Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. MATERIALS AND METHODS: This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7-1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix). RESULTS: 31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded. CONCLUSIONS: Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

Pre-transplant donor CD4- invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease.

Clinically useful pre-transplant predictive factors of acute graft-versus-host-disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT) are lacking. We prospectively analyzed HSC graft content in CD34+, NK, conventional T, regulatory T and invariant natural killer T (iNKT) cells in 117 adult patients before allo-SCT. Results were correlated with occurrence of aGVHD and relapse. In univariate analysis, iNKT cells were the only graft cell populations associated with occurrence of aGVHD. In multivariate analysis, CD4- iNKT/T cell frequency could predict grade II-IV aGVHD in bone marrow and peripheral blood stem cell (PBSC) grafts, while CD4- iNKT expansion capacity was predictive in PBSC grafts. Receiver operating characteristic analyses determined the CD4- iNKT expansion factor as the best predictive factor of aGVHD. Incidence of grade II-IV aGVHD was reduced in patients receiving a graft with an expansion factor above versus below 6.83 (9.7 vs 80%, P<0.0001), while relapse incidence at two years was similar (P=0.5).The test reached 94% sensitivity and 100% specificity in the subgroup of patients transplanted with human leukocyte antigen 10/10 PBSCs without active disease. Analysis of this CD4- iNKT expansion capacity test may represent the first diagnostic tool allowing selection of the best donor to avoid severe aGVHD with preserved graft-versus-leukemia effect after peripheral blood allo-SCT.

Pharmacokinetics and exposure-effect relationships of capecitabine in elderly patients with breast or colorectal cancer.

PURPOSE: The aims of the present study were (1) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (2) to evaluate the exposure-effect relationship of capecitabine in elderly patients. METHODS: Data collected from 20 elderly patients (75-92 years old) with breast or colorectal cancer who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine were added in the database. The population pharmacokinetic analysis was based on a four-compartment model describing the sequence of capecitabine and three of its metabolites. RESULTS: The absorption rate constant was found lower in the oldest patient group (≥75 years) compared with the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e., after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared with patients who did not. CONCLUSION: This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity.

Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Interest in antifibrinolytic tranexamic acid (TA) has grown since the widespread removal of aprotinin, but its dosing during cardiac surgery is still debated. The objectives of this study were to investigate the population pharmacokinetics (PK) of TA given with either low- or high-dose continuous infusion schemes in adult cardiac surgery patients during cardiopulmonary bypass (CPB). METHODS: Patients were randomized to receive either low-dose (10 mg kg(-1) followed by an infusion of 1 mg kg(-1) h(-1) throughout the operation, and 1 mg kg(-1) into the CPB) or high-dose (30 mg kg(-1), then 16 mg kg(-1) h(-1), and 2 mg kg(-1) into the CPB) TA. Serum TA concentrations were measured in 61 patients and the data were modelled using Monolix. RESULTS: TA concentrations were 28-55 µg ml(-1) in the low-dose group and 114-209 µg ml(-1) in the high-dose group throughout surgery. TA PK was best described by a two-compartment open model. The main covariate effect was bodyweight, whereas the CPB did not influence the PK. Assuming a bodyweight of 70 kg, the population estimates were 4.8 litre h(-1) for clearance, 6.6 litre for the volume of the central compartment, 32.2 litre h(-1) for the diffusional clearance, and the peripheral volume of distribution was 10.8 litre. CONCLUSIONS: The PK of TA was satisfactorily described by an open two-compartmental model, which was used to propose a dosing scheme suitable for obtaining and maintaining the desired plasma concentration in a stable and narrow range in cardiac surgery patients.

Pharmacokinetic evaluation of the vinorelbine-lapatinib combination in the treatment of breast cancer patients.

PURPOSE: The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients. METHODS: Women with HER2 + locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m(2))] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib + vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a non-linear mixed effect model program (Monolix version 3.1 s). RESULTS: A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote inter-compartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h(-1). The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib. CONCLUSIONS: The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m(2) D1 & D8.

Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.

PURPOSE: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. METHODS: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. RESULTS: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. CONCLUSION: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide.

