Area Under The Concentration Curve Research Articles

A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer

Background:The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy.Methods:Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin.Results:Combretastatin A4 phosphate was escalated from 36 to 54 mg m−2 with the carboplatin area under the concentration curve (AUC) 4–5, from 27 to 54 mg m−2 with paclitaxel 135–175 mg m−2, and from 54 to 72 mg m−2 with carboplatin AUC 5 and paclitaxel 175 mg m−2. Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1–3 hypertension (26% of patients) and grade 1–3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m−2. Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma.Conclusion:The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.

Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period

The study presented here was performed to determine the pharmacokinetics of intravenously administered clindamycin in pregnant women. Seven pregnant women treated with clindamycin were recruited. Maternal blood and arterial and venous umbilical cord blood samples were obtained. Maternal clindamycin concentrations were analyzed by nonlinear mixed-effects modeling with the NONMEM program. The data were best described by a linear three-compartment model. The clearance and the volume of distribution at steady state were 10.0 liters/h and 6.32 x 10(3) liters, respectively. Monte Carlo simulations were performed to determine the area under the concentration curve (AUC) for the free (unbound) drug (f) in maternal serum for 24 h divided by the MIC (fAUC(0-24)/MIC). At a MIC of 0.5 mg/liter, which is the EUCAST breakpoint, the attainment at the lower 95% confidence interval (CI) was 24.6 if the level of protein binding was 65%, and this value concurred well with the target value of 27. However, for higher degrees of protein binding, as has been described in the literature, the attainment was lower, down to 10.2 for a protein binding level of 85% (lower 95% CI). The concentrations in umbilical cord blood were lower than those in maternal blood. The concentration-time profiles in maternal serum indicate that the level of exposure to clindamycin may be too low in these patients. Together with the lower concentrations in umbilical cord blood, this finding suggests that the current dosing regimen may not be adequate to protect all neonates from group B streptococcal disease.

In-vivo kinetics of the interaction between midazolam and erythromycin in rats, taking account of metabolic intermediate complex formation.

To predict, quantitatively, the extent of drug interaction during repeated administration of a metabolic inhibitor, we analysed the effects of erythromycin treatment under several regimens on the area under the concentration curve (AUC) of midazolam in rats. Midazolam was administered into the portal vein 12 h after erythromycin treatment for 1, 2 or 3 days, or 12, 24, 36, 48, 72 and 96 h after erythromycin treatment for 4 days, and the plasma-concentration profiles of midazolam were analysed to assess the AUC. Moreover, the contents of total cytochrome P450 and inactive metabolic intermediate (MI) complex were simultaneously quantitated. While the AUC value of midazolam was not affected by the administration of erythromycin for 1 day, repeated administration of erythromycin evoked an increase in AUC ratio (AUC in erythromycin-treated rats/AUC in vehicle-treated rats), which reached a maximum value of 1.99 at 12 h after 4 days' treatment with erythromycin. The total content of cytochrome P450 in liver microsomes was unaffected by erythromycin treatment. Although the MI complex was undetectable after 1 day's treatment with erythromycin, its content increased with duration of erythromycin treatment, and the complex disappeared after the end of erythromycin treatment with a half-life of 12.3 h. In conclusion, the interaction between erythromycin and midazolam could be well predicted when the formation of MI complex in the liver was taken into account.

Lack of association between stavudine exposure and lipoatrophy, dysglycaemia, hyperlactataemia and hypertriglyceridaemia: a prospective cross sectional study.

