Volume Of Peripheral Compartment Research Articles

Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, onartuzumab (MetMAb), in patients with advanced solid tumors

Onartuzumab is a unique, humanized, monovalent (one-armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non-small cell lung cancer (NSCLC) patients. The potential for drug-drug interaction (DDI) was assessed during co-administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration-time profiles of onartuzumab were adequately described using a two-compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1 ), and median terminal half-life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1 , and weight on peripheral compartment volume (V2 ), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients.

Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation

Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation. Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients' demographics, biochemical test results and physiological characteristics. The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253L, 115L/day and 314L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5h(-1) and 100L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution. We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM.

Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures beyond Two-Thirds or Three-Fourths

Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergillosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)(3/4). The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)(3/2), an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.).

A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients.

Mycophenolate mofetil (MMF) is a key component of postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5-sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC(0-12 h) for Q12-hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC(0-8) (h) for Q8-hour dosing.

Diabetes Mellitus Reduces the Clearance of Atorvastatin Lactone

Patients with diabetes mellitus might be at a higher risk of HMG-CoA reductase inhibitor (statin)-induced myotoxicity, possibly because of reduced clearance of the statin lactone. The present study was designed to investigate the effect of diabetes on the biotransformation of atorvastatin acid, both in vivo in nondiabetic and diabetic renal transplant recipients, and in vitro in human liver samples from nondiabetic and diabetic donors. A total of 312 plasma concentrations of atorvastatin acid and atorvastatin lactone, from 20 nondiabetic and 32 diabetic renal transplant recipients, were included in the analysis. Nonlinear mixed-effects modelling was employed to determine the population pharmacokinetic estimates for atorvastatin acid and atorvastatin lactone. In addition, the biotransformation of these compounds was studied using human liver microsomal fractions obtained from 12 nondiabetic and 12 diabetic donors. In diabetic patients, the plasma concentration of atorvastatin lactone was significantly higher than that of atorvastatin acid throughout the 24-hour sampling period. The optimal population pharmacokinetic model for atorvastatin acid and atorvastatin lactone consisted of a two- and one-compartment model, respectively, with interconversion between atorvastatin acid and atorvastatin lactone. Parent drug was absorbed orally with a population estimate first-order absorption rate constant of 0.457 h(-1). The population estimates of apparent oral clearance (CL/F) of atorvastatin acid to atorvastatin lactone, intercompartmental clearance (Q/F), apparent central compartment volume of distribution after oral administration (V(1)/F) and apparent peripheral compartment volume of distribution after oral administration (V(2)/F) for atorvastatin acid were 231 L/h, 315 L/h, 325 L and 4910 L, respectively. The population estimates of apparent total clearance of atorvastatin lactone (CL(M)/F), apparent intercompartmental clearance of atorvastatin lactone (Q(M)/F) and apparent volume of distribution of atorvastatin lactone after oral administration (V(M)/F) were 85.4 L/h, 166 L/h and 249 L, respectively. The final covariate model indicated that the liver enzyme lactate dehydrogenase was related to CL/F and alanine aminotransferase (ALT) was related to Q/F. Importantly, diabetic patients have 3.56 times lower CL(M)/F than nondiabetic patients, indicating significantly lower clearance of atorvastatin lactone in these patients. Moreover, in a multivariate population pharmacokinetics model, diabetes status was the only significant covariate predicting the values of the CL(M)/F. Correspondingly, the concentration of atorvastatin acid remaining in the microsomal incubation was not significantly different between nondiabetic and diabetic liver samples, whereas the concentration of atorvastatin lactone was significantly higher in the samples from diabetic donors. In vitro studies, using recombinant enzymes, revealed that cytochrome P450 (CYP) 3A4 is the major CYP enzyme responsible for the biotransformation of atorvastatin lactone. These studies provide compelling evidence that the clearance of atorvastatin lactone is significantly reduced by diabetes, which leads to an increased concentration of this metabolite. This finding can be clinically valuable for diabetic transplant recipients who have additional co-morbidities and are on multiple medications.

