Pharmacokinetics of dibromodulcitol in humans: a phase I study.

1986 ◽  
Vol 4 (5) ◽  
pp. 753-761 ◽  
Author(s):  
S L Kelley ◽  
W P Peters ◽  
J Andersen ◽  
E A Furlong ◽  
E Frei ◽  
...  
Keyword(s):  
Phase I ◽  
Half Life ◽  
Phase I Study ◽  
Drug Level ◽  
Compartment Model ◽  
Hepatic Function ◽  
Apparent Volume ◽  
Pharmacokinetic Parameters ◽  
Elimination Constant ◽  
The Mean

A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed. Twenty-three patients with advanced neoplasms received DBD doses ranging from 600 to 1,800 mg/m2 body surface area (BSA). The dose-limiting toxicity was myelosuppression, with both significant granulocytopenia and thrombocytopenia occurring at dose levels of 1,500 to 1,800 mg/m2. The average pharmacokinetic parameters for DBD, calculated on the basis of a one-compartment model with first-order absorption and elimination, include the elimination constant, .005 +/- .002/min; absorption constant, .012 +/- .009/min; and an apparent volume of distribution, 1.03 +/- .4 L/kg. The area under the drug concentration curve (AUC) and the peak drug level (Cmax) were linearly related to the dose administered (P less than .001). The mean AUC was 18.7 +/- 6.1 mmol/L min, and the mean Cmax was 47.1 +/- 16.8 mumol/L when normalized to a DBD dose of 1 gm/m2. The elimination constant was significantly reduced in patients with abnormal hepatic function (P less than .01). The elimination constant was not correlated with renal function. The half-life of DBD in plasma (158 minutes) was considerably shorter than the four-to eight-hour half-life of total radioactivity in plasma measured by previous investigators following the administration of radiolabeled DBD.

Pharmacokinetics of C1 Esterase Inhibitor, Human (Pasteurized) in Subjects with Hereditary Angioedema.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1031-1031
Author(s):  
Wolfhart Kreuz ◽  
Inmarculada Martinez-Saguer ◽  
Hildegard Stoll ◽  
Sigurd Knaub ◽  
Thomas Klingebiel
Keyword(s):  
Plasma Concentration ◽  
Hereditary Angioedema ◽  
Half Life ◽  
Compartment Model ◽  
Rapid Onset ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
On Demand ◽  
The Mean

Abstract Hereditary and acquired deficiencies in C1 inhibitor (C1-INH) function can result in potentially life-threatening attacks of hereditary angioedema (HAE). A highly purified and pasteurized C1-INH concentrate has been used effectively as prophylaxis against and treatment for angioedema attacks in patients with hereditary C1-INH deficiencies, but relatively little is known about its pharmacokinetic properties. Objective: To evaluate the pharmacokinetics and in vivo recovery (IVR) of C1-INH concentrate (Berinert®P) in two groups of patients with hereditary angioedema (HAE) receiving this preparation either as individual replacement therapy (IRT, regular, immediate treatment of first HAE symptoms in patients with frequent and severe attacks) or as on-demand treatment. Methods: Forty subjects (15 under IRT, 25 under on-demand treatment) with HAE received intravenous injections of C1-INH (542–1,617 U) in an attack-free interval in a prospective, open, uncontrolled, single-center study. Blood was sampled for determination of C1-INH with a commercially available functional chromogenic assay for up to 72 hours after dosing. Pharmacokinetic parameters were calculated using a single-compartment model and IVR was determined using standard methods. Results: The mean (± SD) time to maximum plasma concentration (Tmax) for C1-INH administered in patients under IRT was 1.3 ± 2.1 hours, the area under the time versus plasma concentration curve (AUC) was 20.5 ± 19.1 hour•U/mL, the elimination half-life (t½) was 33.3 ± 19.8 hours, mean residence time (MRT) was 48.0 ± 28.5 hours, total body clearance (Cl) was 1.1 ± 0.6 mL/kg/hour, and volume of distribution at steady state (Vss) was 39.5 ± 9.9 mL/kg. The respective values for patients treated on demand were 2.9 ± 6.5 hours, 20.0 ± 14.5 hour•U/mL, 43.9 ± 22.4 hours, 63.4 ± 32.3 hours, 1.2 ± 1.0 mL/kg•hour, and 51.4 ± 10.9 mL/kg. The mean IVRs for IRT and on-demand treatment were 108.2 ± 48.3% and 85.8 ± 28.3%, respectively. Children tended to have slightly lower half-life and a slightly higher Vss compared to adults. Conclusions: C1-INH concentrate has a short Tmax and a long, t½ and MRT consistent with the rapid onset of clinical efficacy for this preparation in subjects suffering angioedema attacks and the ability to effectively carry out IRT with injections administered every 2–5 days. This analysis provides to our knowledge the most comprehensive pharmacokinetic evaluation in subjects with HAE.

scholarly journals Serum bactericidal activities and comparative pharmacokinetics of meropenem and imipenem-cilastatin.