BackgroundStavudine continues to be widely used in resource poor settings despite its toxicity. Our objective was to determine association between plasma stavudine concentrations and lipoatrophy, concentrations of glucose, lactate and triglycerides.MethodsParticipants were enrolled in a cross-sectional study with lipoatrophy assessment, oral glucose tolerance test, fasting triglycerides, finger prick lactate, and stavudine concentrations. Individual predictions of the area under the concentration curve (AUC) were obtained using a population pharmacokinetic approach. Logistic regression models were fitted to assess the association between stavudine geometric mean ratio > 1 and impaired fasting glucose, impaired glucose tolerance, hyperlactataemia, hypertriglyceridaemia, and lipoatrophy.ResultsThere were 47 study participants with a median age of 34 years and 83% were women. The median body mass index and waist:hip ratio was 24.5 kg/m2 and 0.85 respectively. The median duration on stavudine treatment was 14.5 months. The prevalence of lipoatrophy, impaired fasting glucose, impaired glucose tolerance, hyperlactataemia, and hypertriglyceridaemia were 34%, 19%, 4%, 32%, and 23% respectively. Estimated median (interquartile range) stavudine AUC was 2191 (1957 to 2712) ng*h/mL. Twenty two participants had stavudine geometric mean ratio >1. Univariate logistic regression analysis showed no association between stavudine geometric mean ratio >1 and impaired fasting glucose (odds ratio (OR) 2.00, 95% CI 0.44 to 9.19), impaired glucose tolerance (OR 1.14, 95% CI 0.07 to 19.42), hyperlactataemia (OR 2.19, 95%CI 0.63 to 7.66), hypertriglyceridaemia (OR 1.75, 95%CI 0.44 to 7.04), and lipoatrophy (OR 0.83, 95% CI 0.25 to 2.79).ConclusionsThere was a high prevalence of metabolic complications of stavudine, but these were not associated with plasma stavudine concentrations. Until there is universal access to safer antiretroviral drugs, there is a need for further studies examining the pathogenesis of stavudine-associated toxicities.

Fluconazole Dosing for the Prevention or Treatment of Invasive Candidiasis in Young Infants

Young infants are susceptible to developmental factors influencing the pharmacokinetics of drugs. Fluconazole is increasingly used to prevent and treat invasive candidiasis in infants. Dosing guidance remains empiric and variable because limited pharmacokinetic data exist. Our population pharmacokinetic model derived from 357 fluconazole plasma concentrations from 55 infants (23-40 week gestation) illustrates expected changes in fluconazole clearance based upon gestational age, postnatal age, weight, and creatinine. We used a Monte Carlo simulation approach based on parametric description of a patient population's pharmacokinetic response to fluconazole to predict fluconazole exposure (median: 10th and 90th percentile population variability range) after 3, 6, and 12 mg/kg dosing. For the treatment of invasive candidiasis, a dose of at least 12 mg/kg/d in the first 90 days after birth is needed to achieve an area under the concentration curve (AUC) of >400 mg*h/L and an AUC/minimum inhibitory concentration (MIC) >50 for Candida species with MIC <8 microg/mL in > or =90% of <30 week gestation infants and 80% of 30 to 40 week gestation infants. The more preterm infants achieve a higher median AUC (682 mg*hr/L) compared with more mature infants (520 mg*hr/L). For early prevention of candidiasis in 23 to 29 week infants, a dose of 3 or 6 mg/kg twice weekly during the first 42 days of life is equivalent to an AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations > or =2 or 4 microg/mL, respectively, for half of the dosing interval. For late prevention, the 6 mg/kg dose every 72 hours provides similar exposure to 3 mg/kg daily dose. Infants with serum creatinine > or =1.3 mg/dL have delayed drug clearance and dose adjustment is indicated if creatinine does not improve within 96 hours. A therapeutic concentration of fluconazole in premature infants with invasive candidiasis requires dosing substantially greater than commonly recommended in most reference texts. To prevent invasive candidiasis, twice weekly prophylaxis regimens can provide adequate exposure when unit specific MICs are taken into account.