Diabetes Mellitus Reduces the Clearance of Atorvastatin Lactone

Patients with diabetes mellitus might be at a higher risk of HMG-CoA reductase inhibitor (statin)-induced myotoxicity, possibly because of reduced clearance of the statin lactone. The present study was designed to investigate the effect of diabetes on the biotransformation of atorvastatin acid, both in vivo in nondiabetic and diabetic renal transplant recipients, and in vitro in human liver samples from nondiabetic and diabetic donors. A total of 312 plasma concentrations of atorvastatin acid and atorvastatin lactone, from 20 nondiabetic and 32 diabetic renal transplant recipients, were included in the analysis. Nonlinear mixed-effects modelling was employed to determine the population pharmacokinetic estimates for atorvastatin acid and atorvastatin lactone. In addition, the biotransformation of these compounds was studied using human liver microsomal fractions obtained from 12 nondiabetic and 12 diabetic donors. In diabetic patients, the plasma concentration of atorvastatin lactone was significantly higher than that of atorvastatin acid throughout the 24-hour sampling period. The optimal population pharmacokinetic model for atorvastatin acid and atorvastatin lactone consisted of a two- and one-compartment model, respectively, with interconversion between atorvastatin acid and atorvastatin lactone. Parent drug was absorbed orally with a population estimate first-order absorption rate constant of 0.457 h−1. The population estimates of apparent oral clearance (CL/F) of atorvastatin acid to atorvastatin lactone, intercompartmental clearance (Q/F), apparent central compartment volume of distribution after oral administration (V1/F) and apparent peripheral compartment volume of distribution after oral administration (V2/F) for atorvastatin acid were 231 L/h, 315 L/h, 325 L and 4910 L, respectively. The population estimates of apparent total clearance of atorvastatin lactone (CLM/F), apparent intercompartmental clearance of atorvastatin lactone (QM/F) and apparent volume of distribution of atorvastatin lactone after oral administration (VM/F) were 85.4 L/h, 166 L/h and 249 L, respectively. The final covariate model indicated that the liver enzyme lactate dehydrogenase was related to CL/F and alanine aminotransferase (ALT) was related to Q/F. Importantly, diabetic patients have 3.56 times lower CLM/F than nondiabetic patients, indicating significantly lower clearance of atorvastatin lactone in these patients. Moreover, in a multivariate population pharmacokinetics model, diabetes status was the only significant covariate predicting the values of the CLM/F. Correspondingly, the concentration of atorvastatin acid remaining in the microsomal incubation was not significantly different between nondiabetic and diabetic liver samples, whereas the concentration of atorvastatin lactone was significantly higher in the samples from diabetic donors. In vitro studies, using recombinant enzymes, revealed that cytochrome P450 (CYP) 3A4 is the major CYP enzyme responsible for the biotransformation of atorvastatin lactone. These studies provide compelling evidence that the clearance of atorvastatin lactone is significantly reduced by diabetes, which leads to an increased concentration of this metabolite. This finding can be clinically valuable for diabetic transplant recipients who have additional co-morbidities and are on multiple medications.

Population Pharmacokinetic/Pharmacodynamic Modeling of Clopidogrel in Korean Healthy Volunteers and Stroke Patients

Population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of clopidogrel was developed from pooled data from healthy volunteers (n = 44) and stroke patients (n = 35). The PK modeling used plasma concentrations of the clopidogrel metabolite (SR26334), and the PD modeling used platelet aggregation. The models were developed using NONMEM and evaluated via visual predictive check (VPC). Data were analyzed by 2-compartment modeling with Erlang's absorption and first-order elimination. There was no statistically significant covariate for each model parameter. The typical point estimates of PK were k(tr) (identical transfer rate constant) = 5.97 h(-1), k(e) (elimination rate constant) = 0.126 h(-1), k(d) (distribution rate constant) = 0.212 h(-1), V(2) (volume of central compartment) = 21.0 L, and V(3) (volume of peripheral compartment) = 38.8 L. The typical point estimates of PD were k(in) (input rate) = 27.9 h(-1), E(max) (maximum effect on input rate) = 0.292 h(-1), EC(5) (0) (median effective concentration) = 0.00629 ng/mL, and BASE (predose aggregation) = 66.7%. The final model was used to estimate individual parameters using patient data and showed good predictions using VPC.

