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Leslie Z Benet - One of the best experts on this subject based on the ideXlab platform.
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Volume of Distribution is unaffected by metabolic drug drug interactions
Clinical Pharmacokinectics, 2021Co-Authors: Jasleen K Sodhi, Caroline H Huang, Leslie Z BenetAbstract:It has been recognized that significant transporter interactions result in Volume of Distribution changes in addition to potential changes in clearance. For drugs that are not clinically significant transporter substrates, it is expected that drug–drug interactions would not result in any changes in Volume of Distribution. An evaluation of this hypothesis proceeded via an extensive analysis of published intravenous metabolic drug–drug interactions, based on clinically recommended index substrates and inhibitors of major cytochrome P450 (CYP) isoforms. Seventy-two metabolic drug interaction studies were identified where Volume of Distribution at steady-state (Vss) values were available for the CYP index substrates caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), theophylline (CYP1A2), and tolbutamide (CYP2C9). Changes in exposure (area under the curve) up to 5.1-fold were observed; however, ratios of Vss changes have a range of 0.70–1.26, with one outlier displaying a Vss ratio of 0.57. These results support the widely held founding tenant of pharmacokinetics that clearance and Vss are independent parameters. Knowledge that Vss is unchanged in metabolic drug–drug interactions can be helpful in discriminating changes in clearance from changes in bioavailability (F) when only oral dosing data are available, as we have recently demonstrated. As Vss remains unchanged for intravenous metabolic drug–drug interactions, following oral dosing changes in Vss/F will reflect changes in F alone. This estimation of F change can subsequently be utilized to assess changes in clearance alone from calculations of apparent clearance. Utilization of this simple methodology for orally dosed drugs will have a significant impact on how drug–drug interactions are interpreted from drug development and regulatory perspectives.
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a simple methodology to differentiate changes in bioavailability from changes in clearance following oral dosing of metabolized drugs
Clinical Pharmacology & Therapeutics, 2020Co-Authors: Jasleen K Sodhi, Leslie Z BenetAbstract:Accurately discriminating changes in clearance (CL) from changes in bioavailability (F) following an oral drug-drug interaction is difficult without carrying out an intravenous interaction study. This may be true for drugs that are clinically significant transporter substrates; however, for interactions that are strictly metabolic, it has been recognized that Volume of Distribution remains unchanged between both phases of the interaction study. With the understanding that changes in Volume of Distribution will be minimal for metabolized drugs, the inverse of the change in apparent Volume of Distribution can provide adequate estimates of the change in bioavailability alone. Utilization of this estimate of F change in tandem with the observed apparent clearance (CL/F) change in an oral drug-drug interaction can provide an estimate of the change in clearance alone. Here, we examine drug-drug interactions involving five known inhibitors and inducers of cytochrome P450 3A4 isozyme on victim drugs midazolam and apixaban for which the interaction was carried out both orally and intravenously, allowing for evaluation of this methodology. Predictions of CL and F changes based on oral data were reasonably close to observed changes based on intravenous studies, demonstrating that this simple yet powerful methodology can reasonably differentiate changes in F from changes in CL for oral metabolic drug interactions when only oral data are available. Utilization of this relatively simple methodology to evaluate DDIs for orally dosed drugs will have a significant impact on how DDIs are interpreted from a drug development and regulatory perspective.
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Effects of Drug Transporters on Volume of Distribution
The AAPS Journal, 2009Co-Authors: Anita Grover, Leslie Z BenetAbstract:Recently, drug transporters have emerged as significant modifiers of a patient’s pharmacokinetics. In cases where the functioning of drug transporters is altered, such as by drug-drug interactions, by genetic polymorphisms, or as evidenced in knockout animals, the resulting change in Volume of Distribution can lead to a significant change in drug effect or likelihood of toxicity, as well as a change in half life independent of a change in clearance. Here, we review pharmacokinetic interactions at the transporter level that have been investigated in animals and humans and reported in literature, with a focus on the changes in Distribution Volume. We pay particular attention to the differing effects of changes in transporter function on the three measures of Volume. Further, trends are discussed as they may be used to predict Volume changes given the function of a transporter and the primary location of the interaction. Because the liver and kidneys express the greatest level and variety of transporters, we denote these organs as the primary location of transporter-based interactions. We conclude that the liver is a larger contributor to Distribution Volume than the kidneys, in consideration of both uptake and efflux transporters. Further, while altered Distribution due to secondary interactions at tissues other than the liver and kidneys may have a pharmacodynamic effect, these interactions, at least at the blood-brain barrier, do not appear to significantly influence overall Distribution Volume. The analysis provides a framework for understanding potential pharmacokinetic interactions rooted in drug transporters as they modify drug Distribution.
Feng Gao - One of the best experts on this subject based on the ideXlab platform.