Correlation of C0 and C2 Levels With Cyclosporine Side Effects in Kidney Transplantation

Cyclosporine has a narrow therapeutic window requiring close monitoring to ensure adequate immunosuppression while avoiding nephrotoxicity and other side effects. Pharmacokinetic studies have suggested that cyclosporine levels at 2 hours postdose (C2) is the best single time point to predict area under the concentration curve (AUC) in kidney transplant recipients. C2 also predicted acute rejection episodes and nephrotoxicity better than trough levels (C0). Targeting cyclosporine levels to minimize side effects while maintaining adequate immunosuppressive effects is of clinical interest. There are conflicting evidence and few reports about whether cyclosporine-related side effects are a dose-dependent phenomenon. The aim of this single center study was to ascertain whether cyclosporine side effects were dose-dependent and which single time point level (C0 or C2) was more closely related to them. We analyzed 225 patients on Neoral-based immunosuppression with C0 and C2 levels measured on the same day of 2 different visits. Serum creatinine, glucose, uric acid, potassium, total cholesterol, triglycerides, and 24-hour urinary sodium elimination were measured by routine biochemical analyses. Blood pressure was measured at each visit. A significant positive correlation was observed between C2 and C0 concentrations and levels of potassium (P < .001), total cholesterol (P < .001), systolic blood pressure (P < .001), and pulse pressure (P < .01). There was a significant negative correlation between C2 and uric acid (P < .001). AUCs of receiver operating characteristic (ROC) curves for both C2 and C0 levels were significant as predictors of hyperkalemia (P < .001), hyperuricemia (P = .001), hypercholesterolemia (P < .05), and high systolic blood pressure (P < .05). There were no significant differences between the capacities of C2 or C0 to predict these variables. In conclusion, potassium, total cholesterol, uric acid, and systolic hypertension were influenced by cyclosporine in a dose-dependent manner. Both C2 and C0 were useful to predict cyclosporine side effects.

Evaluation of the individual 50% inhibitory area under the concentration curve of 5-fluorouracil based on the collagen gel droplet embedded culture drug sensitivity test in colorectal cancer

We have previously reported the 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Moreover, the area under the concentration curve (AUC) and growth inhibition rate (IR) were combined, resulting in the AUC-IR curve, which was approximated to the logarithmic curve. In the present study, we used the AUC-IR curve to calculate the individualized AUCIR50, the AUC value that imparts 50% growth inhibition. Individual AUCIR50 was calculated in CRC patients, and its distribution was evaluated. The cumulative distribution of individual AUCIR50 was regressed over two lines (logarithmic scale). Among the 45 resectable CRC patients, those who achieved more than the individual AUCIR50 during post-operative 5-FU-based chemotherapy demonstrated a trend towards better disease-free survival compared to those who did not achieve AUCIR50. Of the Dukes' D patients (n=10), those who achieved more than twice the individual AUCIR50 during post-operative 5-FU-based chemotherapy demonstrated significantly better survival rates (p=0.05) than those who did not. In this study, the distribution of the individual AUCIR50 suggested that approximately 6% of patients demonstrated very low 5-FU sensitivity. Therefore, the individual AUCIR50 was useful in classifying good, intermediate and poor 5-FU response. Achievement of the individual AUCIR50 may be a prerequisite for individualized 5-FU-based adjuvant chemotherapy. As well, the early achievement of twice the individual AUCIR50 may indicate an improved prognosis in Dukes' D patients. The individual AUCIR50 using CD-DST is useful in determining the individualized chemotherapy of CRC patients, thus CD-DST has the potential to facilitate the establishment of individualized chemotherapy for CRC.

Investigation of the Clinical Efficacy and Dosage of Intravenous Ciprofloxacin in Patients with Respiratory Infection

Infection control is particularly vital in hospitals, and proper use of antimicrobial drugs is one of the most important roles of hospital pharmacists. In this study, we surveyed patients who had been prescribed single-use ciprofloxacin (CPFX), and evaluated the blood concentration of CPFX from the predictive AUC (area under the concentration curve). This study was performed retrospectively to 112 adult patients diagnosed as having respiratory infections who had been treated as inpatients with intravenous CPFX for more than 3 days at Toho University Omori Hospital in Tokyo. The predictive AUC of each patient was obtained from the modified formulae reported by Forrest et al. (1993) [1]. The relation between the antimicrobial activity of CPFX and pharmacokinetic/pharmacodynamic (Cmax, AUC and AUC/MIC (minimum inhibitory concentration)) was studied. Although CPFX is excreted from the kidney, standard treatment with this drug does not take renal function into consideration. Our results indicated that CPFX was effective in less than 50% of the patients who received it. Moreover, the AUC/MIC ratio in both the effective group and the failure group was less than 125 when the clinical target was gram-negative bacteria. These results suggest that the clinical use of CPFX for the treatment of infectious diseases does not reach the target AUC/MIC ratio, and that the concentration of CPFX is not within the range to which many pathogens are susceptible in a large proportion of patients. To ensure the effective treatment of patients with infectious diseases and to prevent the development of resistance in bacteria, we recommend therapeutic drug monitoring (TDM) of CPFX in hospitals.

