المؤلفون: Wakuda, Hirokazu, Xiang, Yue, Sodhi, Jasleen K, Uemura, Naoto, Benet, Leslie Z

المصدر: The AAPS Journal. 26(1)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Cancer, Pharmaceutical Preparations, Biological Availability, Injections, Intravenous, Area Under Curve, Administration, Oral, bioavailability, Kirchhoff's Laws, systemic concentrations, urinary excretion, Kirchhoff’s Laws, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We teach and believe, based on differential equation derivations, that rate of absorption has no influence on measured systemic clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought that any difference in calculating F from urine data versus that from systemic concentration AUC data was due to the inability to accurately measure urine data. A PubMed literature search for drugs exhibiting F > 1.0 and studies for which F was measured using both AUC and urinary excretion dose-corrected analyses yielded data for 35 drugs. We show and explain, using Kirchhoff's Laws, that these universally held concepts concerning bioavailability may not be valid in all situations. Bioavailability, determined using systemic concentration measurements, for many drugs may be overestimated since AUC reflects not only systemic elimination but also absorption rate characteristics, which is most easily seen for renal clearance measures. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for F(AUC) to correctly correspond with F(urine). The primary purpose of this paper is to demonstrate that studies resulting in F > 1.0 and/or greater systemic vs urine bioavailability predictions may be accurate. Importantly, these explications have no significant impact on current regulatory guidance for bioequivalence testing, nor on the use of exposure (AUC) measures in making drug dosing decisions.

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الوصول الحر: https://escholarship.org/uc/item/4zz6b01dTest

المؤلفون: Benet, Leslie Z

المصدر: Journal of Pharmaceutical Sciences. 112(9)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Orphan Drug, Rare Diseases, Humans, Solubility, Permeability, Biopharmaceutics, Chemical and Drug Induced Liver Injury, Brain, Pharmaceutical Preparations, Permeability rate, BDDCS, ECCS, BCS, Food effects, Brain penetration, DILI, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: Here I detail the use of measures of permeability rate and solubility in predicting drug disposition characteristics through the utilization of the Biopharmaceutics Drug Disposition Classification System (BDDCS) and the Extended Clearance Classification System (ECCS) as well as the accuracy of the systems in predicting the major route of elimination and the extent of oral absorption of a new small molecule therapeutics. I compare the BDDCS and ECCS with the FDA Biopharmaceutics Classification System (BCS). I also detail the use of the BCS in predicting food effects and the BDDCS in predicting brain disposition of small molecule therapeutics and in validating DILI predictive metrics. This review provides an update of the current status of these classification systems and their uses in the drug development process.

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الوصول الحر: https://escholarship.org/uc/item/8pt21240Test

المؤلفون: Liu, Wei, Yu, Zhiheng, Wang, Ziyu, Waubant, Emmanuelle L, Zhai, Suodi, Benet, Leslie Z

المصدر: Clinical and Translational Science. 16(3)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, Multiple Sclerosis, Brain Disorders, Autoimmune Disease, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Humans, Animals, Mice, Rats, Immunosuppressive Agents, Fingolimod Hydrochloride, Multiple Sclerosis, Relapsing-Remitting, Dimethyl Fumarate, Cardiorespiratory Medicine and Haematology, Oncology and Carcinogenesis, Other Medical and Health Sciences, General Clinical Medicine, Cardiovascular medicine and haematology, Pharmacology and pharmaceutical sciences

الوصف: The objective of this study was to determine the potential usefulness of an animal model to predict the appropriate dose of newly developed drugs for treating relapsing remitting multiple sclerosis (RRMS). Conversion of the lowest effective dose (LEffD) for mice and rats in the experimental autoimmune encephalomyelitis (EAE) model was used to predict the human effective dose utilizing the body surface area correction factor found in the 2005 US Food and Drug Administration (FDA) Guidance for Industry in selecting safe starting doses for clinical trials. Predictions were also tested by comparison with doses estimated by scaling up the LEffD in the model by the human to animal clearance ratio. Although initial proof-of-concept studies of oral fingolimod tested the efficacy and safety of 1.25 and 5 mg in treating RRMS, the EAE animal model predicted the approved dose of this drug, 0.5 mg daily. This approach would have also provided useful predictions of the approved human oral doses for cladribine, dimethyl fumarate, ozanimod, ponesimod, siponimod, and teriflunomide, drugs developed with more than one supposed mechanism of action. The procedure was not useful for i.v. dosed drugs, including monoclonal antibodies. We maintain that drug development scientists should always examine a simple allometric method to predict the therapeutic effective dose in humans. Then, following clinical studies, we believe that the animal model might be expected to yield useful predictions of other drugs developed to treat the same condition. The methodology may not always be predictive, but the approach is so simple it should be investigated.

