Biomedical subjects

M O Karlsson

Publications and source records attributed to M O Karlsson.

At least 19 recordsLinked to original sources

PubMed2006

Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients.

PURPOSE: The aims of the study were (a) to characterise the pharmacokinetics (PK), including inter-individual variability (IIV) and inter-occasion variability (IOV) as well as covariate relationships and (b) to characterise the relationship between the PK and the haematological toxicity of the component drugs of the fluorouracil (5-FU)-epirubicin (EPI)-cyclophosphamide (CP) regimen in breast cancer patients. PATIENTS AND METHODS: Data from 140 breast cancer patients, either within one of different studies or in routine clinical management, were included in the analyses. The patients were all treated with the fluorouracil-epirubicin-cyclophosphamide (FEC) regimen every third week for 3-12 courses, either in standard doses, i.e. 600/60/600 mg/m(2) of 5-FU, EPI and CP, respectively, or according to a dose escalation/reduction protocol (tailored dosing). PK data were available from 84 of the patients, whereas time-courses of haematological toxicity were available from 87 patients. The data analysis was carried out using mixed effects models within the NONMEM program. RESULTS: The PK of 5-FU, EPI and 4-hydroxy-cyclophosphamide (4-OHCP), the active metabolite of CP, were described with a one-compartment model with saturable elimination, a three-compartment linear model and a two-compartment linear model, respectively. No clinical significant correlation was found between PK across drugs. The unexplained variability in clearance was found to be less within patients, between courses (inter-occasion variability, IOV) than between patients (inter-individual variability, IIV) for EPI and 5-FU. For 4-OHCP, however, the IIV diminished by approximately 45% when significant covariates were included and the final population model predicts an IIV that is equal to IOV. Significant covariates for elimination capacity parameters were serum albumin (5-FU, EPI and 4-OHCP), creatinine clearance (5-FU), bilirubin (EPI) and body surface area (BSA) (4-OHCP). Elimination capacity of 5-FU and EPI was not related to BSA and for none of the studied drugs did body weight explain the PK variability. The time-course of haematological toxicity after treatment was well described by a semi-physiological model that assumes additive haematological toxicity between CP and EPI with negligible contribution from 5-FU. The influence of G-CSF could be incorporated into the model in a mechanistic manner as shortening the maturation time to 43% of the normal duration and increasing the mitotic activity to 269% of normal activity. CONCLUSIONS: The models presented describe the dose-concentration-toxicity relationships for the FEC therapy and may provide a basis for implementation and comparison of different individualisation strategies based on covariates, therapeutic drug monitoring and/or pharmacodynamic (PD) feedback. The PD model extends on previous semi-mechanistic models in that it also takes G-CSF administration into account.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Model describing the relationship between pharmacokinetics and hematologic toxicity of the epirubicin-docetaxel regimen in breast cancer patients.

PURPOSE: The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients. PATIENTS AND METHODS: Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m(2). Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m(2)) or reduced (minimum, 40/50 mg/m(2)). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment. RESULTS: In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data. CONCLUSION: The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.

Adult↗

PubMed2004

Population pharmacokinetics of sibrotuzumab, a novel therapeutic monoclonal antibody, in cancer patients.

Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5 mg/m(2) to an absolute dose of 100 mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1 ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6 ml/h (9.6); for the nonlinear clearance Vmax was 0.0338 mg/h (25) and Km 0.219 microg/ml (57). At serum concentrations between approximately 20 ng/ml and 7 microg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7 microg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration-time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.

Adult↗

PubMed2003

Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients.

The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112-233 mg/m(2)). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m(2) typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 microM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.

Adult↗

PubMed2003

Variable expression of CYP and Pgp genes in the human small intestine.

BACKGROUND: The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome p450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. METHODS: The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. RESULTS: Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. CONCLUSIONS: Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation.

Adult↗

PubMed2001

Mechanism-based pharmacokinetic model for paclitaxel.

PURPOSE: To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia. PATIENTS AND METHODS: Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively. RESULTS: The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug. CONCLUSION: Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.

Adult↗

PubMed2001

In vivo activity of CHS 828 on hollow-fibre cultures of primary human tumour cells from patients.