Clinical Implications of Pathophysiological and Demographic Covariates on the Population Pharmacokinetics of Trastuzumab Emtansine, a HER2‐Targeted Antibody‐Drug Conjugate, in Patients With HER2‐Positive Metastatic Breast Cancer

Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates (interindividual variability [IIV]) for pharmacokinetic parameters were clearance, 0.7 L/d (21.0%); central compartment volume (V(c)), 3.33 L (13.2%); peripheral compartment volume (V(p)), 0.89 L (50.4%); and intercompartmental clearance, 0.78 L/d. Body weight, albumin, tumor burden, and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in T-DM1 pharmacokinetics, with body weight having a greater effect on IIV of clearance and V(c) than other covariates. T-DM1 exposure was relatively consistent across the weight range following body weight-based dosing. This analysis suggests no further T-DM1 dose adjustments are necessary in heavily pretreated patients with MBC.

Population Pharmacokinetics of Vancomycin in Thai Patients

Population pharmacokinetics of vancomycin in Thai adult patients was determined by non-linear mixed-effects approach using 319 vancomycin serum concentrations from 212 patients. The data were best fitted by a two-compartment model and it was used to examine the effect of patient characteristics on the vancomycin pharmacokinetics. In the final model, there was a linear relationship between vancomycin clearance, CL (L/h), and creatinine clearance calculated by Cockcroft-Gault equation, CLCr (mL/min): CL =0.044 × CLCr. Meanwhile, volume of central compartment, V 1 (L), was linearly related with the age (years old): V 1 = 0.542 × Age. Intercompartment clearance (Q) and volume of peripheral compartment (V 2) was 6.95 L/h and 44.2 L, respectively. The interindividual variability for CL, V 1, Q, and V 2 was 35.78, 20.93, 39.50, and 57.27%, respectively. Whereas, the intraindividual variability was 4.51 mg/L. Final model then was applied to predict serum vancomycin concentrations on validation group. Predictive performance revealed a bias of −1.43 mg/L (95% CI: −5.82–2.99) and a precision of 12.2 mg/L (95% CI: −1.60–26.16). In conclusion, population pharmacokinetic of vancomycin in Thai adult patients was developed. The model could be used to create vancomycin dosage regimen in the type of patient similar with the present study.

The influence of distributional kinetics into a peripheral compartment on the pharmacokinetics of substrate partitioning between blood and brain tissue

Development of CNS-targeted agents often focuses on identifying compounds with "good" CNS exposure (brain-to-blood partitioning >1). Some compounds undergoing enterohepatic recycling (ER) evidence a partition coefficient, K (p,brain) (expressed as C (brain) /C (plasma)), that exceeds and then decreases to (i.e., overshoots) a plateau (distribution equilibrium) value, rather than increasing monotonically to this value. This study tested the hypothesis that overshoot in K (p,brain) is due to substrate residence in a peripheral compartment. Simulations were based on a 3-compartment model with distributional clearances between central and brain (CL (br)) and central and peripheral (CL (d)) compartments and irreversible clearance from the central compartment (CL). Parameters were varied to investigate the relationship between overshoot and peripheral compartment volume (V (p)), and how this relationship was modulated by other model parameters. Overshoot magnitude and duration were characterized as peak C (brain)/C (plasma) relative to the plateau value (%OS) and time to reach plateau (TRP). Except for systems with high CL (d), increasing V (p) increased TRP and %OS. Increasing brain (V (br)) or central (V (c)) distribution volumes eliminated V (p)-related OS. Parallel increases in all clearances shortened TRP, but did not alter %OS. Increasing either CL or CL (d) individually increased %OS related to V (p), while increasing CL (br) decreased %OS. Under realistic peripheral distribution scenarios, C (brain)/C (plasma) may overshoot substantially K (p,brain) at distribution equilibrium. This observation suggests potential for erroneous assessment of brain disposition, particularly for compounds which exhibit a large apparent V (p), and emphasizes the need for complete understanding of distributional kinetics when evaluating brain uptake.

