Biopharmaceutics & Drug Disposition (Biopharm Drug Dispos)

Publisher: Wiley

Journal description

The Journal publishes original reports of studies in biopharmaceutics drug disposition and pharmacokinetics especially those which have a direct relation to the therapeutic use of drugs. This includes human pharmacological studies and therapeutic response and toxicity related to plasma and tissue concentrations of drugs and their metabolites. Research on factors affecting the disposition of the clinical response to drugs and on the design of drug dosage regimens and the treatment of overdose based on pharmacokinetic principles are accepted. Papers on analytical methodology in vitro drug metabolism and on animal models are also published provided that either they facilitate the preceding types of investigation or they are related to the use of drugs in man. The Journal also publishes review articles.

Current impact factor: 2.18

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 2.178
2012 Impact Factor 2.09
2011 Impact Factor 2.074
2010 Impact Factor 1.394
2009 Impact Factor 1.246
2008 Impact Factor 1.542
2007 Impact Factor 1.238
2006 Impact Factor 1.152
2005 Impact Factor 1.11
2004 Impact Factor 1.068
2003 Impact Factor 1.763
2002 Impact Factor 0.688
2001 Impact Factor 0.772
2000 Impact Factor 0.819
1999 Impact Factor 1.068
1998 Impact Factor 0.789
1997 Impact Factor 0.802
1996 Impact Factor 0.824
1995 Impact Factor 0.737
1994 Impact Factor 0.809
1993 Impact Factor 0.609
1992 Impact Factor 0.595

Impact factor over time

Impact factor
Year

Additional details

5-year impact 1.73
Cited half-life 8.10
Immediacy index 0.57
Eigenfactor 0.00
Article influence 0.46
Website Biopharmaceutics & Drug Disposition website
Other titles Biopharmaceutics & drug disposition (Online), Biopharmaceutics & drug disposition, Biopharmaceutics and drug disposition
ISSN 1099-081X
OCLC 43974207
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Wiley