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الوصول الحر: https://escholarship.org/uc/item/3ct1x72wTest

المؤلفون: Benet, Leslie Z, Sodhi, Jasleen K

المصدر: The AAPS Journal. 25(3)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, clearance, differential equations, Kirchhoff, oral absorption, rate constants, volumes of distribution, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: In chemistry, rate processes are defined in terms of rate constants, with units of time-1, and are derived by differential equations from amounts. In contrast, when considering drug concentrations in biological systems, particularly in humans, rate processes must be defined in terms of clearance, with units of volume/time, since biological volumes, which are highly dependent on drug partition into biological tissues, cannot be easily determined. In pharmacology, pharmacokinetics, and in making drug dosing decisions, drug clearance and changes in drug clearance are paramount. Clearance is defined as the amount of drug eliminated or moved divided by the exposure driving that elimination or movement. Historically, all clearance derivations in pharmacology and pharmacokinetics have been based on the use of differential equations in terms of rate constants and amounts, which are then converted into clearance equations when multiplied/divided by a hypothesized volume of distribution. Here, we show that except for iv bolus dosing, multiple volumes may be relevant. We have recently shown that clearance relationships, as well as rate constant relationships, may be derived independent of differential equations using Kirchhoff's Laws from physics. Kirchhoff's Laws may be simply translated to recognize that when two or more rate-defining processes operate in parallel, the total value of the overall reaction parameter is equal to the sum of those rate-defining processes. In contrast, when two or more rate-defining processes operate in series, the inverse of the total reaction parameter is equal to the sum of the inverse of those rate-defining steps.

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الوصول الحر: https://escholarship.org/uc/item/4vb3277kTest

المؤلفون: Pachter, Jonathan Asher, Dill, Ken A, Sodhi, Jasleen K, Benet, Leslie Z

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Patient Safety, Liver Disease, Digestive Diseases, Kidney Disease, Clearance, Intrinsic clearance, Kirchhoff's Laws, Liver, Kidney, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: Dosing rate decisions for drugs and changes in dosing in a patient due to disease states, drug interactions and pharmacogenomics are all based on clearance, a measure of the body's ability to eliminate drug. The primary organs of elimination are the liver and the kidney. Clearance for each of these organs is a summative composition of biologic processes. In 1857, Gustav Kirchhoff first developed his laws to describe the "motion of electricity in conductors... [and] ...in wires", recognizing that summative processes occur either in parallel or in series. Since then, Kirchhoff's Laws have also been applied to heat transfer, diffusion and drag force on falling objects, but not to pharmacology. Although not previously recognized, renal clearance always follow Kirchhoff's Laws, as does hepatic clearance for drugs where basolateral transporters are not clinically relevant. However, when basolateral transporters are clinically relevant, we demonstrate that the present accepted approach is inconsistent with recognized drug disposition processes. However, this clearance relationship can be easily corrected using Kirchhoff's Laws. The purpose of this review is to demonstrate that Kirchhoff's Laws, which define how to approach rate processes that occur in parallel versus processes that occur in series, can be applicable to pharmacology in addition to the over 160-year recognition of their use in physical sciences. We anticipate that the application to clearance will be only the first of many such pharmacological analyses.

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الوصول الحر: https://escholarship.org/uc/item/6zf0652nTest

المؤلفون: Benet, Leslie Z, Sodhi, Jasleen K

المصدر: Clinical Pharmacology & Therapeutics. 111(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Hepatocytes, Humans, Kinetics, Liver, Metabolic Clearance Rate, Models, Biological, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: For a number of years, our laboratory has been investigating the underlying reasons for the published poor in vitro-in vivo extrapolation (IVIVE) predictability of human clearance both from a theoretical and from an experimental perspective. Here, we critically examine clearance concepts and commonly employed IVIVE approaches, concluding that there is no theoretical reason that IVIVE should work, just as it does not. Our analysis, however, has identified 10 misconceptions and/or poorly understood aspects of clearance that are listed in the Conclusion section of this manuscript. Chief among these are that all published human drug clearance values are arterial clearances-clearance calculated as organ blood flow multiplied by the extraction ratio is the arterial clearance of the organ of elimination (and not the published drug clearance value)-and that the well-stirred model equation taught in all pharmacokinetic courses that relates organ blood flow, fraction unbound in blood, and intrinsic clearance has no validity. We further list 10 conclusions relating to the IVIVE process. The primary IVIVE-related conclusions are that the intrinsic clearance value determined from an in vitro incubation is an arterial intrinsic clearance, there is no theoretical basis upon which an arterial intrinsic clearance can be related to a whole-body arterial clearance to accomplish IVIVE, there are no published data demonstrating that in vitro intrinsic metabolic clearance can predict in vivo organ clearance as IVIVE assumes, and the scientific basis for the hypothesized albumin-mediated hepatic uptake phenomenon is invalid. We further propose three IVIVE process recommendations.