Effect of Cigarette Smoking on Imatinib in Patients in the Soft Tissue and Bone Sarcoma Group of the EORTC

Smoking is a potent inducer of cytochrome P450 (CYP) 1A2 and may affect the pharmacokinetics of CYP1A2 metabolized drugs. The effect of smoking on the pharmacokinetics of imatinib, which is metabolized by CYP3A4 and partly by CYP1A2, is unknown. We studied the effect of smoking on imatinib pharmacokinetics, safety, and efficacy. Imatinib pharmacokinetics, safety, and efficacy was analyzed in 45 patients with gastrointestinal stromal tumors (GIST) or soft-tissue sarcoma included in two European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials, including 15 smokers and 30 nonsmokers. Apparent oral clearance, distribution volume, elimination half-life, and dose-standardized area under the concentration curve (AUC) were assessed in 34 patients using nonlinear mixed-effect modeling. Mean +/- SD pharmacokinetic variables in smokers (n = 9) versus nonsmokers (n = 25) groups were 9.6 +/- 5.5 versus 9.2 +/- 4.6 L/h (apparent oral clearance), 216.5 +/- 114.3 versus 207.0 +/- 116.9 L (distribution volume), 16.1 +/- 6.0 versus 16.5 +/- 6.0 h (elimination half-life), and 133.6 +/- 71.0 versus 142.3 +/- 84.0 ng h/mL mg area under the concentration curve; P > 0.05. Smokers experienced more grade 2/3 anemia (P = 0.010) and fatigue (P = 0.011) and those with GIST had a significantly shorter overall survival (P = 0.037) and time to progression (P = 0.052). This retrospective study suggests that the pharmacokinetics of imatinib is not affected by smoking. However, smokers have an increased risk of anemia and fatigue. Smokers with GIST have a shorter overall survival and time to progression.

Estimation of Abbreviated Mycophenolic Acid Area Under the Concentration-Time Curve During Early Posttransplant Period by Limited Sampling Strategy

Area under the concentration curve (AUC) of mycophenolic acid (MPA) could help to optimize therapeutic drug monitoring during the early post–renal transplant period. The aim of this study was to develop a limited sampling strategy to estimate an abbreviated MPA AUC within the first month after renal transplantation. In this study we selected 19 patients in the early posttransplant period with normal renal graft function (glomerular filtration rate > 70 mL/min). Plasma MPA concentrations were measured using reverse-phase high-performance liquid chromatography. MPA AUC 0–12h was calculated using the linear trapezoidal rule. Multiple stepwise regression analysis was used to determine the minimal and convenient time points of MPA levels that could be used to derive model equations best fitted to MPA AUC 0–12h. The regression equation for AUC estimation that gave the best performance was AUC = 14.46 * C 10 + 15.547 ( r 2 = .882). The validation of the method was performed using the jackknife method. Mean prediction error of this model was not different from zero ( P > .05) and had a high root mean square prediction error (8.06). In conclusion, this limited sampling strategy provided an effective approach for therapeutic drug monitoring during the early posttransplant period.

