ABSTRACT:Previous studies have shown the importance of the addition of albumin for characterization of hepatic glucuronidation in vitro; however, no reports exist on the effects of albumin on renal or intestinal microsomal glucuronidation assays. This study characterized glucuronidation clearance (CL int, UGT ) in human kidney, liver, and intestinal microsomes in the presence and absence of bovine serum albumin (BSA) for seven drugs with differential UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B7 specificity, namely, diclofenac, ezetimibe, gemfibrozil, mycophenolic acid, naloxone, propofol, and telmisartan.
Abstract. The ability to predict subcutaneous (SC) absorption rate and tissue distribution of therapeutic proteins (TPs) using a bottom-up approach is highly desirable early in the drug development process prior to clinical data being available. A whole-body physiologically based pharmacokinetic (PBPK) model, requiring only a few drug parameters, to predict plasma and interstitial fluid concentrations of TPs in humans after intravenous and subcutaneous dosing has been developed. Movement of TPs between vascular and interstitial spaces was described by considering both convection and diffusion processes using a 2-pore framework. The model was optimised using a variety of literature sources, such as tissue lymph/plasma concentration ratios in humans and animals, information on the percentage of dose absorbed following SC dosing via lymph in animals and data showing loss of radiolabelled IgG from the SC dosing site in humans. The resultant model was used to predict t max and plasma concentration profiles for 12 TPs (molecular weight 8-150 kDa) following SC dosing. The predicted plasma concentration profiles were generally comparable to observed data. t max was predicted within 3-fold of reported values, with one third of the predictions within 0.8-1.25-fold. There was no systematic bias in simulated C max values, although a general trend for underprediction of t max was observed. No clear trend between prediction accuracy of t max and TP isoelectric point or molecular size was apparent. The mechanistic whole-body PBPK model described here can be applied to predict absorption rate of TPs into blood and movement into target tissues following SC dosing.
This study aimed to derive quantitative abundance values for key hepatic transporters suitable for in vitro–in vivo extrapolation within a physiologically based pharmacokinetic modeling framework. A meta-analysis was performed whereby data on abundance measurements, sample preparation methods, and donor demography were collated from the literature. To define values for a healthy Caucasian population, a subdatabase was created whereby exclusion criteria were applied to remove samples from non-Caucasian individuals, those with underlying disease, or those with subcellular fractions other than crude membrane. Where a clinically relevant active genotype was known, only samples from individuals with an extensive transporter phenotype were included. Authors were contacted directly when additional information was required. After removing duplicated samples, the weighted mean, geometric mean, standard deviation, coefficient of variation, and between-study homogeneity of transporter abundances were determined. From the complete database containing 24 transporters, suitable abundance data were available for 11 hepatic transporters from nine studies after exclusion criteria were applied. Organic anion transporting polypeptides OATP1B1 and OATP1B3 showed the highest population abundance in healthy adult Caucasians. For several transporters, the variability in abundance was reduced significantly once the exclusion criteria were applied. The highest variability was observed for OATP1B3 > OATP1B1 > multidrug resistance protein 2 > multidrug resistance gene 1. No relationship was found between transporter expression and donor age. To our knowledge, this study provides the first in-depth analysis of current quantitative abundance data for a wide range of hepatic transporters, with the aim of using these data for in vitro–in vivo extrapolation, and highlights the significance of investigating the background of tissue(s) used in quantitative transporter proteomic studies. Similar studies are now warranted for other ethnicities.
Understanding inter-subject variability in drug pharmacokinetics and pharmacodynamics is important to ensure that all patients attain suitable drug exposure to achieve efficacy and avoid toxicity. Inter-subject variability in the pharmacokinetics of therapeutic monoclonal antibodies (mAbs) is generally moderate to high; however, the factors responsible for the high inter-subject variability have not been comprehensively reviewed. In this review, the extent of inter-subject variability for mAb pharmacokinetics is presented and potential factors contributing to this variability are explored and summarised. Disease status, age, sex, ethnicity, body size, genetic polymorphisms, concomitant medication, co-morbidities, immune status and multiple other patient-specific details have been considered. The inter-subject variability for mAb pharmacokinetics most likely depends on the complex interplay of multiple factors. However, studies aimed at investigating the reasons for the inter-subject variability are sparse. Population pharmacokinetic models and physiologically based pharmacokinetic models are useful tools to identify important covariates, aiding in the understanding of factors contributing to inter-subject variability. Further understanding of inter-subject variability in pharmacokinetics should aid in development of dosing regimens that are more appropriate.
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