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    • Author can archive a pre-print version
  • Post-print
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    • 12 months embargo
  • Conditions
    • Some journals have separate policies, please check with each journal directly
    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
    • Author's pre-print must acknowledge acceptance for publication
    • On a non-profit server
    • Publisher's version/PDF cannot be used
    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • Peimin Dai · Feifei Luo · Ying Wang · Huangyu Jiang · Liping Wang · Guiyu Zhang · Lijun Zhu · Ming Hu · Xinchun Wang · Linlin Lu · Zhongqiu Liu
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    ABSTRACT: Flavonoids occur naturally as glucosides and aglycones. Their common phenolic hydroxyl groups may trigger extensive UDP-glucuronosyltransferase (UGT)- catalyzed metabolism. Unlike aglycones, glucosides contain glucose moieties. However, the influence of these glucose moieties on glucuronidation of glucosides and aglycones remains unclear. In this study, the flavonoid glucoside tilianin and its aglycone acacetin were used as model compounds. The glucuronidation characteristics and enzyme kinetics of tilianin and acacetin were compared using human UGT isoforms, liver microsomes, and intestinal microsomes obtained from different animal species. Tilianin and acacetin were metabolized into different glucuronides, with UGT1A8 produced as the main isoform. Assessment of enzyme kinetics in UGT1A8, human liver microsomes, and human intestinal microsomes revealed that compared with tilianin, acacetin displayed lower Km (0.6-, 0.7-, and 0.6-fold, respectively), higher Vmax (20-, 60-, and 230-fold, respectively) and higher clearance (30-, 80-, and 300-fold, respectively). Furthermore, glucuronidation of acacetin and tilianin showed significant species- and gender-dependent differences. In conclusion, glucuronidation of flavonoid aglycones is faster than that of glucosides in the intestine and the liver. Understanding the metabolism and species- and gender-dependent differences between glucosides and aglycones is crucial for development of drugs from flavonoids. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1989
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    ABSTRACT: We evaluated if the renal function decline rates per year with age in adults vary based on two primary statistical analyses: cross-section (CS), using one observation per subject, and, longitudinal (LT), using multiple observations per subject along a time. A total of 16,628 records (3,946 subjects; age ranged from 30 to 92 years) of creatinine clearance and relevant demographic data were used. On an average, 4 samples per subjects were collected up to 2,364 days (mean: 793 days). A simple linear regression and random coefficient models were selected for CS and LT analyses, respectively. The renal function decline rates per year were 1.33 and 0.95 mL/min/year for CS and LT analyses, respectively, and, are slower when the repeated individual measurements are considered. Our study confirms that rates are different based on statistical analyses, and, that a statistically robust longitudinal model with a proper sampling design provides reliable individual as well as population estimates of the renal function decline rates per year with age in adults. In conclusion, our findings indicated that one should be cautious in interpreting the renal function decline rate with aging information because its estimation was highly depended on the statistical analyses. From our analyses, a population LT analysis (e.g., random coefficient model) is recommended if individualization is critical, such as a dose adjustment based on the renal function during a chronic therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1988
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    ABSTRACT: Entacapone is an inhibitor of catechol-O-methyltransferase (COMT) and is being used to extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. Entacapone has low and variable oral bioavailability and the underlying mechanism(s) for this behavior have not been studied. To explain such behavior and to characterize the dynamic changes in metabolism of entacapone, we developed a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model integrating in silico, in vitro, and in vivo pharmacokinetic data. The model was developed and verified in healthy volunteers and subsequently expanded to predict the pharmacokinetic parameters of entacapone phosphate, a prodrug of entacapone, and to assess the impact of hepatic impairment on pharmacokinetics of entacapone. Low and inter-individual variability in bioavailability could be attributed to the extensive first-pass metabolism by UGTs in the liver and, to a lesser extent, small intestine. The predictive performance of this model was acceptable with predicted Cmax , AUC, and PD parameters lie within 20% of the observed data. The model indicates that the low bioavailability could be attributed to the extensive first-pass effect of entacapone. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1986
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    ABSTRACT: PurposeRepaglinide and pioglitazone are both CYP2C8 and CYP3A4 substrates. This study is to determine whether repaglinide has an inhibitory effect on the metabolism of pioglitazone in vitro,in silico and in vivo.Method In vitro, the effect of repaglinide on the metabolism of pioglitazone was assessed in pooled human liver microsomes. In silico, an IVIVE-PBPK linked model was built with Simcyp®. Then, a randomized, 2-phase cross-over clinical study was conducted in 12 healthy volunteers.ResultsRepaglinide showed a strong inhibitory effect on the metabolism of pioglitazone in vitro (Ki = 0.0757 μM), [I]/Ki > 0.1. The Simcyp® prediction ratios of AUC and Cmax between the two treatment groups were both about 1.01. The pharmacokinetics of poglitazone in clinical trials showed no significant difference between these two treatment groups (P > 0.05).Conclusion Repaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo,which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1987