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prediction of human Volume of Distribution values for neutral and basic drugs 2 extended data set and leave class out statistics
Journal of Medicinal Chemistry, 2004Co-Authors: Franco Lombardo, Scott R Obach, Marina Shalaeva, Feng GaoAbstract:We present an extension and confirmation of our previously published method (J. Med. Chem. 2002, 45, 2867−2876) for the prediction of Volume of Distribution (VD) in humans for neutral and basic compounds. It is based on two experimentally determined physicochemical parameters, ElogD(7.4) and fi(7.4), the latter being the fraction of compound ionized at pH 7.4, and on the fraction of free drug in plasma (fu). By regressing the fraction unbound in tissues, fut, vs the above parameters, we demonstrate the ruggedness of the method in predicting VD through the Oie−Tozer equation, via the use of several testing approaches. A comparison is also presented between several methods based on animal pharmacokinetic data, using the same set of proprietary compounds, and it lends further support for the use of this method, as opposed to methods that require the gathering of pharmacokinetic data in laboratory animals. The reduction in the use of animals and the overall faster and cheaper accessibility of the parameters u...
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prediction of human Volume of Distribution values for neutral and basic drugs 2 extended data set and leave class out statistics
Journal of Medicinal Chemistry, 2004Co-Authors: Franco Lombardo, Scott R Obach, Marina Shalaeva, Feng GaoAbstract:We present an extension and confirmation of our previously published method (J. Med. Chem. 2002, 45, 2867-2876) for the prediction of Volume of Distribution (VD) in humans for neutral and basic compounds. It is based on two experimentally determined physicochemical parameters, ElogD(7.4) and f(i(7.4)), the latter being the fraction of compound ionized at pH 7.4, and on the fraction of free drug in plasma (fu). By regressing the fraction unbound in tissues, fut, vs the above parameters, we demonstrate the ruggedness of the method in predicting VD through the Oie-Tozer equation, via the use of several testing approaches. A comparison is also presented between several methods based on animal pharmacokinetic data, using the same set of proprietary compounds, and it lends further support for the use of this method, as opposed to methods that require the gathering of pharmacokinetic data in laboratory animals. The reduction in the use of animals and the overall faster and cheaper accessibility of the parameters used make this method highly attractive for prospectively predicting the VD of new chemical entities in humans.
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prediction of Volume of Distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data
Journal of Medicinal Chemistry, 2002Co-Authors: Franco Lombardo, Scott R Obach, Marina Shalaeva, Feng GaoAbstract:We present a method for the prediction of Volume of Distribution in humans, for neutral and basic compounds. It is based on two experimentally determined physicochemical parameters, ElogD(7.4) and f(i(7.4)), the latter being the fraction of compound ionized at pH 7.4 and on the fraction of free drug in plasma (f(u)). The fraction unbound in tissues (f(ut)), determined via a regression analysis from 64 compounds using the parameters described, is then used to predict VD(ss) via the Oie-Tozer equation. Accuracy of this method was determined using a test set of 14 compounds, and it was demonstrated that human VD(ss) values could be predicted, on average, within or very close to 2-fold of the actual value. The present method is as accurate as reported methods based on animal pharmacokinetic data, using a similar set of compounds, and ranges between 1.62 and 2.20 as mean-fold error. This method has the advantage of being amenable to automation, and therefore fast throughput, it is compound and resources sparing, and it offers a rationale for the reduction of the use of animals in pharmacokinetic studies. A discussion of the potential errors that may be encountered, including errors in the determination of f(u), is offered, and the caveats about the use of computed vs experimentally determined logD and pK(a) values are addressed.
Iftekhar Mahmood - One of the best experts on this subject based on the ideXlab platform.
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interspecies scaling predicting Volumes mean residence time and elimination half life some suggestions
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Iftekhar MahmoodAbstract:Extrapolation of animal data to assess pharmacokinetic parameters in man is an important tool in drug development. Clearance, Volume of Distribution and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. Extensive work has been done to improve the predictive performance of allometric scaling for clearance. In general there is good correlation between body weight and Volume, hence Volume in man can be predicted with reasonable accuracy from animal data. Besides the Volume of Distribution in the central compartment (V c ), two other Volume terms, the Volume of Distribution by area (V β ) and the Volume of Distribution at steady state (Vd ss ), are also extrapolated from animals to man. This report compares the predictive performance of allometric scaling for V c , V β and Vd ss in man from animal data. The relationship between elimination half-life (t1/2) and body weight across species results in poor correlation, most probably because of the hybrid nature of this parameter. To predict half-life in man from animal data, an indirect method (CL=VK, where CL=clearance, V is Volume and K is elimination rate constant) has been proposed. This report proposes another indirect method which uses the mean residence time (MRT). After establishing that MRT can be predicted across species, it was used to predict half-life using the equation MRT = 1.44 x t1/2. The results of the study indicate that V c is predicted more accurately than V β and Vd ss in man. It should be emphasized that for first-time dosing in man, V c is a more important pharmacokinetic parameter than V β or Vd ss . Furthermore, MRT can be predicted reasonably well for man and can be used for prediction of half-life.