Population pharmacokinetics of intravenous bolus etomidate in children over 6 months of age

Information has been very limited on the population pharmacokinetics (PK) of etomidate in pediatric patients. The purpose of this study was to characterize the PK of etomidate in children. Forty-nine children aged over 6 months undergoing elective surgery received etomidate 0.3 mg·kg(-1) bolus i.v. within 15 s for anesthesia induction. Arterial blood samples were collected for 2 h after injection. A population nonlinear mixed effects modeling approach was used to characterize etomidate PK. Estimates were standardized to a 70-kg adult using allometric size models. Children had a median age of 4 years (0.53-13.21 years) and weight 15.7 kg (7.5-52 kg). PK of etomidate was best estimated using a three-compartment model with weight on systemic (Cl(1)) and inter-compartmental clearances (Cl(2), Cl(3)), central (V(1)), and peripheral compartment volumes (V(2), V(3)). The most significant PK covariate was age, with increasing age having reduced size-adjusted Cl(1), V(1), and V(3) (all P < 0.01). The estimates of PK parameter (standardized to 70-kg adult) for a typical 4-year-old children were Cl(1) = 1.50 l·min(-1), Cl(2) = 1.95 l·min(-1), Cl(3) = 1.23 l·min(-1), V(1) = 9.51 l, V(2) = 11.0 l, and V(3) = 79.2 l, respectively. Owing to enhanced clearance and increased central compartment volume of etomidate, smaller (younger) children will require higher etomidate bolus dose than larger (older) children to achieve equivalent plasma concentrations. The dependence of Cl(1) and V(1) on age does not support weight-based etomidate dosing in smaller children.

Pharmacokinetics, Safety, and Biologic Effects of Azithromycin in Extremely Preterm Infants at Risk for Ureaplasma Colonization and Bronchopulmonary Dysplasia

Ureaplasma spp. respiratory tract colonization is a significant risk factor for bronchopulmonary dysplasia (BPD), a chronic lung disorder in preterm infants. As an initial step preparatory to future clinical trials to evaluate the clinical efficacy of azithromycin to prevent BPD, the authors characterized the pharmacokinetics, safety, and biological effects of a single intravenous dose of azithromycin (10 mg/kg) in preterm neonates (n = 12) 24 to 28 weeks gestation at risk for Ureaplasma infection and BPD. A 2-compartment structural model with the clearance and volume of peripheral compartment (V2) allometrically scaled on body weight (WT) best described the pharmacokinetics of azithromycin in preterm neonates. The estimated parameters were clearance [0.18 L/h × WT(kg)(0.75)], intercompartmental clearance [1.0 L/h], volume of distribution of central compartment [0.93 L], and V2 [14.2 L × WT(kg)]. There were no serious adverse events attributed to azithromycin. A single dose of azithromycin did not suppress inflammatory cytokines or myeloperoxidase activity in tracheal aspirates. These results demonstrated the safety of azithromycin and developed a pharmacokinetic model that is useful for future simulation-based clinical trials for eradicating Ureaplasma and preventing BPD in preterm neonates.

Pharmacokinetics of sulfobutylether- -cyclodextrin (SBECD) in subjects on hemodialysis

The disposition of sulfobutylether-β-cyclodextrin (SBECD), the solubilizing excipient in intravenous (i.v.) voriconazole, was assessed in seven male subjects with end-stage renal disease on hemodialysis and six subjects with normal renal function. All subjects received twice-daily i.v. voriconazole at the standard voriconazole dose [6 mg/kg (96 mg/kg SBECD) every 12 h (Q12h) on Day 1 followed by 3 mg/kg (48 mg/kg SBECD) Q12h on Days 2-4, with a single i.v. dose on the morning of Day 5]. Subjects were sampled at selected pre-dose trough times, at selected times after infusions and intensively on Day 3 (non-dialysis) and Day 4 (dialysis with high-flux membranes). Compartmental analyses were performed by NONMEM. SBECD disposition was characterized by a two-compartment model. In renal failure, mean central (V(1)) and peripheral compartment volumes (V(2)) were 9.9 and 6.5 L, respectively. In normal subjects, V(1) and V(2) were 9.6 and 5.2 L, respectively; SBECD clearance (CL) was 130 mL/min. CL in renal failure off-dialysis was 2.6 and 48 mL/min during dialysis; mean half-life decreased from 79 to 5 h during dialysis (normal subjects: 2.1 h). Hemodialysis can significantly reduce levels of SBECD in subjects with end-stage renal disease.