The impact of perioperative atelectasis on antibiotic penetration into lung tissue: an in vivo microdialysis study

Postoperative pneumonia is a potentially devastating complication associated with high mortality in intensive care unit (ICU)-patients. One of the major predisposing factors is the perioperative occurrence of atelectatic formations in non-dependent lung areas. Perioperative ventilation/perfusion mismatch due to atelectasis may influence antibiotic distribution to lung tissue, hence increasing the risk of postoperative pneumonia. We evaluated whether differences in ventilation/perfusion mismatch can influence antibiotic distribution into lung tissue by means of in vivo microdialysis, comparing patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) (atelectasis model), with patients operated with the off-pump coronary artery bypass grafting (OPCAB)-technique. We compared five patients operated with CPB (CPB-group) and five patients undergoing CABG with OPCAB-technique (OPCAB-group). Levofloxacin (500 mg) was administered intravenously, after surgery, in the ICU. Time versus concentration profiles of levofloxacin in lung tissue and plasma were measured at regular time-intervals. In the OPCAB-group, the median of the maximum concentration of levofloxacin in lung tissue (4.1 microg ml(-1) +/- 7, range 3.7-11.8 microg ml(-1)) was significantly higher compared with the CPB-group (2.5 microg ml(-1) +/- 0.3, range 2.0-2.9 microg ml(-1)) (P = 0.046). Median levofloxacin tissue/plasma area under the concentration curve (AUC) ratio in lung tissue was 0.3 +/- 0.2 (range 0.1-0.7) in the CPB-group versus 0.7 +/- 1.6 (range 0.4-0.8) in the OPCAB-group (P = 0.015). Data indicate that postoperative interstitial antibiotic concentration is influenced by perioperative atelectasis formation. Our findings suggest the re-evaluation of clinical dosing schemas of antibiotic therapy in a variety of diseases associated with atelectasis formation.

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (Cmax) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUCsum (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.

Comparative pharmacokinetics of ivermectin alone and a novel formulation of ivermectin and rafoxanide in calves and sheep

This study investigated the comparative serum disposition kinetics of ivermectin (IVM) after a single subcutaneous dose of 200 microg/kg body weight of IVM alone or in combination with an anthelmintic consisting of ivermectin and rafoxanide (200 microg/kg of IVM and 2.5 mg/kg rafoxanide) for use in calves and sheep. The IVM concentrations in serum samples were analyzed by high-performance liquid chromatography with fluorescence detection. In sheep serum, rafoxanide induced a rapid absorption of IVM when given in combined form manifested by a shorter absorption half-life time of IVM by 68.49% when given in combination as compared with IVM when given alone. In addition, there is an increase in the value of the area under the concentration curve (AUC) by 15.48% while the value of elimination rate constant was decreased by 38.2% and significantly increased the half-life time of elimination from 2.04 days for IVM alone to 3.3 days when given in combination with rafoxanide. In calves serum, the mean t1/2ab for IVM/rafoxanide was 0.131 days and for the control formulation 0.16 days, and t1/2el was 5.78 and 4.95, respectively. IVM Cmax for IVM/rafoxanide was 22.4 ng/ml and for the control formulation 19.1 ng/ml. T (max) values were 0.99 and 1.12 days, and the mean AUC values were 188.9 and 165.4 ng/ml/day. The difference in Cmax, AUC, Kab, K el, and t1/2el was significant. However, there was no statistical difference between the Tmax and t1/2ab. These findings revealed that the combination of rafoxanide with IVM in sheep and calves increased the absorption of IVM and delayed its elimination.