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prediction of clearance Volume of Distribution and half life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants a comparative study
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Iftekhar MahmoodAbstract:Pharmacokinetic parameters (clearance, CL, Volume of Distribution in the central compartment, VdC, and elimination half-life, t1/2beta) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, alpha and beta, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and alpha and beta are the rate constants, both pairs of constants being for the Distribution and elimination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, alpha and beta obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t1/2beta. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t1/2beta predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdC and t1/2beta predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant approach (except for actisomide). The results of this study indicate that caution should be employed in interpreting plasma concentrations predicted for a drug in man by use of pharmacokinetic constants obtained in animals.
Swati Nagar - One of the best experts on this subject based on the ideXlab platform.
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drug Distribution part 2 predicting Volume of Distribution from plasma protein binding and membrane partitioning
Pharmaceutical Research, 2017Co-Authors: Ken Korzekwa, Swati NagarAbstract:Purpose Volume of Distribution is an important pharmacokinetic parameter in the Distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug Distribution.
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drug Distribution part 2 predicting Volume of Distribution from plasma protein binding and membrane partitioning
Pharmaceutical Research, 2017Co-Authors: Ken Korzekwa, Swati NagarAbstract:Volume of Distribution is an important pharmacokinetic parameter in the Distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug Distribution. Here we present a simple relationship that estimates the Volume of Distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two-compartment system and the experimental fractions unbound in plasma and microsomes represent binding to plasma proteins and cellular lipids, respectively. The protein and lipid binding components were parameterized using a dataset containing human in vitro and in vivo parameters for 63 drugs. The resulting equation explains ~84% of the variance in the log of the Volume of Distribution with an average fold-error of 1.6, with 3 outliers. These results suggest that Vss can be predicted for most drugs from plasma protein binding and microsomal partitioning.
Honghui Zhou - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of golimumab an anti tumor necrosis factor α human monoclonal antibody in patients with psoriatic arthritis
The Journal of Clinical Pharmacology, 2009Co-Authors: Zhenhua Xu, Hugh M Davis, Chuanpu Hu, Charles Pendley, Anna Beutler, Jie Ling, Carrie Wagner, Thuy Vu, Daniel Baker, Honghui ZhouAbstract:: The population pharmacokinetics of subcutaneously administered golimumab (50 mg or 100 mg every 4 weeks) were characterized in patients with active psoriatic arthritis (PsA) in GO-REVEAL, a randomized, double-blind, placebo-controlled, phase 3 study. A total of 2029 serum golimumab concentrations from 337 patients were analyzed using NONMEM. A 1-compartment pharmacokinetic model with first-order absorption and elimination was chosen to describe the observed concentration-time data. For a patient of standard weight (70 kg), the population estimates (typical value +/- standard error) for golimumab pharmacokinetic parameters were as follows: apparent clearance = 1.38 +/- 0.04 L/d, apparent Volume of Distribution = 24.9 +/- 1.04 L, and absorption rate constant = 0.908 +/- 0.121 per day. The between-subject variability was 37.6% in apparent clearance and 37.9% in apparent Volume of Distribution. Body weight, antibody-to-golimumab status, baseline C-reactive protein level, and smoking status were identified as significant covariates on apparent clearance. Body weight was also a significant covariate on apparent Volume of Distribution. None of the concomitant medications examined (methotrexate, corticosteroids, and nonsteroidal anti-inflammatory drugs) were significant covariates on apparent clearance, although the median trough golimumab concentration in patients receiving methotrexate was higher than for those not receiving methotrexate. These significant covariates account for part of the variability in systemic exposure to golimumab observed in patients with PsA.
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population pharmacokinetic modeling of ustekinumab a human monoclonal antibody targeting il 12 23p40 in patients with moderate to severe plaque psoriasis
The Journal of Clinical Pharmacology, 2009Co-Authors: Yaowei Zhu, Hugh M Davis, Sam Liao, Joseph C Marini, Jennifer Yohrling, Newman Yeilding, Honghui ZhouAbstract:The population pharmacokinetics of ustekinumab are characterized in patients with moderate to severe plaque psoriasis in 2 Phase 3 studies (PHOENIX 1 and PHOENIX 2). Serum concentration data from 1937 patients are analyzed to determine pharmacokinetic characteristics of ustekinumab and to assess factors that may contribute to their variability. The population typical mean (percentage relative standard error) values for apparent clearance, apparent Volume of Distribution, and absorption rate constant from the final covariate model are 0.465 L.day(-1) (2.0%), 15.7 L (2.0%), and 0.354 day(-1) (16.2%), respectively. The interindividual variabilities for apparent clearance and apparent Volume of Distribution are 41.0% and 33.2%, respectively. of the factors evaluated in this analysis, body weight, diabetes, and positive immune response (antibodies to ustekinumab) are important covariates affecting the apparent clearance and/or apparent Volume of Distribution of ustekinumab. To fully understand the clinical relevance of these results, the covariate findings need to be evaluated concurrently with the efficacy and safety data.