Aluminum toxicokinetics in peritoneal dialysis patients

Context. Despite the risk of aluminum (Al) toxicity in dialysis patients, little is known about its toxicokinetics (TK) in this population. A national contamination of dialysate solutions with Al provided the opportunity to study Al TK in peritoneal dialysis (PD) patients and to better understand the influence of covariates on its disposition. Methods. Al levels in serum and dialysate as well as other laboratory values were collected prospectively from 83 PD patients after correction of Al contamination. Population TK analyses were conducted with NONMEM VI using standard model discrimination criteria. Covariate analyses were also performed using stepwise forward regression followed by backward deletion. Results. After correction of Al exposure, serum levels declined in a biphasic manner, which was captured by the TK model. The TK of Al were best described by a 2-compartment model with linear elimination. Total creatinine clearance was a significant covariate for total clearance (CL). Mean parameter estimates for volume of central compartment (V1), CL, volume of peripheral compartment (V2), volume of distribution at steady-state (Vss), and intercompartmental clearance (Q) were 168 L, 8.99 L/day, 12 000 L, 12 168 L, and 4.93 L/day, respectively. Inter-individual variability for CL and V2 were 22.6 and 51.1%, respectively. Al distributional half-life was 8.5 days, while the terminal elimination half-life was 7.2 years. This model confirms that the large Vss reflects the widespread distribution of Al in bone, lungs, liver, and other tissues. Conclusion. This study describes the first population Al TK model in a large group of PD patients, which includes a covariate effect. The model confirms the extensive half-life and tissue distribution of Al in a dialysis-dependent population.

Pharmacokinetics of Intravenous and Oral Linezolid in Adults with Cystic Fibrosis

Linezolid is a treatment option for methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h(-1); clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of ≥ 2 μg/ml.

Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma

The objectives of this study were (1) to develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukaemia (ALL) and malignant lymphoma (ML) in order to investigate the influence of common polymorphisms in SLC19A1, MTHFR and ABCB1 on plasma levels of MTX and (2) to estimate MTX exposure in individual patients to study the association of genetic variability in the folate metabolic pathway with MTX toxicity. The study population comprised 64 children with ALL/ML (age 1.6-16.8years) who had received a total of 252 MTX courses (2-4 per patient). Common putative functional polymorphisms in the SLC19A1, MTHFR, MS, MTRR, TS and ABCB1 genes were analysed by PCR-based genotyping. Nonlinear mixed effects modelling was used for the pharmacokinetic analysis. The population typical value of clearance was 7.43L/h (inter-individual variability 43.9%), central compartment volume was 16.7L (46.6%), peripheral compartment volume was 2.6L (63.3%) and distribution clearance was 0.0952L/h (66.6%). MTX clearance decreased to 73.8% in patients with the MTHFR 677TT genotype. Patients homozygous for the variant MTHFR 1298A > C [odds ratio (OR) 0.14, 95% confidence interval (CI) 0.037-0.54] and SLC19A1 80A > G (OR 0.15, 95% CI 0.039-0.60) were at decreased risk for leucopenia. The TS 2R > 3R polymorphism was associated with a lower incidence of thrombocytopenia (OR 0.15, 95% CI 0.039-0.61) and mucositis (OR 0.016, 95% CI 0.0012-0.20). In contrast, the MTHFR 677TT polymorphism was associated with an increased incidence of mucositis (OR 23, 95% CI 2.1-240). A population pharmacokinetic model developed in this study implies only a limited influence of genetic factors on the systemic disposition of MTX. Clearance is moderately reduced in patients with the MTHFR 677TT genotype. Genetic polymorphisms in the folate metabolic pathway and SLC19A1 were associated with HD-MTX toxicity.