Fresh human tumour cells from patients with ovarian cancer and chronic lymphocytic leukaemia were cultured in semipermeable hollow fibres. The fibres were implanted on immunocompetent rats, which were treated with the cyanoguanidine N-(4-chlorophenoxyhexyl)-N'-cyano-N"-4-pyridylguanidine (CHS 828). CHS 828 showed high antitumour activity against all eight tumour samples; the fibres from control animals had a mean net growth of 73% while CHS 828 treatment induced a 37% mean reduction of cell density, without observable haematological toxicity. The results show a feasibility of using tumour cells directly from patients in the hollow-fibre rat model.

Aged↗

PubMed2001

Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles.

Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 (CrEL dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83 +/- 0.11 (at 135 mg/m2) to 0.68 +/- 0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.

Adult↗

PubMed2001

Role of modelling and simulation in Phase I drug development.

Although the use of pharmacokinetic/pharmacodynamic modelling and simulation (M&S) in drug development has increased during the last decade, this has most notably occurred in patient studies using the population approach. The role of M&S in Phase I, although of longer history, does not presently have the same impact on drug development. However, trends such as the increased use of biomarkers and clinical trial simulation as well as adoption of the learn/confirm concept can be expected to increase the importance of modelling in Phase I. To help identify the role of M&S, its main advantages and the obstacles to its rational use, an expert meeting was organised by COST B15 in Brussels, January 10-11, 2000. This article presents the views expressed at that meeting. Although it is clear that M&S occurs in only a minority of Phase I clinical trials, it is used for a large number of different purposes. In particular, M&S is considered valuable in the following situations: censoring because of assay limitation, characterisation of non-linearity, estimating exposure-response relationship, combined analyses, sparse sampling studies, special population studies, integrating PK/PD knowledge for decision making, simulation of Phase II trials, predicting multiple dose profile from single dose, bridging studies and formulation development. One or more of the following characteristics of M&S activities are often present and severely impede its successful integration into clinical drug development: lack of trained personnel, lack of protocol and/or analysis plan, absence of pre-specified objectives, no timelines or budget, low priority, inadequate reporting, no quality assurance of the modelling process and no evaluation of cost-benefit. The early clinical drug development phase is changing and if these implementation aspects can be appropriately addressed, M&S can fulfill an important role in reshaping the early trials by more effective extraction of information from studies, better integration of knowledge across studies and more precise predictions of trial outcome, thereby allowing more informed decision making.

Clinical Trials, Phase I as Topic↗

PubMed2001

Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man.

H 335/25, a 4-amino quinoline, belongs to a new class of reversible gastric acid pump inhibitors. A potential advantage of such drugs over the irreversible proton pump inhibitors (PPIs) is better control over the effect-time profile. Dose escalation studies were performed to characterize the effect on acid secretion in dogs (n=24) and healthy male subjects (n=12). The effect-time profile was delayed compared to the concentration-time profile. A model-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three different models were investigated: (1) a slow equilibration preceding the formation of drug-enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug-enzyme complex, described by a kinetic binding model, and (3) a delay between enzyme inhibition and the measured response, described by an indirect response model. Model 2 was shown to be superior to models 1 and 3, for both dog and human data. The dissociation rate constant, k(off), was estimated to be 0.85 and 0.88 h and the calculated equilibration constant, K(d), was 160 and 250 nM in dog and man, respectively. Simulations of the predicted time-course of the effect beyond the 4-5-h observation period was similar for the three models.

Administration, Oral↗

PubMed2001

Assessment of actual significance levels for covariate effects in NONMEM.