The Effect of Bucolome, a CYP2C9 Inhibitor, on the Pharmacokinetics of Losartan

Losartan, a selective angiotensin receptor antagonist, is mainly metabolized by CYP2C9 to an active carboxylic acid, E3174, which is pharmacologically more potent inhibitor than the parent compound. We evaluated the effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan and E3174, which were measured by high performance liquid chromatography in human volunteers and rats. A randomized crossover design study with two phases was done in the volunteer study. In the first phase, the volunteers received losartan 25 mg alone orally (LOS group), and, in the second phase, losartan 25 mg was given after repeated oral administration of 300 mg bucolome for 7 days (LOS+BUC group). In the LOS group, the maximum concentration (C(max)) and area under the concentration curve (AUC) of losartan were significantly higher than in the LOS+BUC group. On the other hand, in the LOS+BUC group, the C(max) and AUC of E3174 were significantly lower than in the LOS group. In the rat study, male Wistar ST rats were used. In the first phase, the rats orally received losartan 10 mg/kg alone or after bucolome was given repeatedly at a dose of 20, 50, or 200 mg/kg for 7 days. In the second phase for steady state, the rats were given losartan 10 mg/kg for 14 days (group A) or losartan 10 mg/kg and bucolome 50 mg/kg for 14 days (Group B). Bucolome at doses 50 and 200 mg/kg significantly increased the AUC losartan and significantly decreased the AUC of 3174. At the steady state, there were no significant differences in AUC of losartan between Group A and B, but the C(max) and AUC of E3174 were significantly lower in Group B than Group A.

Quantitative evaluation of dichloroacetic acid kinetics in human—a physiologically based pharmacokinetic modeling investigation

Dichloroacetic acid is a common disinfection by-product in surface waters and is a probable minor metabolite of trichloroethylene. Dichloroacetic acid (DCA) liver carcinogenicity has been demonstrated in rodents but epidemiological evidence in humans is not available. High doses of DCA (∼50 mg/kg) are used clinically to treat metabolic acidosis. Biotransformation of DCA by glutathione transferase zeta (GSTzeta) in the liver is the major elimination pathway in humans. GSTzeta is also inactivated by DCA, leading to slower systemic clearance and nonlinear pharmacokinetics after multiple doses. A physiologically based pharmacokinetic (PBPK) model was developed to quantitatively describe DCA biotransformation and kinetics in humans administered DCA by intravenous infusion and oral ingestion. GSTzeta metabolism was described using a Michaelis–Menten equation coupled with rate constants to account for normal GSTzeta synthesis, degradation and irreversible covalent binding and inhibition by the glutathione-bound-DCA intermediate. With some departures between observation and model prediction, the human DCA PBPK model adequately predicted the DCA plasma kinetics over a 20,000-fold range in administered doses. Apparent inhibition of GSTzeta mediated metabolism of DCA was minimal for low doses of DCA (μg/kg day), but was significant for therapeutic doses of DCA. Plasma protein binding of DCA was assumed to be an important factor influencing the kinetics of low doses of DCA (μg/kg day). Polymorphisms of GSTzeta may help explain inter-individual variability in DCA plasma kinetics and warrants evaluation. In conclusion, using a previously published rodent DCA PBPK model (Keys, D.A., Schultz, I.R., Mahle, D.A., Fisher, J.W., 2004. A quantitative description of suicide inhibition of dichloroacetic acid in rats and mice. Toxicol. Sci. 82, 381–393) and this human DCA PBPK model, human equivalent doses (HEDs) were calculated for a 10% increase in mice hepatic liver cancer (2.1 mg/kg day). The HEDs for the dosimetrics, area-under-the-concentration-curve (AUC) for total and free DCA in plasma, AUC of DCA in liver and amount of DCA metabolized per day were 0.02, 0.1, 0.1 and 1.0 mg/kg day, respectively. Research on the mechanism of action of DCA and the relevance of mouse liver cancer is needed to better understand which dosimetric may be appropriate for extrapolation from animal studies to human.

Intestinal Absorption of Luteolin from Peanut Hull Extract Is More Efficient than That from Individual Pure Luteolin