Volume kinetics of 6% hydroxyethyl starch 130/0.4 in healthy volunteers

Objective To investigate the volume kinetics of 6% hydroxyethyl starch 130/0.4 in healthy volunteers.Methods Seven healthy volunteers aged 18-32 yr weighing 46-84 kg were selected in this study. 6% hydroxyethyl starch 130/0.4 30 ml/kg was infused over 60 min. Volume kinetics analysis of 6% hydroxyethyl starch 130/0.4 was performed with Matlab 6.0 software, compartment model was determined by F test.Results One-compartment model parameters: basic clearance, clearance and distribution volume of one-compartment model were (3.5 ± 1.3) ml/min,(19± 11) ml/min and (5746 ± 1371) ml respectively. Two-compartment model parameters: clearance, K1, the volume of central compartment, the volume of peripheral compartment, distribution volume of two-compartment model were (63 ±29) ml/min,(11 ±4) ml/min, (1551 ± 995) ml, (908 ±398) ml,(2460 ± 1332) ml respectively. There was no difference between the distribution volume of one-compartment model and blood volume of healthy volunteers ( P ＞ 0.05) .The distribution of infused 6% hydroxyethyl starch 130/0.4 was accordant with one-compartment model (F value was 3.81, P ＞ 0.05)and 4 h clearance was (75 ± 10)% .Conclusion The distribution of infused 6% hydroxyethyl starch 130/0.4 for volume expansion is accordant with one-compartment model, and the effective duration of plasma volume expansion is 4 h. Key words: Hetastarch; Fluid therapy; Kinetics

Assessment of micafungin regimens by pharmacokinetic-pharmacodynamic analysis: a dosing strategy for Aspergillus infections

A pharmacokinetic (PK)-pharmacodynamic (PD) analysis was conducted to assess various micafungin regimens for Candida and Aspergillus infections, as appropriate regimens have not been established, especially for Aspergillus infections. Plasma drug concentrations (48 samples from 10 adult patients with haematological malignancies) were determined chromatographically, and used for population PK modelling and Monte Carlo simulation to evaluate the ability of regimens (1 h infusions) to attain genus-dependent PK-PD targets, namely fungistatic and fungicidal targets against Candida spp. [area under the plasma unbound (1%) drug concentration-time curve over 24 h/MIC (fAUC/MIC) = 10 and 20] and an effective concentration target against Aspergillus spp. (plasma unbound drug concentration = 0.05 mg/L). Mean (variance) values for two-compartment PK model parameters were: clearance, 0.762 L/h (15.4%); volume of central compartment, 9.25 L (24.6%); intercompartmental clearance, 7.02 L/h (fixed); and volume of peripheral compartment, 8.86 L (71.8%). The Monte Carlo simulation demonstrated that 50 mg once daily and 100 mg once daily for the fungistatic and fungicidal targets achieved a >95% probability of target attainment against Candida spp. To achieve such probability against Aspergillus spp., 250 mg once daily or 100 mg twice daily was required. These results rationalize the approved micafungin dosages for Candida infections (50 mg once daily for prophylaxis and 100-150 mg once daily for treatment), and on the basis of these results we propose a PK-PD-based dosing strategy for Aspergillus infections. A regimen of 200-250 mg/day should be initiated to ensure the likelihood of a favourable outcome. The regimen can be optimized by decreasing the dosing interval.

Population pharmacokinetics of CNTO 95, a human anti-αv integrin antibody, in patients with solid tumors

