A Limited Sampling Model for Estimating Pharmacokinetics of CPT-11 and Its Metabolite SN-38

The objective of this study was to develop a limited sampling model (LSM) to estimate the area under the curve (AUC) of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and that of 7-ethyl-10-hydroxycamptothecin (SN-38) as predictive pharmacokinetic variables for leukopenia and episodes of diarrhea induced by CPT-11 administration. The model was developed with a training set consisting of pharmacokinetic studies in 36 patients who received a 90-min i.v. infusion of CPT-11 at a dose of 100 mg/m². A multiple regression analysis of CPT-11 or SN-38 concentrations observed at each time point in the training set was used to predict the AUC of CPT-11 or SN-38. The final sampling models using only two time points were:
AUC_CPT-11=3.7891★C2.5+14.0479*C13.5+1.5463
AUC_SN-38=0.5319★C2.5+19.1468*C13.5+72.7349
where C2.5 and C13.5 are the plasma concentration of CPT-11 (μg/ml) or SN-38 (ng/ml) at 2.5 and 13.5 h after the initiation of CPT-11 infusion, respectively. The models were validated prospectively on a separate test data set of 12 patients receiving the same dose of CPT-11 investigated in a previous study. Validation of the final LSM on the test data set gave values of root mean square error (RMSE) of 12.72% and 5.97% for the AUC of CPT-11 and that of SN-38, respectively. The model can be used to monitor the AUCs of both CPT-11 and SN-38 for the early prediction of toxicities and to establish a pharmacokinetically based dose modification strategy for safe administration of CPT-11.     

Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials*

BACKGROUND: Irinotecan (CPT-11) is a novel water-soluble camptothecin derivativeselected for clinical testing based on its good in vitro andin vivo activity in various experimental systems, includingpleiotropic drug-resistant tumors. Its mechanism of action appearsmediated through topoiso-merase I inhibition. The purpose ofthis study was to describe CPT-11 and active metabolite SN-38population pharmacokinetics, examine patient characteristicsthat may influence pharmacokinetics, and to investigate pharmacokinetic-phar-macodynamicrelationships that may prove useful in the future clinical managementof this drug. PATIENTS AND METHODS: As part of 3 Phase I studies including 235 patients, pharmacokineticsof CPT-11 and metabolite SN-38 were determined in 107 patients.CPT-11 was administered as a 30-min i.v. infusion accordingto 3 different schedules: daily for 3 consecutive days every3 weeks, weekly for 3 weeks, and once every 3 weeks. Patientscharacteristics were the following: median age 53 years; men,45 women; 105 Caucasians, 2 blacks; performance status was 0–1in 96 patients; tumor sites were predominantly colon, rectum,head and neck, lung, ovary and breast; with the exception of6 patients, all had been previously treated with surgery, chemotherapyand/or radiotherapy. CPT-11 and metabolite SN-38 were simultaneouslydetermined by HPLC using fluorescence detection. Pharmacokineticparameters were determined using model-independent and model-dependentanalyses. RESULTS: 168 pharmacokinetic data sets were obtained in 107 patients(97 first courses, 43 second courses, 23 third courses, 4 fourthcourses, and 1 fifth course). Rebound concentrations of CPT-11were frequently observed at about 0.5 to 1 h following the endof the i.v. infusion, which is suggestive of enterohepatic recyclingof the drug. Model-independent analysis yielded the followingmean population pharmacokinetic parameters for CPT-11: a terminalhalf-life of 10.8 h, a mean residence time (MRT) of 10.7 h,a volume of distribution at stedy state (Vdss) of 150 L/m²,and a total body clearance of 14.3 L/m²/h. Model-dependent analysisdisclosed a CPT-11 plasma disposition as either biphasic ortri-phasic with a mean terminal half-life of 12.0 h. The volumeof distribution Vdss (150 L/m²) and total body clearance (14.8L/m²/h) yielded almost identical values to the above model-independentanalysis. The active metabolite SN-38 presented rebound concentrationsin many courses at about 1 h following the end of the i.v. infusionwhich is suggestive of enterohepatic recycling. The mean timeat which SN-38 maximum concentrations was reached was at 1 hsince the beginning of the 0.5 h infusion (i.e., 0.5 h posti.v.). SN-38 plasma decay followed closely that of the parentcompound with a mean apparent terminal half-life of 10.6 h.Mean 24 h CPT-11 urinary excretion represented 16.7% of theadministered dose, whereas metabolite SN-38 recovery in urinewas minimal (0.23% of the CPT-11 dose). The number of CPT-11treatments did not influence pharmacokinetic parameters of eitherthe parent compound or metabolite SN-38. Although CPT-11 pharmacokineticspresented an important interpatient variability, both CPT-11maximum concentrations (Cmax) and the CPT-11 area under theplasma concentration versus time curves (AUC) increased proportionallyand linearly with dosage (Cmax, r=0.78, p<0.001); CPT-11AUC, r=0.88, p<0.001). An increase in half-life and MRT wasobserved at higher dosages, although this did not influencethe linear increase in AUC as a function of dose. The volumeof distribution at steady state (Vdss) and the total body clearance(CL) were not affected by the CPT-11 dose. Metabolite SN-38AUC increased proportionally to the CPT-11 dose (r=0.67, p<0.001)and also with the parent compound AUC (r=0.75, p<0.001).The increase in dose did not lead to a change in the fractionof drug metabolized into SN-38 (percentage SN-38 AUC/CPT-11AUC = mean value of 3.08%. There was also no significant influenceof CPT-11 dose on the 24-h percent recovery of the parent compoundor of its metabolite in urine. Patient physio-pathological characteristics were examined aspossible determinant of pharmacokinetics. No detectable relationshipwas observed between CL or the metabolic ratio (% SN-38 AUC/CPT-11AUC), with the following physio-pathological factors: age, sex,height, weight, body surface, tumor type, or renal function.However, with regard to hepatic function, significant correlations(negative) were observed with CPT-11 CL and some hepatic functionmarkers, e.g., bilirubinemia and gamma-glutamyl transpeptidase.Also of interest, a significant positive correlation betweenthe metabolic ratio and some liver function parameters wereobserved, e.g., bilirubinemia, aspartate transferase (AST),and alanine transferase (ALT). For the pharmacokinetic-pharmacodynamic studies, CPT-11 AUCcorrelated significantly with the percent decrease of eitherthe white blood cells or the neutrophils. CPT-11 AUC also correlatedsignificantly with the intensity of diarrhea, and the intensityof nausea and vomiting. CPT-11 CL correlated negatively withthe intensity of the principal toxicities observed. MetaboliteSN-38 AUC was also significantly correlated with the percentdecrease in white blood cells and neutrophils. Significant correlationswere also observed between SN-38 AUC and the intensity of diarrhea,and the intensity of nausea and vomiting. The metabolic ratiodid not correlate with any of the principal toxicities encounteredin these clinical studies. With regard to antitumor responses,although the optimal schedule and dose were not obviously definedat the beginning of these phase I trials, 17 tumor responseswere nevertheless observed (2 complete, 9 partial, 6 minor).The observation that most of these responses were obtained atthe highest doses administered is highly suggestive of a dose-responserelationship with this drug. CONCLUSIONS: These data indicate that CPT-11 population pharmacokineticsis linear within the large dose range investigated, that thenumber of treatments do not influence pharmacokinetics, thatliver function affects CPT-11 clearance. Also of interest, theintensity of the major toxicities encountered with this drug(e.g., leukoneutropenia, diarrhea, nausea and vomiting) correlatedwith the exposure (AUC) to CPT-11 and metabolite SN-38. A dose-effectrelationship was also noted for anticancer activity since mosttumor responses were observed at the highest doses administered.These pharmacological data are of importance for the conductof future clinical studies with this active drug.     