Luteoin is one of the main flavones and the crucial effective component of peanut hull extract (PHE). The present paper aims to elucidate the absorption mechanism of luteolin and clarify whether its absorption occurs primarily at a specific site of the intestine by an in situ single-pass intestinal perfusion (SPIP) model. Moreover, the paper investigates the difference in absorption of luteolin when it is administered in PHE form and as pure luteolin by the SPIP model and in vivo pharmacokinetics studies. Results showed that the effective permeability ( P eff) and absorption rate constant ( k a) of pure luteolin(5.0 microg/mL) in duodenum and jejunum were not significantly different, but markedly higher than that in the colon and ileum. The P eff and k a of luteolin in jejunum were concentration-independent, and the ATP inhibitor (DNP) did not influence P eff and k a of pure luteolin. However, the P eff and k a of luteolin in PHE were significantly greater than that of pure luteolin. The pharmacokinetics study showed that following oral administration of a single dose of pure luteolin (14.3 mg/kg) or PHE (= 14.3 mg/kg of luteolin) in rats, the peak concentration of luteolin in plasma ( C max) and the area under the concentration curve (AUC) for pure luteolin were 1.97 +/- 0.15 microg/mL and 10.7 +/- 2.2 microg/mL.h, respectively. These parameters were significantly lower than those of the PHE group ( P < 0.05), C max = 8.34 +/- 0.98 microg/mL and AUC = 20.3 +/- 1.3 microg/mL.h, respectively. It can be concluded that luteolin is absorbed passively in the intestine of rats and that its absorption is more efficient in the jejunum and duodenum than in the colon and ileum. The bioavailability of luteolin in PHE form is significantly greater than that of pure luteolin.

TheCYP3A4*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

The objective of this study was to identify CYP3A4 variants in Koreans and to characterize their functional consequences in vitro and in vivo. Four single nucleotide polymorphisms were identified in 50 Koreans by direct DNA sequencing. In an additional genotyping using 248 subjects, CYP3A4(*)18 was confirmed as the most frequent coding variant in Koreans at 1.7%, and its frequency was similar to that of Asians, suggesting that CYP3A4(*)18 would be the highest coding variant in Asians. The recombinant CYP3A4.18 protein prepared in baculovirus expression system showed 67.4% lower Vmax and 1.8-fold higher K(m) for midazolam 1'-hydroxylation compared with the wild type. The mean values of Cmax and area under the concentration curve (AUC) in the CYP3A4(*)1/(*)18 and CYP3A5(*)1/(*)3 subjects (n = 8) were 63% and 32% higher than in CYP3A4(*)1/(*)1 and CYP3A5(*)1/(*)3 carriers (n = 8), respectively. Although the in vitro assay exhibited a significant reduction of the enzyme activity for midazolam, the in vivo differences associated with the CYP3A4(*)1/(*)18 tend to be low (P < 0.07 in Cmax and P < 0.09 in AUC). In summary, the heterozygous CYP3A4(*)1/(*)18 does not appear to cause a significant change of midazolam disposition in vivo; however, the clinical relevance of CYP3A4(*)18/(*)18 remains to be evaluated.

A study for establishment of individualized chemotherapy for colorectal cancer based on the individual 50% inhibitory area under the concentration curve (AUCIR50) using the collagen gel droplet embedded culture-drug sensitivity test (CD- DST)

14553 Background: The drug sensitivity of tumor cells is one of the key issues to explore in individualized 5-fluorouracil (5-FU) based chemotherapy for colorectal cancer patients. We reported that growth inhibition rate (IR) and area under the concentration curve (AUC) approximated to a logarithmic curve using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) in ASCO 2003 (#1283). We also reported that the individual 50% inhibitory area under the concentration curve (AUC IR50) could be obtained using the individual AUC-IR curve in ASCO 2006 (#13560). The aim of this study was to evaluate the achievement of the individual AUCIR50 in 5-FU based adjuvant chemotherapy for the establishment of individualized chemotherapy. Methods: Surgical specimen was obtained from resectable 33 CRC patients without any preoperative chemotherapy during 2001 to 2005. 5-FU based adjuvant chemotherapy was administered in all patients. CD-DST was performed under 6–9 different conditions. The individual AUCIR50 was obtained from the individual AUC-IR curve. The patients were divided into 2 groups, the achieved group and the non-achieved group. In the achieved group, total administered AUC was more than the individual AUCIR50 and in non-achieved group, the total administered AUC was less than the individual AUCIR50. Recurrence rates were evaluated from the 2 groups. Results: In all patients, the recurrence rates were 6.7% (1/15) in the achieved group and 27.8% (5/18) in the non-achieved group. In the colon cancer patients, the recurrence rates were 8.3% (1/12) in the achieved group and 10.0% (1/10) in the non-achieved group. In the rectal cancer patients, the recurrence rates were 0% (0/3) in the achieved group and 50.0% (4/8) in the non-achieved group. Conclusions: The recurrence rate of the achieved group was lower than that of the non-achieved group. Therefore, this study demonstrated that the achievement of the individual AUCIR50 could be a prerequisite of individualized 5-FU based adjuvant chemotherapy. No significant financial relationships to disclose.