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الوصول الحر: https://escholarship.org/uc/item/9wq762wwTest

المؤلفون: Kameyama, Tsubasa, Sodhi, Jasleen K, Benet, Leslie Z

المصدر: Drug Metabolism and Disposition. 50(4)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Patient Safety, Digestive Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Hepatocytes, Kinetics, Liver, Metabolic Clearance Rate, Microsomes, Liver, Models, Biological, Pharmaceutical Preparations, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: Accurate prediction of in vivo hepatic clearance is an essential part of successful and efficient drug development; however, many investigators have recognized that there are significant limitations in the predictability of clearance with a tendency for underprediction for primarily metabolized drugs. Here, we examine the impact of adding serum or albumin into hepatocyte and microsomal incubations on the predictability of in vivo hepatic clearance. The addition of protein into hepatocyte incubations has been reported to improve the predictability for high clearance (extraction ratio) drugs and highly protein-bound drugs. Analyzing published data for 60 different drugs and 97 experimental comparisons (with 17 drugs being investigated from two to seven) we confirmed the marked underprediction of clearance. However, we could not validate any relevant improved predictability within twofold by the addition of serum to hepatocyte incubations or albumin to microsomal incubations. This was the case when investigating all measurements, or when subdividing analyses by extraction ratio, degree of protein binding, Biopharmaceutics Drug Disposition Classification System class, examining Extended Clearance Classification System class 1B drugs only, or drug charge. Manipulating characteristics of small data sets of like compounds and adding scaling factors can appear to yield good predictability, but the carryover of these methods to alternate drug classes and different laboratories is not evident. Improvement in predictability of poorly soluble compounds is greater than that for soluble compounds, but not to a meaningful extent. Overall, we cannot confirm that protein addition improves in vitro-in vivo extrapolation predictability to any clinically meaningful degree when considering all drugs and different subsets. SIGNIFICANCE STATEMENT: The addition of protein into microsomal or hepatocyte incubations has been widely proposed to improve hepatic clearance predictions. To date, studies examining this phenomenon have not included appropriate negative controls where predictability is achieved without protein addition and have been conducted with small data sets of similar compounds that don't apply to alternate drug classes. Here, an extensive analysis of published data for 60 drugs and 97 experimental comparisons couldn't validate any relevant clinically improved clearance predictability with protein addition.

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الوصول الحر: https://escholarship.org/uc/item/1q14d0nkTest

المؤلفون: Bocci, Giovanni, Oprea, Tudor I, Benet, Leslie Z

المصدر: The AAPS Journal. 24(2)

مصطلحات موضوعية: Animals, Biopharmaceutics, Chemical and Drug Induced Liver Injury, Permeability, Pharmaceutical Preparations, Solubility, BDDCS, BCS, DILI, dose number, extent of metabolism, food effects, solubility, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy

الوصف: The Biopharmaceutics Drug Disposition Classification system (BDDCS) is a four-class approach based on water solubility and extent of metabolism/permeability rate. Based on the BDDCS class to which a drug is assigned, it is possible to predict the role of metabolic enzymes and transporters on the drug disposition of a new molecular entity (NME) prior to its administration to animals or humans. Here, we report a total of 1475 drugs and active metabolites to which the BDDCS is applied. Of these, 379 are new entries, and 1096 are revisions of former classification studies with the addition of references for the approved maximum dose strength, extent of the systemically available drug excreted unchanged in the urine, and lowest solubility over the pH range 1.0-6.8 when such information is available in the literature. We detail revised class assignments of previously misclassified drugs and the literature analyses to classify new drugs. We review the process of solubility assessment for NMEs prior to drug dosing in humans and approved dose classification, as well as the comparison of Biopharmaceutics Classification System (BCS) versus BDDCS assignment. We detail the uses of BDDCS in predicting, prior to dosing animals or humans, disposition characteristics, potential brain penetration, food effect, and drug-induced liver injury (DILI) potential. This work provides an update on the current status of the BDDCS and its uses in the drug development process.