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    ABSTRACT: There is an ongoing debate on the use of single concentration time point C2 for therapeutic drug monitoring (TDM) and exposure prediction for cyclosporine. The objective of the present work was to evaluate the relationship between peak concentration (Cmax ) versus area under the curve (AUC) for cyclosporine. Using published data from renal transplant patients from a 8-12 week study with two formulations, a simple linear regression model represented by AUC - cyclosporine = Cmax - Cyclosporine × 3.9965 + 384.5 (r = 0.9647; p < 0.001) was developed. Using the regression equation, predictions of AUC from the reported Cmax data were performed; the fold difference between observed vs predicted AUC was computed and root mean square error for the prediction was calculated. While all but one of the predicted AUCs were contained within 0.5-to 2-fold difference (99.1%), a greater proportion of the AUC values were predicted within a narrower range of 0.75 to 1.5-fold difference (78.2%) suggesting the utility of Cmax as the right surrogate for predicting AUC for cyclosporine with a correlation coefficient of 0.8698 (n = 126; P < 0.001) and RMSE of 26.2%. Since time to Cmax generally varies from 1 to 2 hours, although the results validate the use of C2, there may be an opportunity to explore the suitability of C1 or C1.5 in a prospective study for the purpose of TDM and AUC prediction of cyclosporine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 07/2015; DOI:10.1002/bdd.1967
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    ABSTRACT: The in vitro metabolism of (-)-cis- and (-)-trans-rose oixde was investigated using human liver microsomes and recombinant cytochrome P450 (P450 or CYP) enzymes for the first time. Both isomers of rose oxide were incubated with human liver microsomes, and the formation of respective 9-oxidized metabolite was determined by using gas chromatography-mass spectrometry (GC-MS). Of 11 different recombinant human P450 enzymes used, CYP2B6 and CYP2C19 were the primary enzymes catalyzing the metabolism of (-)-cis- and (-)-trans-rose oxide. CYP1A2 also efficiently oxidized (-)-cis-rose oxide at the 9-position but did not (-)-trans-rose oxide. α-Naphthoflavone (a selective CYP1A2 inhibitor), thioTEPA (a CYP2B6 inhibitor) and anti-CYP2B6 antibody inhibited (-)-cis-rose oxide 9-hydroxylation catalyzed by human liver microsomes. On the other hand, the metabolism of (-)-trans-rose oxide was suppressed by thioTEPA and anti-CYP2B6 at significant level in human liver microsomes. However, omeprazole (a CYP2C19 inhibitor) had no significant effects on the metabolism of both isomers of rose oxide. Using microsomal preparations from 9 different human liver samples, (-)-9-hydroxy-cis- and (-)-9-hydroxy-trans-rose oxide formations correlated with (S)-mephenytoin N-demethylase activity (CYP2B6 marker activity). These results suggest that CYP2B6 plays important roles on the metabolism of (-)-cis- and (-)-trans-rose oxide in human liver microsomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1965
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    ABSTRACT: Mefenamic acid (MEF) is a widely prescribed non-steroidal anti-inflammatory drug that has been found associated with rare but severe cases of hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. Formation of protein-reactive acylating metabolites such as 1-O-acyl-MEF glucuronide (MEFG) and 3'-hydroxymethyl-MEF 1-O-acyl-glucuronide is one proposed cause. In addition to the well-reported 3'-hydroxymethyl-MEF, two mono-hydroxyl-MEF (OH-MEFs) were recently identified in vitro. However, in vivo evidence and whether these OH-MEFs would be further glucuronidated to the potentially reactive 1-O-acyl-glucuronides (OH-MEFGs) is lacking. Utilizing UPLC-Q-TOF/MS and LC-MS/MS, the current study for the first time identified four OH-MEFs and their corresponding OH-MEFGs from plasma after single oral MEF (40 mg/kg) administration to rats, including an OH-MEF that has not been previously reported. The systemic exposure of these identified metabolites was high, with metabolic to parent AUC0→24h ratios reaching 23-52% (OH-MEFs) and 8-29% (OH-MEFGs). These metabolites also had long systemic exposure time in both single and 5-day multiple oral MEF-treated rats, with elimination half-lives between 9 h and >24 h. In addition to these novel metabolites, the previously reported MEFG was also identified and its systemic exposure was found to be doubled after multiple MEF administrations. These pharmacokinetic results suggest that systemic toxicities caused by the potentially reactive MEFG and OH-MEFGs could be considerable, especially after repeated MEF treatment. Nevertheless, MEFG and OH-MEFGs had negligible brain uptakes, indicating minimal risk of brain toxicities. Furthermore, in situ intestinal perfusion study revealed that during MEF absorption, it was extensively metabolized to MEFG while <5% was metabolized to OH-MEFs and OH-MEFGs. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1964
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    ABSTRACT: Protein phosphorylation is a vital posttranslational modification. In this study, we investigated the effect of phosphorylation on human uridine diphosphate (UDP)-glucuronosyltransferase 1A3 (UGT1A3) activity. Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so we examined three predicted PKC phosphorylationsites inUGT1A3. Site-directed mutation analysis at residues 28, 43, and 436 (from serine to glycine) was conducted. Compared with the wild-type, the S43G-mutant showed significantly decreased UGT1A3 catalytic activity. Furthermore, the UGT1A3 activity of wild-type and S43G-mutant was downregulated by calphostin C, whereas the calphostin C inhibitory effect was much weaker on S43G-mutant than wild-type. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1963