BACKGROUND: Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols. METHODS: Mice and dogs received IV IPM daily for 3 days. Single-day dosing-oral and IV-to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared. RESULTS: For mice, the LD(10) for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87-134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T(1/2beta) was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T(1/2alpha) 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T(1/2) was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation. CONCLUSIONS: Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m(2) with a clearance of 39.5 l/h, and a T(1/2) of 1 h 45 min for a 70-kg patient.

Population pharmacokinetics of short intravenous vinorelbine infusions in patients with metastatic breast cancer.

PURPOSE: To develop a population pharmacokinetic model of vinorelbine administered by short intravenous infusion in metastatic breast cancer patients. METHODS: Vinorelbine was administered as infusions of 5-10 min at 15, 20 or 25 mg/m(2) to 30 patients. Blood samples were collected over 18 h. Plasma concentrations of vinorelbine were determined by HPLC. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method. RESULTS: Vinorelbine concentration-time profiles were best described by a three-compartment open model. Plasma clearance (CL) was high and positively related to lean body weight (LBW) and body surface area (BSA) or to a combination of height and body weight (BW). Elevated serum alkaline phosphatases had a negative effect on CL. Typical population estimates of CL and central distribution volume (V(1)) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V(1) were 17.0% and 32.0%, respectively. The stability and predictive performance of the final population pharmacokinetic model were assessed using 200 bootstrap samples of the original data. CONCLUSION: This study identified combined effects of BSA and serum alkaline phosphatases on clearance. These results partly support the conventional dose adjustment of vinorelbine based on BSA, but suggest dose modification in cases of extreme values of serum alkaline phosphatases.

Population pharmacokinetics of oxaliplatin in patients with metastatic cancer.

Our aim was to develop a population pharmacokinetic model of ultrafilterable oxaliplatin in metastatic cancer patients. Oxaliplatin was administered by 2- or 4-h infusions, 50, 65, 75, 85, 100 or 130 mg/m2 to 56 patients. Blood samples were collected over 28 h. Plasma concentrations of ultrafilterable oxaliplatin were determined by flameless atomic absorption spectrophotometry. Population pharmacokinetic analysis was performed using a non-linear mixed-effects modeling method. Ultrafilterable oxaliplatin concentration-time profiles showed a secondary peak or a shoulder aspect post-infusion, attributed to the existence of an enterohepatic recirculation (EHR). They were best described by a two-compartment model incorporating an EHR component. Plasma clearance (CL) was related positively to body weight (BW) and negatively to serum creatinine (SCr), and was greater in male patients than in female patients. This covariate modeling resulted in a decrease in the interindividual variability for CL from 104 to 62%. The central distribution volume (V1) and inter-compartmental clearance (Q) were related to BW. Typical population estimates of CL, central distribution volume (V1), input rate constant into gallbladder (k1B) and lag time for drug reabsorption (TLAG) were 14.1 or 8.5 l/h (male or female patients), 24.9 l, 1.8 h-1 and 2.0 h, respectively. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. We conclude that a two-compartment with EHR model adequately described ultrafilterable oxaliplatin pharmacokinetics, explaining a secondary transient increase in concentration. This study identified combined-covariate-effects ultrafilterable oxaliplatin clearance, supporting dose adjustment of oxaliplatin based on BW, gender and corrected for SCr level, if drug exposure is thought to be related to therapeutic or toxic issues.

Phase I population pharmacokinetics of irofulven.

Our aim was to develop a population pharmacokinetic model for irofulven and to assess covariates that might affect irofulven pharmacokinetics. Irofulven was administered by 5- or 30-min i.v. infusion to cancer patients during a phase I study. Blood samples were collected over 4 h. Plasma samples were analyzed to quantitate irofulven by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a non-linear mixed effects modeling program, MP2. Fifty-nine patients were available for pharmacokinetic analysis. Irofulven plasma concentration-time profiles were best described by a two-compartment pharmacokinetic model. Clearance and central volume of distribution were not significantly influenced by individual characteristics, i.e. body weight (BW), body surface area (BSA), age and gender. Final parameter estimates of clearance and central volume of distribution were 616 l/h and 37 l, respectively, resulting in a very short terminal half-life of less than 10 min. A relatively high level of variability was observed in irofulven pharmacokinetics, which was mainly due to a significant residual variability, 39%. For a 30-min irofulven infusion, the optimal sampling schedule for clearance estimation using the Bayesian method was the three time points 0.35-0.45, 0.80 and 1-1.2 h from the beginning of a 30-min infusion. We conclude that after i.v. infusion of irofulven, plasma clearance was high and not dependent upon patient age, gender, BSA or BW.