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الوصول الحر: https://escholarship.org/uc/item/9xq9c3c6Test

المؤلفون: Liu, Shuaibing, Sodhi, Jasleen K, Benet, Leslie Z

المصدر: Pharmaceutical Research. 38(10)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Substance Misuse, Clinical Research, Digestive Diseases, Drug Abuse (NIDA only), ATP Binding Cassette Transporter, Subfamily B, Member 1, Citrus paradisi, Cyclosporine, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Diltiazem, Drug Interactions, Fruit and Vegetable Juices, Humans, Intestinal Absorption, Intestines, Ketoconazole, Rifampin, Ticagrelor, drug-drug interactions, mean absorption time, ticagrelor, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: PurposePrevious studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here.MethodsUsing recently published methodologies from our laboratory to differentiate metabolic- from transporter-mediated drug-drug interactions, a critical evaluation of five published ticagrelor drug-drug interactions was carried out to investigate the purported clinical significance of enzymes and transporters in ticagrelor disposition.ResultsThe suggested CYP3A4 inhibitors, ketoconazole and diltiazem, displayed unchanged mean absorption time (MAT) and time of maximum concentration (Tmax) values as was expected, i.e., the interactions were mainly mediated by metabolic enzymes. The potential CYP3A4/P-gp inhibitor cyclosporine also showed an unchanged MAT value. Further analysis assuming there was no P-gp effect suggested that the increased AUC and unchanged t1/2 for ticagrelor after cyclosporine administration were attributed to the inhibition of intestinal CYP3A4 rather than P-gp. Rifampin, an inducer of CYP3As after multiple dosing, unexpectedly showed decreased MAT and Tmax values, which cannot be completely explained. In contrast, grapefruit juice, an intestinal CYP3A/P-gp/OATP inhibitor, significantly increased MAT and Tmax values for ticagrelor, which may be due to activation of P-gp or inhibition of OATPs expressed in intestine.ConclusionsThis study provides new insight into the role of transporter pathways in ticagrelor intestinal absorption by examining potential MAT and Tmax changes mediated by drug-drug interactions.

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الوصول الحر: https://escholarship.org/uc/item/824025xcTest

المؤلفون: Okochi, Hideaki, Louie, Alexander, Phung, Nhi, Zhang, Kevin, Tallerico, Regina M, Kuncze, Karen, Spinelli, Matthew A, Koss, Catherine A, Benet, Leslie Z, Gandhi, Monica

المصدر: Drug Testing and Analysis. 13(7)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, HIV/AIDS, Infectious Diseases, Sexually Transmitted Infections, Adenine, Anti-HIV Agents, Chromatography, High Pressure Liquid, Cobicistat, Dose-Response Relationship, Drug, Emtricitabine, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination, HIV Infections, Hair, Hair Analysis, Humans, Ritonavir, Tandem Mass Spectrometry, Tenofovir, Tissue Distribution, emtricitabine, hair concentrations, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, Analytical Chemistry, Biochemistry and Cell Biology, Pharmacology and pharmaceutical sciences

الوصف: Tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) is the backbone for both human immunodeficiency virus (HIV) treatment and pre-exposure prophylaxis (PrEP) worldwide. Tenofovir alafenamide (TAF) with FTC is increasingly used in HIV treatment and was recently approved for PrEP among men-who-have-sex-with-men. TDF and TAF are both metabolized into tenofovir (TFV). Antiretrovirals in plasma are taken up into hair over time, with hair levels providing a long-term measure of adherence. Here, we report a simple, robust, highly sensitive, and validated high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS)-based analytical method for analyzing TFV and FTC from individuals on either TDF/FTC or TAF/FTC in small hair samples. TFV/FTC are extracted from ~5 mg hair and separated on a column using a gradient elution. The lower quantification limits are 0.00200 (TFV) and 0.0200 (FTC) ng/mg hair; the assay is linear up to 0.400 (TFV) and 4.00 (FTC) ng/mg hair. The intra-day and inter-day coefficients of variance (CVs) are 5.39-12.6% and 6.40-13.5% for TFV and 0.571-2.45% and 2.45-5.16% for FTC. TFV concentrations from participants on TDF/FTC-based regimens with undetectable plasma HIV RNA were 0.0525 ± 0.0295 ng/mg, whereas those from individuals on TAF/FTC-based regimens were 0.0426 ± 0.0246 ng/mg. Despite the dose of TFV in TDF being 10 times that of TAF, hair concentrations of TFV were not significantly different for those on TDF versus TAF regimens. Pharmacological enhancers (ritonavir and cobicistat) did not boost TFV concentrations in hair. In summary, we developed and validated a sensitive analytical method to analyze TFV and FTC in hair and found that hair concentrations of TFV were essentially equivalent among those on TDF and TAF.

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الوصول الحر: https://escholarship.org/uc/item/43g8c7x5Test
https://escholarship.org/content/qt43g8c7x5/qt43g8c7x5.pdfTest