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    ABSTRACT: 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ-opioid receptor. AZD2327 and N-deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time-dependent inhibition of CYP3A4. The aim of current work was to develop a physiologically based pharmacokinetic (PBPK) model to quantitatively predict the magnitude of CYP3A4 mediated drug-drug interaction with midazolam as the substrate. Integrating in silico, in vitro, and in vivo PK data, a PBPK model was successfully developed to simulate clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (Cmax ) and area under the concentration-time curve (AUC) for midazolam were increased by 1.75 and 2.45-fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinical relevant drug-drug interactions (DDI). These results are in agreement with those obtained in a clinical trial of 1.4 and 1.5-fold increase in Cmax and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than two-fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways, and inhibitors (parent and metabolite) can be predicted using well developed PBPK model. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1962
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    ABSTRACT: We evaluated the effect of hypothermia on the in vivo pharmacokinetics of midazolam (MDZ), with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with MDZ (which is metabolized mainly by CYP3A2) at 37, 32, or 28 °C. The Michaelis-Menten constant (Km ) and maximum velocity (Vmax ) of MDZ were estimated using the Michaelis-Menten equation. The Km of CYP3A2 MDZ remained unchanged, but the Vmax decreased at 28 °C. In rats, whose temperature was maintained at 37, 32, or 28 °C by a heat lamp or ice pack, plasma concentrations of MDZ were higher, whereas those in the brain and liver were unchanged at 28 °C. Tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of MDZ in serum at 28 °C was half that at 37 °C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1960
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    ABSTRACT: The current study was designed to cross-validate rat liver microsomes (RLM), suspended rat hepatocytes (SRH) and the isolated perfused rat liver (IPRL) model against in vivo pharmacokinetic data, using verapamil as a model drug. Michaelis-Menten constants (Km), for metabolic disappearance kinetics of verapamil in RLM and SRH (freshly-isolated and cryopreserved), were determined and corrected for non-specific binding. The "unbound" Km determined with RLM (2.8 μM) was divided by the "unbound" Km determined with fresh and cryopreserved SRH (3.9 μM and 2.1 μM, respectively) to calculate the ratio of intracellular to extracellular unbound concentration (Kpu,u ). Kpu,u was significantly different between freshly-isolated (0.71) and cryopreserved (1.31) SRH, but intracellular capacity for verapamil metabolism was maintained after cryopreservation (200 vs. 191 µl/min/million cells). Direct comparison of intrinsic clearance values (Clint ) in RLM versus SRH, yielded an activity-based scaling factor (SF) of 0.28-0.30 mg microsomal protein/million cells (MPPMC). Merging the IPRL-derived Clint with MPPMC and SRH data, resulted in SFs for MPPGL (80 and 43 mg microsomal protein/g liver) and HPGL (269 and 153 million cells/g liver), respectively. Likewise, the hepatic blood flow (61 ml/min/kg b.wt.) was calculated using IPRL Clint and the in vivo Cl. SFs determined here are consistent with previously reported CYP450-content based SFs. Overall, our results show that integrated interpretation of data obtained with multiple preclinical tools (i.e. RLM, SRH, IPRL) can contribute to more reliable estimates for scaling factors and ultimately to improved in vivo clearance predictions based on in vitro experimentation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 05/2015; DOI:10.1002/bdd.1959
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    ABSTRACT: Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment of the familial chylomicronemia syndrome. We present the results of two studies that evaluated the effect of food on the oral bioavailability of pradigastat using randomized, open-label, parallel group designs in healthy subjects (N = 24/treatment/study). In study 1, a single dose of 20 mg pradigastat was administered under fasted condition or with a high-fat meal. In study 2, a single dose of 40 mg pradigastat was administered under fasted condition or with a low- or high-fat meal. At the 20 mg dose, pradigastat Cmax and AUClast increased by 38% and 41%, respectively, with a high-fat meal. When 40 mg pradigastat was administered with a low-fat meal, Cmax and AUClast increased by 8% and 18%, respectively, whereas with a high-fat meal the increase was 20% and 18%, respectively. The population pharmacokinetic analysis with pooled data of 13 studies indicated that administration of pradigastat with a meal resulted in an increase of 30% in both Cmax and AUC parameters. Based on these results, food overall increased pradigastat exposure in the range of less than 40%, which is not considered clinically significant. Both 20 and 40 mg doses of pradigastat were well tolerated under fasted or fed conditions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 05/2015; DOI:10.1002/bdd.1958
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    ABSTRACT: Antibody Drug conjugates (ADCs) are a rapidly growing therapeutic platform for the treatment of cancer. ADCs consist of a cytotoxic small molecule drug linked to an antibody to provide targeted delivery of the cytotoxic agent to the tumor. Understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of ADCs is crucial in their design to optimize dose and regimen, to maximize efficacy and minimize toxicity in patients. Significant progress has been made in recent years in this area, however many fundamental questions still remain. This review discusses factors to consider while assessing disposition of ADCs, and the unique challenges associated with these therapeutics. Current tools that are available and strategies to enable appropriate assessment are also discussed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1957