The objectives of this study were to assess the difference between actual and nominal significance levels, as judged by the likelihood ratio test, for hypothesis tests regarding covariate effects using NONMEM, and to study what factors influence these levels. Also, a strategy for obtaining closer agreement between nominal and actual significance levels was investigated. Pharmacokinetic (PK) data without covariate relationships were simulated from a one compartment i.v. bolus model for 50 individuals. Models with and without covariate relationships were then fitted to the data, and differences in the objective function values were calculated. Alterations were made to the simulation settings; the structural and error models, the number of individuals, the number of samples per individual and the covariate distribution. Different estimation methods in NONMEM were also tried. In addition, a strategy for estimating the actual significance levels for a specific data set, model and parameter was investigated using covariate randomization and a real data set. Under most conditions when the first-order (FO) method was used, the actual significance level for including a covariate relationship in a model was higher than the nominal significance level. Among factors with high impact were frequency of sampling and residual error magnitude. The use of the first-order conditional estimation method with interaction (FOCE-INTER) resulted in close agreement between actual and nominal significance levels. The results from the covariate randomization procedure of the real data set were in agreement with the results from the simulation study. With the FO method the actual significance levels were higher than the nominal, independent of the covariate type, but depending on the parameter influenced. When using FOCE-INTER the actual and nominal levels were similar. The most important factors influencing the actual significance levels for the FO method are the approximation of the influence of the random effects in a nonlinear model, a heteroscedastic error structure in which an existing interaction between interindividual and residual variability is not accounted for in the model, and a lognormal distribution of the residual error which is approximated by a symmetric distribution. Estimation with FOCE-INTER and the covariate randomization procedure provide means to achieve agreement between nominal and actual significance levels.

Adult↗

PubMed2001

Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients.

The aims of the present study were (1) to investigate and quantify the pharmacokinetics, including inter-occasion variability and covariate relationships, of busulphan in BMT patients and (2) to develop a user-friendly initial dosing and therapeutic drug monitoring (TDM) strategy for the treatment of those patients with busulphan. The pharmacokinetics of busulphan was studied in 64 adults and 12 children who received busulphan (1 mg/kg) four times daily for 4 days. A one-compartment model with first order absorption and a lag time was sufficient in describing the concentration-time profile. Oral clearance (CL/F) was found to be correlated to weight (+1.2%/kg), ALT (-13%/microcat/l) and concomitant phenytoin treatment (+21%). CL/F and the volume of distribution (V/F) were estimated to 9.23 l/h and 39.3 l, respectively, in a typical individual. Inter-occasion variability (9.4%) in CL/F was estimated to be less than inter-individual variability (28%), a prerequisite for the value of TDM. Bayesian CL/F estimates based on three samples were in good accordance with those based on all samples. The final population model was implemented into the program Excel. The resulting flexible and easy to use dosing program might be used for both initial and, requiring only three plasma samples, maintenance dose individualization of busulphan therapy.

Administration, Oral↗

PubMed2001

Pharmacodynamic models for the cardiovascular effects of moxonidine in patients with congestive heart failure.

AIMS: To assess the pharmacodynamics of moxonidine in patients with functional NYHA Class II-III congestive heart failure (CHF). METHODS: A parallel population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed to assess the effect of moxonidine (0.1, 0.2, 0.3 mg twice daily) and placebo treatment on plasma noradrenaline (NA) levels, standing systolic blood pressure (SBP), and heart rate (HR) over 12 weeks in 97 patients with CHF using a parallel group design with dose escalation. A sequential analysis was also developed, where the relative changes in NA concentration were related to both SBP and HR. RESULTS: In the parallel PD analysis, an effect delay was shown for all three end points (NA, SBP, and HR). An inhibitory Emax model was used to characterize the concentration-effect relationships. For SBP and HR, the EC50 value increased over time. For NA, there was a positive baseline drift over the 12 weeks; this was interpreted as disease progression. Moxonidine delayed this increase by 9.8 weeks. For SBP, there was a circadian pattern at baseline. In the sequential PD analysis, the relationship between the drug response (NA) and SBP or HR was best described by an inhibitory Emax model. No effect delays between the response and effects were found. CONCLUSIONS: Effects of moxonidine on NA, SBP, and HR could be quantified by an effect compartment model in the presence of disease progression and circadian variations. Disease progression, as judged by increasing NA levels with time, was delayed by moxonidine. A direct relationship was found between NA and SBP/HR.

Adult↗

PubMed2001

Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease.

AIMS: The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease. METHODS: Data from five phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non-Q-wave myocardial infarction were evaluated. A total of 3296 pairs of concentration-APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT. RESULTS: The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically significant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and Emax model. A significant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method-dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and Emax, in the model. For the typical healthy subject and patient, the method-corrected population mean parameters were: APTTbaseline 35 and 31 s, slope 8.0 and 5.8 s x l x micromol(-1), Emax 36 and 34 s, and EC50 0.54 and 0.72 micromol x l(-1), respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 micromol x l(-1) in the healthy volunteer and patient, respectively. CONCLUSIONS: The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and Emax model. Pooling of data was made possible by incorporating a centre-specific characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects.