Effect of smoking on imatinib pharmacokinetics

2573 Background: Smoking is a potent inducer of the cytochrome P450 1A2 isoenzyme (CYP1A2) and may therefore effect the pharmacokinetics (PK) of drugs metabolized by CYP1A2. Indeed, clinical studies with erlotinib (metabolized by CYP3A4 and also partly by CYP1A2) have shown a major increase in erlotinib clearance in smokers versus non-smokers. The effect of smoking on the PK of imatinib, which is also metabolized by CYP3A4 and partly by CYP1A2, is unknown. We aimed to study the effect of smoking on imatinib PK in order to explain a part of the interpatient variation. Methods: The effect of smoking on the PK parameters was analyzed in 34 patients with gastro-intestinal stromal tumors or soft tissue sarcoma included in the EORTC-STBSG phase I and phase II trials. This cohort included 9 smokers and 25 non-smokers. The daily smoking habits of the study patients were retrieved retrospectively from the patient’s record. PK parameters assessed with NONMEM, version V were clearance (Cl), distribution volume (V), elimination half life (T1/2) and the dose standardized area under the concentration curve (AUC). We considered a 40% reduction in imatinib exposure clinically relevant and this study is adequately powered to detect this difference. Results: The mean PK parameters in the smokers versus the non-smokers group ± SD were: Cl; 9.6 ± 5.5 L/h vs 9.2 ± 4.6 L/h, V; 216.5 ± 114.3 L vs 207.0 ± 116.9 L, T1/2; 16.1 ± 6.0 h vs 16.5 ± 6.0 h, AUC; 133.6 ± 71.0 ng.h/ml.mg vs 142.3 ± 84.0 ng.h/ml.mg. There was no significant difference in PK parameters observed between the smokers and the non- smokers. Conclusion: This retrospective study suggest that the PK of imatinib was not affected by smoking and therefore does not explain the large variation in imatinib PK. No significant financial relationships to disclose.

HES 130/0.42 shows less alteration of pharmacokinetics than HES 200/0.5 when dosed repeatedly

Hydroxyethyl starches (HES) accumulate in the circulation when administered repeatedly. Accumulation is thought to be partly responsible for undesirable effects (tissue storage, blood coagulation impairment, and itching). HES 130/0.42 with low molecular weight and a low level of substitution has recently been developed in order to reduce those risks. In healthy volunteers, the pharmacokinetics of HES 130/0.42/6:1 were investigated using a crossover design with HES 200/0.5 serving as control. Fifty grams of either HES were administered in 4 h day-1 for a period of five consecutive days. HES serum concentrations were used for computation of pharmacokinetic coefficients. Change between the first and fifth infusion in the area under the concentration curve (AUC) served as the primary measurement. Although the circulation was freed from the load with HES 130/0.42 within 20 h after end of the previous infusion, the amount of HES 200/0.5 increased continuously from one administration to the other. AUC and elimination half-life (t1/2) were significantly lower with HES 130/0.42. AUC and t1/2 of HES 200/0.5 showed an increase between the first and the fifth administration whereas only a minimal shift was present with HES 130/0.42. Haemodilution via HES 200/0.5 did not change over time. Repeated administration of HES 130/0.42 shows no accumulation and fewer tendencies to time-dependent changes in pharmacokinetic parameters than HES 200/0.5. The improved reproducibility may improve drug safety, particularly as the accumulation of residual starch with HES 200/0.5 does not contribute to the colloid's volume effect, but may rather increase the risk of undesired reactions.