A Pharmacokinetic and Pharmacodynamic Analysis of CPT-11 and Its Active Metabolite SN-38

In the present study, an attempt was made to determine the precise pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). The relationship between pharmacokinetic parameters and pharmacodynamic effects was also investigated to elucidate the cause of interpatient variation in side effects. Thirty-six patients entered the study. CPT-11, 100 mg/m², was administered by IV infusion over 90 min weekly for four consecutive weeks. The major dose-limiting toxicities were leukopenia and diarrhea. There was a positive correlation between the area under the concentration-time curve (AUC) of CPT-11 and percent decrease of WBC ( r =0.559). On the other hand, episodes of diarrhea had a better correlation with the AUC of SN-38 ( r =0.606) than that of CPT-11 ( r =0.408). Multivariate analysis revealed that the AUC of SN-38, AUC of CPT-11 and indocyanine green retention test were significant variables for the incidence of diarrhea and that both performance status and AUC of CPT-11 were significant variables for percent decrease of WBC. The large interpatient variability of the degree of leukopenia and diarrhea is due to a great plasma pharmacokinetic variation in CPT-11 or SN-38. The AUCs of CPT-11 and SN-38 obtained from the first administration of CPT-11 correlate with toxicities, but it is impossible to predict severe side effects before the administration of CPT-11 at the present time.     

Pharmacological Correlation between Total Drug Concentration and Lactones of CPT-11 and SN-38 in Patients Treated with CPT-11

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m² of CPT-11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin-containing syringes. Analysis by high-performance liquid chromatography showed that the ratio of CPT-11 lactone to total CPT-11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN-38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT-11 or SN-38 to total drug concentration at each sampling point were less than 12%. The area under the concentration-time curve (AUC) of total CPT-11 and that of total SN-38 were significantly correlated with the AUCs of the lactone CPT-11 and those of lactone SN-38, respectively. We conclude that, for practical purposes, monitoring of total CPT-11 and SN-38 has essentially the same clinical significance as monitoring of lactone CPT-11 and SN-38.     

Relationship between the Pharmacokinetics of Irinotecan and Diarrhea during Combination Chemotherapy with Cisplatin

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m² plus cisplatin at 60 mg/m². The other 13 patients received CPT-11 at 80 or 90 mg/m² plus cisplatin at 80 mg/m² with the granulocyte colony-stimulating factor support (2 μg/kg × 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m² in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3–4 diarrhea than those with a lower SN-38 level ( P =0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea ( P =0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.     

Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors

BACKGROUND: We conducted a phase I and pharmacokinetic study to determinethe maximum tolerable dose (MTD), toxicities, pharmacokineticprofile, and antitumor activity of Irinotecan (CPT-11) in patientswith refractory solid malignancies. PATIENTS AND METHODS: Forty-six patients were entered in this phase I study. CPT-11was administered intravenously over 30 minutes for 3 consecutivedays every 3 weeks. Dose levels ranged from 33 mg/m²/day to115 mg/m²/day on days 1 through 3. The pharmacokinetics of totalCPT-11 and its active metabolite SN-38 were assayed by HPLC. RESULTS: The combination of leukopenia and diarrhea was dose-limitingtoxicity at 115 mg/m²/day dose level, since 50% of the patients(5/10) experienced either grade 3–4 leukopenia, or diarrhea,or both. Leukopenia appeared to be a cumulative toxicity, witha global increase in its incidence and severity upon repeatedadministration of CPT-11. Other toxicities included nausea,vomiting, fatigue and alopecia. CPT-11 and active metaboliteSN-38 inetics were determined in 21 patients (29 courses). BothCPT-11 and SN-38 pharmacokinetics presented a high interpatientvariability. CPT-11 mean maximum plasma concentrations reached2034 ng/ml at the MTD (115 mg/m²). The terminal-phase half-lifewas 8.3 h and the mean residence time 10.2 h. The mean volumeof distribution at steady state was 141 l/m²/h. CPT-11 reboundconcentrations were observed in many courses at about 0.5 to1 hour following the end of the i.v. infusion, which is suggestiveof enterohepatic recycling. Total body clearance did not varywith increased dosage (mean=14.3 l/h/m²), indicating linearpharmacokinetics within the dose range administered in thistrial. The total area under the plasma concentration versustime curve (AUC) increased proportionally to the CPT-11 dose.Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD.A significant correlation was observed between CPT-11 area underthe curve (AUC) and its corresponding metabolite SN-38 AUC (r=0.52,p < 0.05). S-38 rebound concentrations were observed in manycourses at about 0.5 to 1 hour following the end of the i.v.infusion, which is suggestive of enterohepatic recycling. Mean24-h urinary excretion of CPT-11 accounted for 10% of the administereddose by the third day, whereas SN-38 urinary excretion accountedfor 0.18% of the CPT-11 dose. In this phase I trial, the hemato-logicaltoxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrheagrade correlated significantly with CPT-11 AUC. Two partial(breast adenocarcinoma and carcinoma of unknown primary) and2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responseswere observed. CONCLUSION: The MTD for CPT-11 administered in a 3 consecutive-days-every-3weeks schedule in this patient population is 115 mg/m²/day.The recommended dose for phase II studies is 100 mg/m²/day. CPT-11, camptothecin analogue, topoisomerase I inhibitor, phase I, pharmacokinetics     