Individual dosing of carboplatin based on drug monitoring in children receiving high-dose chemotherapy.

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3-17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml x min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients' characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from -41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was -11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between -7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children.

Modelling of ftorafur and 5-fluorouracil pharmacokinetics following oral UFT administration. A population study in 30 patients with advanced breast cancer.

PURPOSE: The pharmacokinetics of ftorafur, 5-fluorouracil (5FU) and uracil were investigated in order to built a population pharmacokinetic model for the anticancer drug UFT, administered with leucovorin and vinorelbine. METHODS: A total of 31 patients with metastatic breast cancer were treated with escalating oral doses of UFT (300 to 500 mg per day) plus leucovorin (90 mg per day) in combination with intravenous vinorelbine (15 to 25 mg/m(2)). Concentration-time data were obtained on days 1, 8, 15 and 21 of cycle 1. RESULTS: Of the 31 patients treated, 30 were available for the pharmacokinetic analysis. Ftorafur, 5FU and uracil appeared rapidly in plasma and showed large interpatient variations. Ftorafur concentrations were higher than those of 5FU and uracil. AUC significantly increased between day 1, and days 8, 15 and 21. Ftorafur C(max) and AUC values were proportional to UFT dose, whereas C(max) and AUC values of 5FU and uracil were not linearly related to UFT dose. The pharmacokinetics of ftorafur were ascribed to a two-compartment open model in which 5FU was produced from the central compartment. The absorption and exponential distribution rate constants were assumed equal. The effect of uracil on 5FU elimination was straightforward, since no reasonable curve-fitting could be obtained for 5FU data when this covariate was not taken into account. The uracil concentration inducing a 50% reduction in 5FU elimination was 2.67 micro mol.l(-1). This result confirms the important role played by uracil as a competitive inhibitor of 5FU catabolism. CONCLUSION: A pharmacokinetic model for ftorafur and 5FU was developed and should be useful to further study drug interactions and establish dosing guidelines.

Pharmacokinetic modelling of total and unbound plasma carboplatin--a population study in 75 children.

AIMS: A compartmental open model was developed to describe the relationship between plasma unbound (C.) and bound (CT) carboplatin concentrations. A population pharmacokinetic study was then undertaken to investigate the effect of demographic covariates on unbound and bound carboplatin clearance and volume parameters. METHODS: Carboplatin and demographic data were collected from 75 children (1-17 years old, 10 children with unilateral nephrectomy) treated using 1-hour daily infusions for various malignancies. Concentration-time data, C(U) and C(T), from children with rich data were used to develop the model. The data from all children were then simultaneously analyzed using a population approach. RESULTS: The average population values for total unbound carboplatin clearance, CL(U), and distribution volume of unbound carboplatin, VI, were 3.87 l/h and 6.26 l/h, respectively. The clearance of plasma-bound carboplatin was comparatively low, 0.11 l/h. CL(U) was dependent on weight, nephrectomy status and serum creatinine. A constant fraction of CL(U), 0.17 l/h, included the disappearance of unbound compound due to irreversible plasma binding. V1 was dependent on body weight. The unbound plasma carboplatin fraction (fu) was simulated and rapidly decreased with post-infusion time. CONCLUSIONS: The body weight was a better predictor for unbound carboplatin clearance than body surface area, and UNP and SCr caused a reduction in clearance of unbound carboplatin, as previously reported. The rate ofcarboplatin plasma binding was low and not dependent on demographic patient characteristics. The f(U) of plasma carboplatin could be predicted as a function of time, infusion rate and covariates affecting CL(U), weight, UNP and SCr.

Expression of the genetic variants of human alpha-1-acid glycoprotein in cancer.