e14593 Background: CNTO 95 is a human anti-αv integrin antibody. The dose-dependent antitumor effect of CNTO 95 has been demonstrated in multiple preclinical studies. The objective of these analyses was to characterize the population pharmacokinetics (PPK) in solid tumor cancer patients treated with CNTO 95 with and without dacarbazine. Methods: Approximately 140 patients with solid tumors from two phase I and one phase II studies were included in this analysis. CNTO 95 was administered via intravenous infusion, with 11 different regimens ranging from 0.1 to 20 mg/kg every 1–4 weeks. Serum CNTO 95 concentrations were determined using a validated enzyme-linked immunosorbent assay. Serum CNTO 95 concentration data were analyzed using noncompartmental analysis (NCA) and a PPK approach. Results: The NCA results indicated that total clearance of CNTO 95 decreased as the dose of CNTO95 increased and approached saturation at 10 mg/kg. Based on the NONMEM analysis, data were best described by a 2-compartment model with dual clearance pathways (linear and nonlinear elimination). The nonlinear elimination process is likely due to the receptor-mediated clearance. Mean estimates of central volume, peripheral compartment volume, intercompartmental clearance and linear clearance, as well as an additional nonlinear clearance, were in agreement with antibodies targeting membrane-bound receptors. No differences in the PPK of CNTO 95 were found in patients treated with and without co-administered dacarbazine. Interindividual variability was moderate (&lt;50%). Conclusions: A PPK model could adequately describe serum CNTO 95 concentration-time profiles. Extensions of this model can be used to assist in the selection of doses in diverse oncology patient populations. [Table: see text]

Population Pharmacokinetic Modeling of BeneFIX in Pediatric and Adult Patients with Hemophilia B Demonstrates Weight as An Important Factor Contributing to Inter-Patient PK Variability.

Clinical trials in patients with hemophilia B have demonstrated considerable inter-patient variability in the pharmacokinetics (PK) of Factor IX (FIX) replacement therapy, including the recovery, an important PK parameter from which individualized clinical dosing decisions are calculated. In clinical trials of plasma-derived and recombinant factor IX replacement therapies, the age of the patient has been demonstrated to affect recovery (younger patients have lower recovery values than older patients), however the specific contribution of age, as well as additional covariates such as body weight and race to PK variability has not been systematically evaluated. We analyzed an extensive database of BeneFIX PK data collected from 8 separate clinical trials conducted over 13 years. A systematic approach involving population PK modeling and simulation was utilized for the first time to estimate the effects of individual-specific covariate factors on PK of BeneFIX in the pooled population that included pediatric and adult patients. A total of 4025 plasma FIX activity PK data sets collected from 191 patients, aged 0 to 69 years were used for the analysis. There were 111 children (£15 years) including 53 infants <2 years, and 80 adults (>15 years) in the pooled data. The majority (84%) of patients were Caucasian. The remaining patients were African American (7%), Hispanic (4%), Asian/Japanese (3%), and other ethnicity (3%).The data were analyzed using nonlinear mixed-effects modeling with the NONMEM software system. Age, weight, and race were examined as covariates for the ability to explain inter-individual variability in the BeneFIX PK. The PK in pediatric and adult patients was described by a two-compartment model with first-order elimination and a zero-order input using the following parameters: clearance (CL), volume of central compartment (V1), volume of peripheral compartment (V2) and inter-compartmental clearance (Q). Population predicted BeneFIX PK parameters, standardized to a 70 kg patient, were 7.46 (standard error; 0.20) mL/hr/kg, 131 (4.4) mL/kg, 71.5 (2.1) mL/kg and 12.1 (1.1) mL/h/kg, for CL, V1, V2 and Q, respectively. The final model was able to simulate data in close agreement with the actual study observations.Variability (%CV) in BeneFIX PK was explained most significantly by allometrically scaled body weight (Figure 1a), while age and race had no discernible effects on BeneFIX PK in the population studied. Observed recovery values were slightly lower in children (£15 years) compared with those in adults (>15 years) since the initial volume of distribution (V1), normalized to body weight, was slightly higher in children than in adults, while the variability in the observed recovery values was comparable between children and adults (Figure 1b).In conclusion, the present analysis, for the first time, systematically describes and quantifies the sources of age-dependent variability of factor IX PK, using BeneFIX data, and provides a better understanding of the importance of body weight in the disposition of BeneFIX. This confirms existing weight-based dosing recommendations and further supports consideration of dosing adjustments that are individualized based on the patient's body weight in the context of the achieving the desired clinical response, such as recovery. This also may be important in pediatric patients during growth periods associated with significant weight change. [Display omitted] [Display omitted]