Limited sampling models for simultaneous estimation of the pharmacokinetics of irinotecan and its active metabolite SN-38

Irinotecan (CPT-11) is a novel topoisomerase I inhibitor with clinical activity in human malignancies. The objective of this study was to develop efficient limited sampling models (LSMs) to estimate simultaneously the area under the plasma concentration versus time curves (AUC) for both CPT-11 and its active metabolite SN-38. A total of 64 pharmacokinetic sets (24-h sampling) were obtained in phase I studies at doses ranging from 50 to 750 mg/m² (0.5-h i.v. infusion). The patients were randomly assigned to a training data set (n=32) and a test set (n=32). Multiple linear regression analyses were used to determine the optimal LSMs based on the correlation coefficient (r), bias (MPE%, percentage of mean prediction error), and precision (RMSE%, percentage of root mean squared prediction error). Of these LSMs, the ones including maximal concentrations of CPT-11 (0.5 h, the end of the i.v. infusion) and metabolite SN-38 ( 1 h) were favored along with predictive precision and clinical constraints. Several bivariate models including a 6-h time point as the last sampling time (or 7 h) were found to be highly predictive of either the CPT-11 AUC or the SN-38 AUC. The chosen sampling time points were the ones that allowed the best compromise between the accurate determination of either compound alone with the same sampling times. The simultaneously best prediction of both CPT-11 and SN-38 AUCs was obtained with sampling time points harvested at 0.5, 1, and 6 h (or 7 h). With these sampling time points a trivariate model was selected for the determination of CPT-11 AUC namely, CPT-11 AUC (ng h ml^–1)=0.820×C_0.5h+0.402×C_1h+15.47 ×C_6h+928, and a corresponding model was selected for the determination of metabolite AUC, i.e., SN-38 AUC (ng h ml^–1)=4.05×C_0.5h–0.81×C_1h+23.01×C_6h–69.78, whereC(t) is the concentration in nanograms per milliliter of either compound at a given timet. These models performed well with the test data sets for CPT-11 AUC (r=0.98, MPE%=–1.4, RMSE%=13.9) and for SN-38 AUC (r=0.95, MPE%=–6.5, RMSE%=37.7). In addition to the determination of AUCs (and hence clearance), these models also allow the determination of the maximal concentrations of both compounds, which might be needed for pharmacodynamics studies. Other bi- and trivariate models including other time points are also presented. These LSMs not only will facilitate ongoing and future clinical trials by significantly reducing the number of blood samples needed for pharmacokinetics studies but will hopefully contribute to a better knowledge of pharmacokinetic-pharmacodynamic relationships for both CPT-11 and its active metabolite SN-38.Abbreviations CPT-11 (7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptothecin - SN-38 7-ethyl-10-hydroxy-camptothecin - AUC area under the plasma concentration versus time curve - MPE% percentage of mean prediction error (bias) - RMSE% percentage root mean squared prediction error (precision) - MRT mean residence time - Vdss volume of distribution at steady state - CL total body clearance     

Real-time dose adjustment of cyclophosphamide in a preparative regimen for hematopoietic cell transplant: a Bayesian pharmacokinetic approach.