OBJECTIVES: We have investigated the AAG and its genetic variants concentrations in plasma samples of 61 patients suffering from different types of cancers. DESIGN AND METHODS: The patients were shared out in three groups, breast, lung, and ovary cancers groups. AAG concentration was measured by an immunonephelometric method and the phenotype was determined, after desialylation of plasma by analytical isoelectric focusing. Detection of AAG variants was made by immunoblotting and their proportions were determined by laser densitometry analysis. A population of 74 healthy individuals served as controls. RESULTS: The plasma concentrations of AAG in the breast and lung cancer groups were 2.5 times increased, while in the ovary cancer group, the concentrations were 1.6 times increased. AAG concentrations in the cancer population ranged between 0.45 and 2.85 g/L (mean value 1.12 +/- 0.51 g/L). The proportions of the ORM1 and ORM2 variants were similar to those in the healthy population. In breast and lung cancer groups, the relative concentrations of genetic variants were increased more than 2.5 fold, whereas a 1. 6-fold increase was observed in the ovary cancer group. CONCLUSIONS: These results show that AAG plasma concentrations are increased in these types of cancers and that changes in the expression of the genetic variants of AAG could also occur according to the type of cancer.

In vitro binding and partitioning of irinotecan (CPT-11) and its metabolite, SN-38, in human blood.

The binding of CPT-11 and SN-38 to human plasma proteins was studied by ultrafiltration at 37 degrees C and pH 7.4. In plasma, CPT-11 was 66-60% bound in the range 100-4000 ng/ml and SN-38 was 94-96% bound in the range 50-200 ng/ml. At these concentrations the plasma binding of CPT-11 was slightly saturable, but the plasma binding of SN-38 was concentration-independent. Albumin was the main carrier of CPT-11 and SN-38 in plasma. In blood, the binding of CPT-11 was moderate (80%), mainly to plasma proteins (47%) and erythrocytes (33%). The binding of SN-38 was high (99%) and most of SN-38 in blood was located in blood cells (approximately 66%) The simulation of a grade 3 hematotoxicity (according to National Cancer Institute's Common Toxicity Criteria grading) on the SN-38 blood distribution yielded an increase in fu (free fraction of drug in plasma) from 1.05 to 2.08 and a decrease in C(Bl)/C(P) from 1.66 to 1.14 (both resulting from a decreased cell binding).

Evidence for different interactions between beta(1)- and beta(2)-adrenoceptor subtypes with adenylyl cyclase in the rat brain: a concentration-response study using forskolin.

The aim of this study was to investigate beta(1)- and beta(2)-adrenoceptor signalling systems in the rat brain studying the synergistic effects between beta-adrenoceptor agonists and forskolin- induced activation of adenylyl cyclase. Experiments were performed in slices from cerebral cortex and cerebellum because they contain mainly beta(1)- and almost exclusively beta(2)- adrenoceptors, respectively. Five beta-adrenergic agonists were used, clenbuterol, flerobuterol, isoproterenol, salbutamol, and tulobuterol. All agonists stimulated cyclic AMP accumulation in the cerebral cortex but flerobuterol was inactive in the cerebellum. Forskolin amplified the generation of cyclic AMP. Forskolin potentiation was observed in glial cells but not in neurons and was not dependent on the number of beta-adrenoceptors. In return the amplitude of the potentiation was highly dependent on the intrinsic activity of the agonist in the cerebral cortex whereas it was constant whatever the agonist tested in the cerebellum. To analyse this difference we developed a modelling approach using a concentration-response study. Isoproterenol and forskolin stimulations of cyclic AMP production were studied either alone or in combination with increasing concentrations of forskolin and isoproterenol, respectively. In the cerebral cortex isoproterenol and forskolin were both able to potentiate the cyclic AMP accumulation induced by the other compound, whereas, in the cerebellum, isoproterenol was unable to increase the stimulation induced by forskolin. The results support the hypothesis that beta(1)- and beta(2)-adrenoceptors display distinct mechanisms of action in the signalling system by which they stimulate the accumulation of cyclic AMP.

Pharmacokinetic modelling of ifosfamide administered by continuous infusion on 5 days at the dose of 6 g/m2.