1996 ◽  
Vol 40 (1) ◽  
pp. 105-109 ◽  
Author(s):  
M Dreetz ◽  
J Hamacher ◽  
J Eller ◽  
K Borner ◽  
P Koeppe ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Dose Administration ◽  
Microdilution Method ◽  
Two Compartment Model ◽  
Elimination Half ◽  
Renal Clearances ◽  
The Mean ◽  
Bactericidal Activities

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.

Withdrawal of cefoperazone with milk after intramammary administration in dairy cows – prospective and retrospective analysis

2017 ◽  
Vol 20 (2) ◽  
pp. 261-268
Author(s):  
A. Burmańczuk ◽  
T. Grabowski ◽  
T. Błądek ◽  
C. Kowalski ◽  
P. Dębiak
Keyword(s):  
Dairy Cows ◽  
Half Life ◽  
Drug Distribution ◽  
Compartment Model ◽  
Clinical Mastitis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Lactation Period ◽  
Milk Samples ◽  
Drug Concentrations

Abstract The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

Pharmacokinetics and Tissue Residues of Sulfathiazole and Sulfamethazine in Pigs

1994 ◽  
Vol 57 (9) ◽  
pp. 796-801 ◽  
Author(s):  
LIEVE S. G. VAN POUCKE ◽  
CARLOS H. VAN PETEGHEM
Keyword(s):  
Intravenous Injection ◽  
Half Life ◽  
Intramuscular Injection ◽  
Compartment Model ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Tissue Concentrations ◽  
Single Intravenous Injection ◽  
The Individual ◽  
Residue Study

The plasma pharmacokinetics and tissue penetration of sulfathiazole (ST) and sulfamethazine (SM) after intravenous and intramuscular injection in pigs were studied. Following a single intravenous dose of 40 mg ST/kg of bodyweight or 80 mg SM/kg of bodyweight, the plasma ST and SM concentrations were best fitted to a two-compartment model. The areas under the curve were 447 ± 39 and 1485 ± 41 mg/h/L, clearances were 0.090 ± 0.007 and 0.054 ± 0.001 L/kg/h, volumes of distribution were 1.16 ± 0.16 and 0.77 ± 0.06 L/kg, half-lifes in distribution phase were l.18 ± 0.57 and 0.23 ± 0.16 h and half-lifes in eliminations phase were 9.0 ± l.6 and 9.8 ± 0.6 h. When the two compounds were administered simultaneously as a single intravenous injection, the pharmacokinetic parameters for ST were not significantly different. The values for SM show statistical differences for some important parameters: α, β and the AUC0–&gt;∞ were significantly decreased and t1/2α, Vd and CIB were significantly increased. It can be concluded that after a single intravenous injection of 40 mg/kg, sulfathiazole has a high tl/2β resulting in higher tissue concentrations. This half-life, which is higher than what is reported in the literature, is not influenced by the simultaneous presence of sulfamethazine. The tl/2β for sulfamethazine after a single intravenous injection of 80 mg/kg is comparable to the data from the literature and is not influenced by the presence of sulfathiazole. Sulfathiazole and SM were also administered simultaneously as an intramuscular injection to healthy pigs at a dosage of 40 and 80 mg/kg bodyweight. Pharmacokinetic experiments were conducted on three pigs. From this pharmacokinetic study it can be concluded that upon a single intramuscular administration of 40 mg/kg of ST and 80 mg/kg of SM the absolute bioavailability in pigs is 0.92 ± 0.04 for ST and l.01 ± 0.07 for SM. Six pigs received five intramuscular im) injections as a single dose of ST and SM every 24 h for five consecutive days for the residue study. The pigs were slaughtered at different times after the last dose was given and samples were taken from various tissues and organs. Concentrations were determined by a microbiological method and a HPTLC method. No edible tissue contained more than 100 μg/kg of the individual sulfonamides after 10 days of withdrawal. It means that adult animals which have a shorter half-life and thus lower tissue concentrations will certainly meet the economic community EC) maximum residue limits after a 10 days withdrawal period.

scholarly journals Safety, toleration, and pharmacokinetics of intravenous azithromycin.

1996 ◽  
Vol 40 (11) ◽  
pp. 2577-2581 ◽  
Author(s):  
D R Luke ◽  
G Foulds ◽  
S F Cohen ◽  
B Levy
Keyword(s):  
Half Life ◽  
Active Drug ◽  
Slow Release ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

scholarly journals Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits

2001 ◽  
Vol 45 (2) ◽  
pp. 596-600 ◽  
Author(s):  
Andreas H. Groll ◽  
Bryan M. Gullick ◽  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
Myrna Candelario ◽  
...  
Keyword(s):  
High Performance ◽  
Pharmacokinetic Model ◽  
Area Under The Curve ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Chromatography Method ◽  
Opportunistic Fungi ◽  
The Mean ◽  
Liquid Chromatography Method

ABSTRACT The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C max) ± standard error of the mean increased from 16.01 ± 0.61 μg/ml at the 1-mg/kg dose to 105.52 ± 8.92 μg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 μg · h/ml, respectively. The mean apparent volume of distribution at steady state (Vdss) was 0.299 ± 0.011 liter/kg at the 1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increasedVdss, there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi.