PURPOSE: Dose-related toxicity of cyclophosphamide may be reduced and therapeutic efficacy may be improved by pharmacokinetic sampling and dose adjustment to achieve a target area under the curve (AUC) for two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM). To facilitate real-time dose adjustment, we developed open-source code within the statistical software R that incorporates individual data into a population pharmacokinetic model. EXPERIMENTAL DESIGN: Dosage prediction performance was compared to that obtained with nonlinear mixed-effects modeling using NONMEM in 20 cancer patients receiving cyclophosphamide. Bayesian estimation of individual pharmacokinetic parameters was accomplished from limited (i.e., five samples over 0-16 hours) sampling of plasma HCY and CEPM after the initial cyclophosphamide dose. Conditional on individual pharmacokinetics, simulations of the AUC of both HCY and CEPM were provided for a range of second doses (i.e., 0-100 mg/kg cyclophosphamide). RESULTS: The results compared favorably with NONMEM and returned accurate predictions for AUCs of HCY and CEPM with comparable mean absolute prediction error and root mean square prediction error. With our method, the mean absolute prediction error and root mean square prediction error of AUC CEPM were 11.0% and 12.8% and AUC HCY were 31.7% and 44.8%, respectively. CONCLUSIONS: We developed dose adjustment software that potentially can be used to adjust cyclophosphamide dosing in a clinical setting, thus expanding the opportunity for pharmacokinetic individualization of cyclophosphamide. The software is simple to use (requiring no programming experience), reads individual patient data directly from an Excel spreadsheet, and runs in less than 5 minutes on a desktop PC.     

Population pharmacokinetics of melphalan,infused over a 24-hour period,in patients with advanced malignancies

Purpose The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies.Methods Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity.Results Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3±4.5 l/h per m²) than in female patients (12.3±4.5 l/h per m²). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m²). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels.Conclusion The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.     

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors

Purpose To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors.Methods We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m² per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling.Results The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C_max 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 g/ml·h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C_max (P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies.Conclusions This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.This work was supported in part by USPHS awards CA 23099, Cancer Center CORE grant CA21765, the Schering Plough Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).     

Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors.

PURPOSE: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d. RESULTS: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response. CONCLUSION: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development.     

Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer.

The objective of the present study was to determine the pharmacokinetic profile of vinorelbine in patients 65 years or older with metastatic cancer in progression. Twelve patients were enrolled in this study. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20-30 mg/m2 through a central venous catheter. Chemotherapy was repeated weekly. A total of 46 courses of vinorelbine was studied. Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Toxicity evaluation was carried out before each course of chemotherapy. Plasma vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorometric detection. A Bayesian estimation of individual pharmacokinetic parameters was carried out using the nonlinear mixed-effect modeling approach as implemented in the NONMEM computer program. An open three-compartment pharmacokinetic model with a zero order input rate was used to describe the kinetics of vinorelbine. Area under the plasma-concentration time curve (AUC) normalized to a 30 mg/m2 administered dose averaged 0.89 mg/liter x h (coefficient of variation = 23.7%). The total plasma clearance averaged 0.93 liter/h/kg (0.61-1.83 liter/h/kg; coefficient of variation = 38.6%). The elimination half-life was 38.1 +/- 5.8 h. A high correlation was found between patient age and total clearance (r = -0.8; P < 0.001). The main hematological toxicity observed was anemia in 11 patients. Neutropenia occurred in 50% of patients. Significant correlations were found between AUC and the decrease in the hemoglobin level (r = 0.60) and between AUC and the decrease in the neutrophil count (r = 0.66). Thrombocytopenia was observed in only one patient. In conclusion, the age-related decrease in clearance found in this study supports the design of a Phase I study of vinorelbine in patients older than 65 years or perhaps 70 years.     

