolymer-D-Asp8 conjugate were prepared and evaluated. Higher molecular weight of the conjugate enhanced the deposition to bone due to the prolonged half-life in circulation, but it weakened the bone selectivity. A higher content of bone-targeting moiety (D-Asp8) in the conjugate is desirable to achieve superior hard tissue selectivity. Further validation of the bone-targeting efficacy of the conjugates in animal models of osteoporosis and other skeletal diseases is needed in the future.

Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49.

PURPOSE: Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both beta and gamma radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. METHODS: Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)2; tetramer, [sc(Fv)2]2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv)2]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. RESULTS: Approximately, 90% of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t1/2alpha) of 177Lu-labeled [sc(Fv)2]2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t1/2beta) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4+/-1.3 and 8.9+/-0.6 for 177Lu-labeled [sc(Fv)2]2 and IgG of CC49, respectively, in the absence of L-lysine. The corresponding values were 8.0+/-0.6 and 8.4+/-1.2 in the presence of L-lysine. Renal accumulation of [sc(Fv)2]2 was significantly (p<0.005) reduced in the presence of L-lysine. CONCLUSION: The results of this study demonstrate that the ITCB-DTPA conjugation and 177Lu-labeling of scFvs are feasible without influencing the antibody characteristics. 177Lu-labeled [sc(Fv)2]2 showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of L-lysine. Therefore, 177Lu-labeled [sc(Fv)2]2 may be a potential radiopharmaceutical for the treatment of cancer.

Pharmacokinetics of hydroxyurea in plasma and cerebrospinal fluid of HIV-1-infected patients.

Hydroxyurea has been shown to potentiate the activity of the antiretroviral nucleoside analogs. A significant complication of AIDS is invasion of the virus into the CNS, resulting in HIV-associated dementia (HAD). Because of the polar nature of these nucleosides and the presence of efflux pumps in the blood-brain barrier, only low CNS drug concentrations are achieved. Introduction of hydroxyurea into the CNS may therefore increase the antiviral activity of these drugs. This study evaluates the accessibility of hydroxyurea to the CNS following oral drug administration. Twelve HIV patients received 800 mg, 1000 mg, or 1200 mg oral hydroxyurea. Cerebrospinal fluid (CSF) and plasma drug concentrations were measured over 8 hours and simultaneously fitted to a pharmacokinetic model. It was determined that CSF hydroxyurea concentrations, corresponding to those found to increase antiretroviral nucleoside activity in vitro, were achieved.

The effect of age on the early disposition of doxorubicin.

PURPOSE: Clinical studies indicate that anthracycline cardiotoxicity increases with patient age. This may be due to altered pharmacokinetics or pharmacodynamics. A parameter termed 'early clearance' has been shown to decrease with age in patients receiving intravenous doxorubicin. This parameter, as defined, has no immediate relationship to any physiologically based pharmacokinetic parameter. We therefore reevaluated the pharmacokinetic data to better define the relationship between doxorubicin disposition and patient age. METHODS: Four studies provided a total of 56 patients with evaluable pharmacokinetics. The volume of the central compartment, V(c), the distribution clearance, CL(d), and total body clearance, CL, were determined for each patient and regressed against age. A physiologically based pharmacokinetic (PBPK) model for doxorubicin was also used to evaluate the effects of age on doxorubicin disposition. Published blood flows associated with various patient ages were used to simulate plasma and tissue doxorubicin concentrations. The relationship between CL(d) and initial tumor regression was also evaluated. RESULTS: No correlation was found between V(c) and age ( P>0.05). A highly significant correlation was observed between CL(d) and age ( P<0.0005) and there was a mild but significant relationship between CL and age ( P<0.01). Use of the PBPK model with different age-related blood flows yielded virtually identical parameter values to the clinical data analyzed. Furthermore, relative tissue AUCs simulated in old and young patients compared well with those reported for daunorubicin disposition in young and old rats. In addition, a linear relationship was observed between initial tumor regression and CL(d). CONCLUSIONS: Initial concentrations of doxorubicin following intravenous administration are higher in the elderly due to a decrease in CL(d) rather than in V(c). On the basis of simulations with the PBPK model, the reduced CL(d) appears to be related to altered regional blood flows in the elderly, and such changes may be of clinical significance.

In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).

The relationship between treatment efficacy and the pharmacokinetics (PK) and pharmacodynamics (PD) of anticancer drugs is poorly defined. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is an alkylating agent used in the treatment of brain and other forms of cancer. It is postulated that BCNU kills cells by forming DNA interstrand cross-links. The present study was undertaken to characterize the PK and PD of BCNU in mouse L1210 cells. L1210 cells were exposed to BCNU (0-160 microM) and analyzed for intracellular BCNU concentrations, DNA interstrand cross-links, cell cycle phase, and cytotoxicity. The half-life of BCNU in cells was approximately 40 min. The maximum reduction of mitochondrial enzyme activity (maximum cell death) achieved within 24 hr after exposure to BCNU was concentration-dependent and could be described by a Hill equation. At lower concentrations, the area under the DNA interstrand cross-link-time curve linearly correlated with the maximum cell death and the area under the BCNU concentration-time curve. BCNU induced cell accumulation in the G(2)/M phase of the cell cycle, which continued even after apparent completion of cross-link repair. Loss of membrane permeability was minimal (approximately 2%) during the first 24 hr. Thereafter, cells died exponentially over the next 9 days, primarily by necrosis. In conclusion, while cytotoxicity was concentration-dependent, an indirect relationship was found among the time-course of BCNU concentrations, DNA interstrand cross-links, and cell death. Because of the disparity between the time-scale of PK and PD, focusing only on the early events may provide limited information about the process of anticancer drug-induced cell death.