Renal transporters in drug development Morrissey, Kari M; Stocker, Sophie L; Wittwer, Matthias B ...
Annual review of pharmacology and toxicology,
01/2013, Letnik:
53
Journal Article
Recenzirano
Odprti dostop
The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the ...proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described.
This white paper provides updated International Transporter Consortium (ITC) recommendations on transporters that are important in drug development following the 3rd ITC workshop. New additions ...include prospective evaluation of organic cation transporter 1 (OCT1) and retrospective evaluation of organic anion transporting polypeptide (OATP)2B1 because of their important roles in drug absorption, disposition, and effects. For the first time, the ITC underscores the importance of transporters involved in drug‐induced vitamin deficiency (THTR2) and those involved in the disposition of biomarkers of organ function (OAT2 and bile acid transporters).
Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the ...patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review.
Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation ...transporter 3 (OCT3, SLC22A3), expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice (P < 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice (0.27 versus 0.58, P < 0.001). Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice (12 versus 30% reduction, respectively, P < 0.05) along with its accumulation in skeletal muscle and adipose tissue (P < 0.05). Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3(-/-) mice. Additional analysis revealed that an OCT3 3' untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action.
The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping ...these onto the phases of adherence (initiation, implementation, and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty-three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g. unacceptability bias, apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a major advance in the fields of diabetology, nephrology, and cardiology. The cardiovascular and renal benefits of SGLT2 inhibitors are likely ...largely independent of their glycaemic effects, and this understanding is central to the use of these agents in the high-risk population of people with type 2 diabetes and chronic kidney disease. There are a number of potential safety issues associated with the use of SGLT2 inhibitors. These include the rare but serious risks of diabetic ketoacidosis and necrotising fasciitis of the perineum. The data regarding a possibly increased risk of lower limb amputation and fracture with SGLT2 inhibitor therapy are conflicting. This article aims to explore the potential safety issues associated with the use of SGLT2 inhibitors, with a particular focus on the safety of these drugs in people with type 2 diabetes and chronic kidney disease. We discuss strategies that clinicians can implement to minimise the risk of adverse effects including diabetic ketoacidosis and volume depletion. Risk mitigation strategies with respect to SGLT2 inhibitor-associated diabetic ketoacidosis are of particular importance during the current coronavirus disease 2019 (COVID-19) pandemic.
A change in pharmacokinetics can alter drug exposure and predispose the patient to either over- or underdosing, potentially resulting in adverse drug reactions or therapeutic failure. Kidney disease ...is characterized by multiple physiologic effects, which induce clinically significant changes in pharmacokinetics. These vary between individuals and may be quantitated in certain instances. An understanding of pharmacokinetic concepts is, therefore, important for a rational approach to the design of drug dosing regimens for the delivery of personalized medical care. Whether kidney disease is acute or chronic, drug clearance decreases and the volume of distribution may remain unchanged or increase. AKI is defined by dynamic changes in kidney function, which complicates attempts to accurately quantify drug clearance. In contrast, changes in drug clearance progress more slowly with CKD. In general, kidney replacement therapies increase drug clearance, but the extent to which this occurs depends on the modality used and its duration, the drug's properties, and the timing of drug administration. However, the changes in drug handling associated with kidney disease are not isolated to reduced kidney clearance and an appreciation of the scale of potential derangements is important. In most instances, the first dose administered in patients with kidney disease is the same as in patients with normal kidney function. However, in some cases, a higher (loading) initial dose is given to rapidly achieve therapeutic concentrations, followed by a lower maintenance dose, as is well described when prescribing anti-infectives to patients with sepsis and AKI. This review provides an overview of how pharmacokinetic principles can be applied to patients with kidney disease to personalize dosage regimens. Patients with kidney disease are a vulnerable population and the increasing prevalence of kidney disease means that these considerations are important for all prescribers.
Many important drugs exhibit substantial variability in pharmacokinetics and pharmacodynamics leading to a loss of the desired clinical outcomes or significant adverse effects. Forecasting drug ...exposures using pharmacometric models can improve individual target attainment when compared with conventional therapeutic drug monitoring (TDM). However, selecting the “correct” model for this model‐informed precision dosing (MIPD) is challenging. We derived and evaluated a model selection algorithm (MSA) and a model averaging algorithm (MAA), which automates model selection and finds the best model or combination of models for each patient using vancomycin as a case study, and implemented both algorithms in the MIPD software “TDMx.” The predictive performance (based on accuracy and precision) of the two algorithms was assessed in (i) a simulation study of six distinct populations and (ii) a clinical dataset of 180 patients undergoing TDM during vancomycin treatment and compared with the performance obtained using a single model. Throughout the six virtual populations the MSA and MAA (imprecision: 9.9–24.2%, inaccuracy: less than ± 8.2%) displayed more accurate predictions than the single models (imprecision: 8.9–51.1%; inaccuracy: up to 28.9%). In the clinical dataset, the predictive performance of the single models applying at least one plasma concentration varied substantially (imprecision: 28–62%, inaccuracy: −16 to 25%), whereas the MSA or MAA utilizing these models simultaneously resulted in unbiased and precise predictions (imprecision: 29% and 30%, inaccuracy: −5% and 0%, respectively). MSA and MAA approaches implemented in TDMx might thereby lower the burden of fit‐for‐purpose validation of individual models and streamline MIPD.
Aim
Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench‐top analysis. The cumbersome nature of these typically constrains studies to at ...most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours‐scale, time‐varying physiological processes. Given the recent advent of in vivo electrochemical aptamer‐based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time‐dense datasets to describe time‐varying pharmacokinetic models with good statistical significance.
Methods
We used seconds‐resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one‐ and two‐compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function.
Results
We found that a modified one‐compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two‐compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one‐compartment, time‐varying model was statistically preferred over the standard one‐compartment model for 80% of our datasets.
Conclusions
Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high‐time resolution EAB sensor measurements to identify such impacts.
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