Pharmacokinetics of CPT-11 in rhesus monkeys

Purpose: To examine the pharmacokinetic relationships between humans and monkeys, we studied the disposition of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), in rhesus monkeys. Methods: CPT-11 was administered to a total of six monkeys at doses of 3, 7, 15 and 25 mg/kg by intravenous infusion for 10 min and plasma concentrations and pharmacokinetic parameters of CPT-11 determined. Results: Maximum plasma concentrations at 25 mg/kg reached around 10 000 ng/ml, and dropped to 500 ng/ml in 8 h. Plasma concentrations of SN-38 remained between 2 and 10 ng/ml. Mean values of systemic clearance, mean residence time and distribution volume at steady state, the major pharmacokinetic parameters for CPT-11, were 13.3 (ml/min per kg), 192 (min) and 2553 (ml/kg), respectively. The initial plasma concentration ratio of lactone to total CPT-11, 76%, declined to about 20% within 75 min, and the final ratio was about 40% at 8 h; the initial ratio of SN-38 was 72%, dropped to 34% within 70 min and finally recovered to 55% at 8 h. Conclusion: Comparison with human data revealed that systemic clearances of CPT-11 and the maximum AUC of SN-38 were not as different between humans and monkeys as between humans and mice, but the metabolic conversion of CPT-11 into SN-38 in monkeys was significantly lower than in humans. Received: 19 December 1996 / Accepted: 9 May 1997     

Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin.

In this study, 11 patients with solid tumors were randomized to receive irinotecan (CPT-11; 200 mg/m2) as a 90-min i.v. infusion, immediately followed by cisplatin (CDDP; 80 mg/m2) as a 3-h i.v. infusion in the first course and the reversed sequence in the second course or vice versa. No significant differences in any toxicity were observed between the treatment schedules (decrease in absolute neutrophil count, 74.7 +/- 18.3 versus 80.3 +/- 18.0%; P = 0.41). CPT-11 lactone clearance was similar to single agent data and not significantly different between study courses (60.4 +/- 17.1 versus 65.5 +/- 16.3 liter/h/m2; P = 0.66). The kinetic profiles of the major CPT-11 metabolites SN-38, SN-38 glucuronide, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidinolcarbonyloxycamptothecine (APC), and 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were also sequence independent (P > or = 0.20). In addition, CPT-11 had no influence on the clearance of nonprotein-bound CDDP (40.8 +/- 16.7 versus 50.3 +/- 18.6 liter/h/m2; P = 0.08) and the platinum DNA-adduct formation in peripheral leukocytes in either sequence (1.94 +/- 2.20 versus 2.42 +/- 1.62 pg Pt/microg DNA; P = 0.41). These data indicate that the toxicity of the combination CPT-11 and CDDP is schedule independent and that there is no mutual pharmacokinetic interaction.     

Area under the curve calculation of nedaplatin dose used in combination chemotherapy with irinotecan in a phase I study of gynecologic malignancies

Purpose

Although the pharmacokinetic mechanism of nedaplatin (NDP) is similar to carboplatin, the dose of NDP is typically determined by body surface area and not by the area under the curve (AUC). We conducted a phase I study to determine the AUC-calculated optimal dosage of NDP used in combination chemotherapy with irinotecan (CPT-11) for gynecologic malignancies.

Methods

A total of 15 patients who were to undergo combination chemotherapy consisting of NDP and CPT-11 were enrolled in this study. The dose of CPT-11 was administered at a fixed dose of 60?mg/m² and that of NDP was gradually increased from 8 to 12???g?h/mL (AUC). The individual dose of NDP was calculated based on cratinine clearance of the patient according following formula: Dose_NDP?=?AUC?×?CL_NDP, where CL_NDP?=?0.0738?×?creatinine clearance?+?4.47 (Ishibashi??s formula).