BACKGROUND: We aimed to create a model for Ifosfamide (IFX) pharmacokinetics for drug monitoring in order to improve protocol dose intensity. MATERIAL AND METHODS: We studied ifosfamide pharmacokinetics in 12 patients aged 8-19 years. Sixteen courses were modelled (6 g/m2, on 5 days). The auto-induction of ifosfamide was taken into account in the model. Ifosfamide measurement was performed on serum samples by gas chromatography with thermo-ionic detection. Two pharmacokinetic models were compared. The following parameters were estimated: volume of distribution (Vd), clearance at the beginning of the induction (CLi), clearance extrapolated to infinity (CLf), clearance at the end of infusion (CL120), a rate constant (Kc) indicating the clearance variation with time and the lag time (Lag) indicating the time elapsed between the start of infusion and the start of induction. The Wilcoxon test was used to investigate possible differences between models. We tested the hypothesis that Boddy's model is an acceptable simplification of Levy's model. RESULTS: Four of six parameters were significantly different between the two models (p = 0.05). The best curve fitting was obtained using the Levy's model which provided the following estimates, Cli = 2.46 +/- 0.94 L.h-1.m-2, CLf = 5.22 +/- 1.02 L.h-1.m-2, Kc = 0.024 +/- 0.014 h-1, Vd = 18.84 +/- 5.04 L and Lag = 4.86 +/- 6.61 h. The most important difference is found for the distribution volume. CONCLUSION: Levy's model is more accurate and takes into account the integration of clearance.

A limited-sampling method for evaluation of the area under the curve of ultrafilterable carboplatin in children.

Carboplatin is a widely used cytotoxic agent in numerous solid tumors of children. Since there is a large degree of interpatient variability in the area under the curve of free carboplatin for a given dose of the drug, the current tendency is to adjust the carboplatin dose so as to reach a target area under the curve rather than to determine a carboplatin dose on the basis of the body surface area. A limited-sampling method was developed for estimation of the ultrafilterable carboplatin area under the curve and for adjustment of the carboplatin dose on subsequent treatments. Population parameters were obtained from 16 children (reference group). We used the maximum a posteriori (MAP) Bayesian approach on 15 children with complete carboplatin pharmacokinetic data (test group). Two blood samples were sufficient to obtain reliable prediction of the area under the curve. The best sampling times were: (a) 30 min after the end of the infusion and (b) 5 h after the end of the infusion. On the basis of these data it is possible to prescribe prospectively a target area under the curve for free carboplatin given in a fractionated daily infusion and to adapt the carboplatin dose directly to ultrafilterable carboplatin measurements.

Role of lipoproteins in the plasma binding of SDZ PSC 833, a novel multidrug resistance-reversing cyclosporin.

AIMS: The plasma binding of the cyclosporin D analogue SDZ PSC 833 was investigated in vitro. METHODS: The plasma total binding constant (corresponding to the bound-to-free concentration or binding ratio) was determined at 37 degrees C by the erythrocyte partitioning technique on plasma samples from three healthy volunteers and three cancer patients. Lipoproteins were also removed from plasma samples from three healthy volunteers by a standard ultracentrifugal technique. RESULTS: SDZ PSC 833 plasma binding was 97.8 +/- 1.1% and 97.3 +/- 0.2% in samples from three healthy volunteers and three cancer patients respectively. More than 95% of blood SDZ PSC 833 was distributed in plasma. When the original plasma samples of three individuals were delipidated, SDZ PSC 833 binding was strongly decreased (58% bound to plasma proteins) and when lipoproteins were resuspended in the delipidated plasma samples to produce varying lipoprotein plasma concentrations, the binding increased continuously with the fraction of added lipoproteins. When lipoproteins were resuspended to restore the original lipoprotein plasma content, the % plasma-bound SDZ PSC 833 increased to 98.2%, close to the value observed with the original plasma (98.7%). CONCLUSIONS: These results clearly indicate that SDZ PSC 833 plasma binding is mainly determined by lipoproteins and that in blood, most of SDZ PSC 833 is distributed in plasma.

Evaluation of two dose individualisation methods for carboplatin.

The pharmacokinetics of carboplatin are usually evaluated by measuring plasma concentrations of ultrafiltered platinum (UP). This approach, however may be less reliable than measuring the plasma concentration of total platinum (TP). In a group of 14 patients, which constituted a reference group, the clearance of TP was highly correlated with creatinine clearance, as estimated by the method of Cockroft and Gault. This relationship, together with only morphological and biological parameters, was used to estimate TP clearance, Vc and AUC, in a validation group of 8 patients. Estimated TP clearance was 97.9 +/- 18% of the actual value. The TP pharmacokinetic parameters of the reference group were used to estimate those of the validation group, using only two or three plasma concentration measurements (Bayesian approach). With the Bayesian approach, the estimated TP clearance was up to 99.9 +/- 2.7% of the actual value. In conclusion, estimation of TP pharmacokinetics may be reliably estimated as an alternative to UP in clinical practice.