Adult↗

PubMed2001

A hollow fiber model for in vitro studies of cytotoxic compounds: activity of the cyanoguanidine CHS 828.

The hollow fiber assay is currently used as an in vivo model for anticancer drug screening in nude mice, but it can also be used as an in vitro model. In the current study, an in vitro hollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.

Antineoplastic Agents↗

PubMed2001

Concentration-controlled or effect-controlled trials: useful alternatives to conventional dose-controlled trials?

Historically, dose-finding trials have been confirmatory in nature despite the fact that these trials represent an important and essential 'learning' phase in the drug development process. About 10 years ago 2 alternatives to the randomised dose-controlled trial (RDCT) were proposed as being more informative trial types. Controlling systemic drug exposure in order to improve efficiency of a trial forms the basis for the suggestion of a randomised concentration-controlled trial (RCCT). For the common instance where pharmacodynamic variability is larger than pharmacokinetic variability, the randomised effect-controlled trial (RECT), where patients are randomised to the effect of interest was suggested as even more informative. A survey of the literature shows that the RCCT has been sparsely applied and RECT not at all. For RCCT, the practical complications of carrying out the study seldom makes it the study type of choice. For RECT, the limited number of suitable situations for its application and the fact that the same effect is used for randomisation and analysis may explain the lack of applications. As a somewhat more favourable trial type, we suggest the randomised biomarker-controlled trial (RBCT), where patients are randomised to a certain value or range of a biomarker whereas the analysis is performed on another, clinically more relevant, effect. Although the RBCT has some attractive features, for example contributing to validation of a biomarker as a surrogate for clinical outcome, it is unlikely to be extensively used. Instead, the main shift from confirming to learning in dose-finding trials is coming from the incorporation of well-known learning components into the RDCT (e.g. sparse concentration measurements combined with population pharmacokinetic-pharmacodynamic, biomarker measurements and analysis of effect measures throughout the entire trial period).

Dose-Response Relationship, Drug↗

PubMed2001

Model for time dependency of cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action.

CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.

Antineoplastic Agents↗

PubMed2000

Models of schedule dependent haematological toxicity of 2'-deoxy-2'-methylidenecytidine (DMDC).

OBJECTIVE: DMDC (2'-deoxy-2'-methylidenecytidine) is-a potential antitumour deoxycytidine analogue of cytosine arabinoside. The major dose-limiting toxicity of DMDC is haematological depression, particularly neutropenia, and therefore quantitative exposure-toxicity relationships for DMDC are warranted. METHODS: Data on the survival fraction at nadir of leukocytes, neutrophils and platelets from 66 patients receiving a once-daily regimen and 85 patients receiving a twice-daily regimen of DMDC were related to DMDC concentration-time profiles using area under the plasma concentration-time curve (AUC), threshold and general models. A semiphysiological model of neutrophils versus time after DMDC administration included transient compartments to imitate the differentiation stages in the bone marrow. RESULTS: The relationship between plasma DMDC concentration-time profiles and the haematological toxicity at nadir was best described using an AUC-dependent model with separate functions for once- and twice-daily dosing, indicating schedule dependence of DMDC effects, even if differences in treatment duration had a similar explanatory value. Twice-daily dosing was associated with greater toxic effects than once-daily dosing. The AUC required for a 70% reduction in the neutrophils was 16 mg.h/l and 4.2 mg.h/l for the once- and twice-daily regimens, respectively. The semiphysiological model included nine proliferating transient compartments that were sensitive to DMDC in a schedule-dependent manner, five non-mitotic, non-sensitive compartments and one compartment for circulating neutrophils. CONCLUSIONS: The haematological toxicity of DMDC is schedule dependent. The survival fractions of leukocytes, neutrophils and platelets are predicted to be lower when given on a twice-daily regimen than on a once-daily regimen. A semiphysiological model with transient compartments successfully described the entire time course of neutropenia after DMDC administration.

Antineoplastic Agents↗