Results

One patient had dose-limiting toxicity (DLT) at level 1, and two patients suffered DLT at level 3. The dosage of NDP at AUC 12 was determined to be the maximum tolerated dose in combination chemotherapy with CPT-11, even though only two of the six patients showed DLT at level 3.

Conclusions

The recommended dosage of NDP calculated by AUC with Ishibashi??s fomula was set to AUC 10 in combination chemotherapy with CPT-11.     

Down-regulation of lipids transporter ABCA1 increases the cytotoxicity of Nitidine

Purpose

This study examined the pharmacokinetics of irinotecan (CPT-11), active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide (SN-38G) amrubicin (AMR), and active metabolite amrubicinol (AMR-OH) after intravenous administration of this combination therapy in rats.

Methods

Male Sprague-Dawley rats were treated with 10 mg/kg CPT-11 with 10 mg/kg AMR. AMR, AMR-OH, CPT-11, SN-38 and SN-38G were measured in plasma, bile, and tissues using high-performance liquid chromatography.

Results

Co-administration of CPT-11 resulted in a significant decrease in plasma concentrations and area under the curves (AUC) of AMR-OH compared with treatment with AMR alone. On the other hand, co-administration of AMR resulted in a slight increase in the initial plasma concentration of SN-38; however, there were no differences in AUC values in CPT-11 and SN-38. The cumulative biliary excretion curves of AMR, CPT-11, and their active metabolites were not changed. CPT-11 inhibited the conversion of AMR to AMR-OH in rat cytosolic fractions.

Conclusions

CPT-11 did not affect the pharmacokinetic of AMR but decreased the plasma concentration of AMR-OH and might affect the formation of AMR-OH from AMR in hepatocytes.     

Population pharmacokinetics of the photodynamic therapy agent 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a in cancer patients

Photodynamic therapy is an effective and often curative treatment for certain solid tumors. The porphyrin-based photosensitizer Photofrin, the only Food and Drug Administration-approved drug for this therapy, suffers from certain disadvantages: its complex chemical nature; retention by skin (leading to protracted cutaneous photosensitivity); and less than optimal photophysical properties. In this study, we examine the population pharmacokinetics and cutaneous phototoxicity of 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-type photosensitizer with more favorable photophysical properties. HPPH plasma concentration-time data were obtained in 25 patients enrolled in Phase I-II clinical trials for the treatment of partially obstructive esophageal carcinoma, high-grade dysplasia associated with Barrett's esophagus, carcinoma of the lung, or multiple basal cell carcinomas. Doses of 3, 4, 5, or 6 mg/m(2) were administered as 1-h i.v. infusions. The pharmacokinetic data for each patient were fitted with a standard two-compartment (biexponential) model with continuous infusion. The model fitting approach was iteratively reweighted nonlinear regression, with weights equal to the reciprocal of the square of the predicted HPPH plasma concentrations. The complete set of data for all 25 patients was then fitted simultaneously with nonlinear mixed effects modeling. Cutaneous phototoxicity responses were determined, as a function of time after HPPH infusion, following exposure to various doses of light from a solar simulator. The estimates of the population mean (variance) for each parameter were as follows: volume of distribution (V(C)), 2.40 liters/m(2) (0.259); steady-state volume (V(SS)), 9.58 liters/m(2) (11.6); systemic clearance (CL), 0.0296 liter/h/m(2) (0.000094); and distributional clearance (CL(D)), 0.144 liter/h/m(2) (0.00166). These parameters were independent of dose. Clearance increased with age. A relative error model was used for the difference in the raw and fitted data, and the overall coefficient of variation estimate across all of the data was 14.5%. The estimated mean population alpha and beta half-lives (95% confidence interval) were 7.77 h (3.46-17.6 h) and 596 h (120-2951 h), respectively. High-performance liquid chromatography analysis of serum showed no circulating HPPH metabolites, and in vitro incubation of HPPH with human liver microsomal preparations resulted in no metabolite or glucuronic acid-HPPH conjugate production. A minimal skin response to the solar simulator was observed, mostly in patients treated with the highest dose of HPPH, 6 mg/m(2). All of the HPPH pharmacokinetic parameters were consistent with a highly lipophilic agent that is concentrated in plasma and is nearly 100% bound to plasma proteins; this was verified by plasma protein binding studies. Whereas low concentrations of HPPH can be detected in plasma several months after a single infusion, no instances of cutaneous photosensitivity have been noted in these patients. In general, HPPH pharmacokinetic profiles are readily predictable from the global population model. This is the first comprehensive human population pharmacokinetic/pharmacodynamic study of a clinical anticancer photodynamic therapy agent.     