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    ABSTRACT: Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. We describe here the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with betahistine dose (R(2) -0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for power model were 0.8684 (Cmax ) and 1.007 (AUC0-4 ). A population pharmacokinetic model with first order absorption of betahistine and metabolism to 2-PAA, followed by a first order elimination of 2-PAA provides estimates of clearance which underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1955
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    ABSTRACT: The pharmacokinetics of lobeglitazone (LB) was studied after intravenous administration of a dose at 1 mg/kg and oral administration of doses at 0.1, 1 and 10 mg/kg in male and female rats. The area under the plasma concentration-time curve from time zero to infinity (AUCinf ) after intravenous administration was approximately 7.1 times higher in female rats than in male rats. In addition, the AUCinf in the case of oral administration was at least 4.4 times higher in female rats and appeared to increase in proportion to the dose in both genders. The in vitro half-lives were 18.8 ± 4.45 min and 60.7 ± 11.2 min, as evidenced by incubating liver microsomes obtained from male and female rats, respectively. As a result, the estimated CLint for LB for male rat liver microsomes (0.0779 ± 0.0233 mL/min/mg protein) was much higher than that for female rat liver microsomes (0.0233 ± 0.0039 mL/min/mg protein, p < 0.05). These observations suggest that there are gender differences in the pharmacokinetics and hepatic metabolism for LB in rats. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1954
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    ABSTRACT: Currently, more than 350 monoclonal antibodies (mAbs) and mAb derivatives are under development as therapeutics. The prediction of mAb pharmacokinetics (PK)/pharmacodynamics (PD) plays a key role in starting dose selection for first-in-human (FIH) studies. This article presents a brief overview of the biology and mechanisms of absorption, distribution, metabolism and excretion (ADME) for mAbs. Additionally, we provide a detailed review of mAb human PK/PD prediction from nonclinical data, including allometry for mAbs with linear or nonlinear PK, species-invariant time method, physiologically based PK (PBPK) modeling and target-mediated drug disposition (TMDD) model, bioavailability projection and immunogenicity impact on PK prediction. Finally, from an industry perspective a decision tree of mAb human PK projection is proposed to facilitate drug development. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1952
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    ABSTRACT: The regression limited sampling strategy approach (R-LSS), which is based on a small number of blood samples drawn at selected time points, has been used as an alternative method for the estimation of the area under the concentration-time curve (AUC). However, deviations from planned sampling times may affect the performance of R-LSS, influencing related therapeutic decisions and outcomes. The aim of this study was to investigate the impact of different sampling time deviation (STD) scenarios on the estimation of AUC by R-LSS using a simulation approach. Three types of scenarios were considered going from the simplest case of fixed deviations, to random deviations and then to a more realistic case where deviations of mixed nature can occur. In addition, the sensitivity of R-LSS to STD in each involved sampling point was evaluated. A significant impact of STD on the performance of R-LSS was demonstrated. The tolerance of R-LSS to STD was found to depend not only on the number of sampling points but more importantly on the duration of the sampling process. Sensitivity analysis showed that sampling points at which rapid concentration changes occur were relatively more critical for AUC prediction by R-LSS. As a practical approach, nomograms were proposed, where the expected predictive performance of R-LSS was provided as a function of STD information. The investigation of STD impact on the predictive performance of R-LSS is a critical element and should be routinely performed to guide R-LSS selection and use. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1951
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    ABSTRACT: CD70 is a tumor necrosis factor (TNF)-like type II integral membrane protein that is transiently expressed on activated T- and B-lymphocytes. Aberrant expression of CD70 was identified in both solid tumors and haematologic malignancies. BMS-936561 (αCD70_MED-A) is an antibody-drug conjugate composed of a fully human anti-CD70 monoclonal antibody (αCD70) conjugated with a duocarmycin derivative, MED-A, through a maleimide-containing citrulline-valine dipeptide linker. MED-A is a carbamate prodrug that is activated by carboxylesterase to its active form, MED-B, to exert its DNA alkylation activity. In vitro serum stability studies suggested the efficiencies of hydrolyzing the carbamate-protecting group in αCD70_MED-A followed a rank order of mouse > rat > monkey > dog ~ human. Pharmacokinetics of αCD70_MED-A was evaluated in mice, monkeys, and dogs after single intravenous doses. In mice, αCD70_MED-A was cleared rapidly, with no detectable exposures after 15 min following dosing. In contrast, αCD70_MED-A was much more stable in monkeys and dogs. The clearance of αCD70_MED-A in monkeys was 58 mL/d/kg, ~2-fold faster than that in dogs (31 mL/d/kg). The human PK profiles of the total αCD70 and αCD70_MED-A were predicted using allometrically scaled monkeys PK parameters of αCD70 and the carbamate hydrolysis rate constant estimated in dogs. Comparing the predicted and observed human PK from the phase I study, the dose-normalized concentration-time profiles of αCD70_MED-A and the total αCD70 were largely within the 5(th) -95(th) percentile of the predicted profiles. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1953