Pharmacokinetics of Intermittent Intraperitoneal Cefazolin in Continuous Ambulatory Peritoneal Dialysis Patients

1999 ◽  
Vol 19 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Harold J. Manley ◽  
George R. Bailie ◽  
Rupesh D. Asher ◽  
George Eisele ◽  
Reginald F. Frye
Keyword(s):  
Body Weight ◽  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Rate Constant ◽  
Half Life ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Number Of Patients ◽  
The Mean ◽  
Concentration Levels

Objective To investigate the pharmacokinetic parameters of intermittent intraperitoneal (IP) cefazolin, and recommend a cefazolin dosing regimen in continuous ambulatory peritoneal dialysis (CAPD) patients. Design Prospective nonrandomized open study. Setting CAPD outpatient clinic in Albany, New York. Patients Seven volunteer CAPD patients without peritonitis. Three of the patients were nonanuric while 4 were anuric. Interventions Cefazolin (15 mg/kg total body weight) was given to each patient during the first peritoneal exchange. Blood and dialysate samples were collected at times 0, 0.5, 1, 2, 3, 6 (end of the first antibiotic-containing dwell), 24, and 48 hours after the administration of IP cefazolin. Urine samples were collected in nonanuric patients over the study period. Results The mean ± SD amount of cefazolin dose absorbed from the dialysate after the 6-hour dwell was 69.7% ± 8.0% of the administered dose. The cefazolin absorption rate constant from dialysate to serum was 0.21 ± 0.1 /hr (absorption half-life 3.5 ± 0.8 hr). The mean serum concentrations reached at 24 and 48 hours were 52.4 ± 3.7 mg/L and 30.3 ± 5.9 mg/L, respectively. The mean dialysate cefazolin concentrations reached at 24 and 48 hours were 15.1 ± 3.4 mg/L and 7.9 ± 1.4 mg/L, respectively. The cefazolin serum elimination rate constant was 0.02 ± 0.01 /hr (elimination half-life 31.5 ± 8.8 hr). The total cefazolin body clearance was 3.4 ± 0.6 mL/min. In the 3 nonanuric patients the mean renal clearance of cefazolin was 0.6 ± 0.4 mL/min. The peritoneal clearance of cefazolin was 1.0 ± 0.3 mL/min. The systemic volume of distribution of cefazolin was 0.2 ± 0.05 L/kg. No statistical difference was detected in pharmacokinetic parameters between anuric and nonanuric patients, although this may be due to the small number of patients in each group. Conclusion A single daily dose of cefazolin dosed at 15 mg/kg actual body weight in CAPD patients is effective in achieving serum concentration levels greater than the minimum inhibitory concentration for sensitive organisms over 48 hours, and dialysate concentration levels over 24 hours. Caution is warranted in extrapolation of dosing recommendations to patients who maintain a significant degree of residual renal function.

Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2567-2567 ◽  
Author(s):  
Manuel Hidalgo ◽  
Antonio Calles ◽  
Dejan Juric ◽  
Rodrigo Dienstmann ◽  
Desamparados Roda Perez ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Population Analysis ◽  
Demographic Data ◽  
Single Agent ◽  
Compartment Model ◽  
Individual Variability ◽  
Study Patient ◽  
Epithelial Tumors ◽  
Dual Action

2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, 4, 10, 15, 22, and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w) of the phase I study. Patient demographic data and other relevant clinical covariates were evaluated in the population analysis. PK simulation of 1000 subjects with a log-normal BW distribution was performed to compare the inter-individual variability of MEHD exposure following fixed or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK. In the noncompartmenal analysis, the apparent clearance (CL) decreased in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30 mg/kg) and approached linearity at doses >10 mg/kg (q2w). In the population analysis, the PK profile of MEHD was well described by a two compartment model with linear and nonlinear clearance. The target-mediated clearance was consistent with that of anti-EGFR antibodies. The nonspecific CL and central volume of distribution (V1) values were approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a moderate effect on V1, but not on CL. PK simulations suggest that, compared with BW-based dosing, fixed dosing would result in less inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650 mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions: The dual-action antibody MEHD demonstrated PK consistent with anti-EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule is supported.

A UGT1A1 *28 and *6 genotype-directed phase I study of irinotecan plus infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously untreated metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3592-3592
Author(s):  
Yong Sang Hong ◽  
Kyu-Pyo Kim ◽  
Jae-Lyun Lee ◽  
Kyun Seop Bae ◽  
Ho-Sook Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Level 3 ◽  
Defective Allele ◽  
The Mean ◽  
Grade 3 ◽  
Higher Doses

3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 (*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA group. The MTD was estimated as 300 mg/m2/2-week for the 1 DA group with 2 DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, respectively (P=0.017). Of the 43 pts, five pts showed AUClast, SN38 that exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete responses and 23 partial responses. Median progression-free and overall survival was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), respectively. Grade 3 or 4 toxicity during all treatment cycles included neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of irinotecan was 330, 270, 150 mg/m2/2-week for pts with 0, 1, 2 DA based on pharmacokinetic analysis. [Table: see text]

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