Clinical pharmacokinetics of irinotecan and its metabolites: a population analysis.

PURPOSE: To build population pharmacokinetic (PK) models for irinotecan (CPT-11) and its currently identified metabolites. PATIENTS AND METHODS: Seventy cancer patients (24 women and 46 men) received 90-minute intravenous infusions of CPT-11 in the dose range of 175 to 300 mg/m(2). The PK models were developed to describe plasma concentration profiles of the lactone and carboxylate forms of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) and the total forms of SN-38 glucuronide (SN-38G), 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC) by using NONMEM. RESULTS: The interconversion between the lactone and carboxylate forms of CPT-11 was relatively rapid, with an equilibration half-life of 14 minutes in the central compartment and hydrolysis occurring at a rate five times faster than lactonization. The same interconversion also occurred in peripheral compartments. CPT-11 lactone had extensive tissue distribution (steady-state volume of distribution [Vss], 445 L) compared with the carboxylate form (Vss, 78 L, excluding peripherally formed CPT-11 carboxylate). Clearance (CL) was higher for the lactone form (74.3 L/h) compared with the carboxylate form (12.3 L/h). During metabolite data modeling, goodness of fit indicated a preference of SN-38 and NPC to be formed out of the lactone form of CPT-11, whereas APC could be modeled best by presuming formation from CPT-11 carboxylate. The interconversion between SN-38 lactone and carboxylate was slower than that of CPT-11, with the lactone form dominating at equilibrium. The CLs for SN-38 lactone and carboxylate were similar, but the lactone form had more extensive tissue distribution. CONCLUSION: Plasma data of CPT-11 and metabolites could be adequately described by this compartmental model, which may be useful in predicting the time courses, including interindividual variability, of all characterized substances after intravenous administrations of CPT-11.     

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/m² 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 (V₁) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V₁ 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.Abbreviations ALT Alanine amino transferase - AST Aspartate amino transferase - AUC Area under the concentration curve - BSA Body surface area - BW Body weight - CL Clearance - ISV Intersubject variability - LBW Lean body weight - OFV Objective function value - SAP Serum alkaline phosphatases - SCr Serum creatinine - V₁ Distribution volume     

Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy

Purpose: A population pharmacokinetic model was developed to describe dose-exposure relationships of methotrexate (MTX) in adults with lymphoid malignancy; this is in order to explore the interindividual variability in relationship with the different physiopathological variables. The final model was applied to the Bayesian estimation of MTX concentrations using two blood samples. Methods: Fifty-one patients receiving 136 courses of MTX (1–6 per patient) were included in this study. The data was analysed using NONMEM software. A linear two-compartment model with linear elimination best described the data. Setting mean parameters values and variabilities to population values, we obtained Bayesian prediction of MTX pharmacokinetic parameters and concentrations. The predictive performance was evaluated by comparing the Bayesian estimated and observed concentrations and the Bayesian estimated parameters with the individual final model estimated parameters. Results: The population pharmacokinetic parameters and the inter-subject variablities expressed as coefficient of variation were: the total body clearance CL, 7.1 l h⁻¹ (22%), the volume of the central and peripheral compartments V1, 25.1 l (22.5%), V2, 2.7 l (64%), respectively, and the transfer constant Q, 2.7 (51%) l h⁻¹. Inter-course variability was only significant on CL. Age and serum creatinine had significant effects on CL and was included in the final model. A good correlation was obtained between Bayesian estimated and experimental concentrations (r2=0.85).