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Open AccessArticle

Timing and Duration of Drug Exposure Affects Outcomes of a Drug-Nutrient Interaction During Ontogeny

by Binbing Ling, Caroline Aziz, Chris Wojnarowicz, Andrew Olkowski and

Jane Alcorn

Pharmaceutics 2010, 2(4), 321-338; https://doi.org/10.3390/pharmaceutics2040321 - 14 Oct 2010

Cited by 1 | Viewed by 7304

Abstract

Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence [...] Read more.

Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence of a significant drug-nutrient interaction (cefepime-carnitine) on the timing and duration of drug exposure relative to postnatal age. Rat pups were administered cefepime (5 mg/kg) twice daily subcutaneously according to different dosing schedules (postnatal day 1-4, 1-8, 8-11, 8-20, or 1-20). Cefepime significantly reduced serum and heart L-carnitine levels in postnatal day 1-4, 1-8 and 8-11 groups and caused severe degenerative changes in ventricular myocardium in these groups. Cefepime also altered the ontogeny of several key L-carnitine homeostasis pathways. The qualitative and quantitative changes in levels of hepatic γ-butyrobetaine hydroxylase mRNA and activity, hepatic trimethyllysine hydroxlase mRNA, intestinal organic cation/carnitine transporter (Octn) mRNA, and renal Octn2 mRNA depended on when during postnatal development the cefepime exposure occurred and duration of exposure. Despite lower levels of heart L-carnitine in earlier postnatal groups, levels of carnitine palmitoyltransferase mRNA and activity, heart Octn2 mRNA and ATP levels in all treatment groups remained unchanged with cefepime exposure. However, changes in other high energy phosphate substrates were noted and reductions in the phosphocreatine/ATP ratio were found in rat pups with normal serum L-carnitine levels. In summary, our data suggest a significant drug-nutrient transport interaction in developing neonates, the nature of which depends on the timing and duration of exposure relative to postnatal age. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics in Children: Establishing Differences from Adults)

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Factors and Mechanisms for Pharmacokinetic Differences between Pediatric Population and Adults

by

Eva Fernandez

, Raul Perez, Alfredo Hernandez, Pilar Tejada, Marta Arteta and

Jose T. Ramos

Pharmaceutics 2011, 3(1), 53-72; https://doi.org/10.3390/pharmaceutics3010053 - 07 Feb 2011

Cited by 208 | Viewed by 25306

Abstract

Many physiologic differences between children and adults may result in age-related changes in pharmacokinetics and pharmacodynamics. Factors such as gastric pH and emptying time, intestinal transit time, immaturity of secretion and activity of bile and pancreatic fluid among other factors determine the oral [...] Read more.

Many physiologic differences between children and adults may result in age-related changes in pharmacokinetics and pharmacodynamics. Factors such as gastric pH and emptying time, intestinal transit time, immaturity of secretion and activity of bile and pancreatic fluid among other factors determine the oral bioavailability of pediatric and adult populations. Anatomical, physiological and biochemical characteristics in children also affect the bioavailability of other routes of administration. Key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein binding and total body water. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I and phase II metabolic enzymes. Immaturity of glomerular filtration, renal tubular secretion and tubular reabsorption at birth and their maturation determine the different excretion of drugs in the pediatric population compared to adults. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics in Children: Establishing Differences from Adults)

Open AccessReview

The Pharmacokinetics and Pharmacodynamics of Iron Preparations

by

Peter Geisser

and Susanna Burckhardt

Pharmaceutics 2011, 3(1), 12-33; https://doi.org/10.3390/pharmaceutics3010012 - 04 Jan 2011

Cited by 163 | Viewed by 38873

Abstract

Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast [...] Read more.

Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast to conventional drugs, no drug-receptor interaction takes place. Notably, the process of erythropoiesis, i.e., formation of new erythrocytes, takes 3−4 weeks. Accordingly, serum iron concentration and area under the curve (AUC) are clinically irrelevant for assessing iron utilization. Iron can be administered intravenously in the form of polynuclear iron(III)-hydroxide complexes with carbohydrate ligands or orally as iron(II) (ferrous) salts or iron(III) (ferric) complexes. Several approaches have been employed to study the pharmacodynamics of iron after oral administration. Quantification of iron uptake from radiolabeled preparations by the whole body or the erythrocytes is optimal, but alternatively total iron transfer can be calculated based on known elimination rates and the intrinsic reactivity of individual preparations. Degradation kinetics, and thus the safety, of parenteral iron preparations are directly related to the molecular weight and the stability of the complex. High oral iron doses or rapid release of iron from intravenous iron preparations can saturate the iron transport system, resulting in oxidative stress with adverse clinical and subclinical consequences. Appropriate pharmacokinetics and pharmacodynamics analyses will greatly assist our understanding of the likely contribution of novel preparations to the management of anemia. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics in Children: Establishing Differences from Adults)

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Open AccessReview

Pediatric Dosing and Body Size in Biotherapeutics

by

Rong Shi

and

Hartmut Derendorf

Pharmaceutics 2010, 2(4), 389-418; https://doi.org/10.3390/pharmaceutics2040389 - 16 Dec 2010

Cited by 27 | Viewed by 11404

Abstract

Although pediatric doses for biotherapeutics are often based on patients' body weight (mg/kg) or body surface area (mg/m²), linear body size dose adjustment is highly empirical. Growth and maturity are also important factors that affect the absorption, distribution, metabolism and excretion [...] Read more.

Although pediatric doses for biotherapeutics are often based on patients' body weight (mg/kg) or body surface area (mg/m²), linear body size dose adjustment is highly empirical. Growth and maturity are also important factors that affect the absorption, distribution, metabolism and excretion (ADME) of biologics in pediatrics. The complexity of the factors involved in pediatric pharmacokinetics lends to the reconsideration of body size based dose adjustment. A proper dosing adjustment for pediatrics should also provide less intersubject variability in the pharmacokinetics and/or pharmacodynamics of the product compared with no dose adjustment. Biological proteins and peptides generally share the same pharmacokinetic principle with small molecules, but the underlying mechanism can be very different. Here, pediatric and adult pharmacokinetic parameters are compared and summarized for selected biotherapeutics. The effect of body size on the pediatric pharmacokinetics for these biological products is discussed in the current review. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics in Children: Establishing Differences from Adults)

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Open AccessReview

Drug Development for Pediatric Populations: Regulatory Aspects

by

Jochen Zisowsky

,

Andreas Krause

and

Jasper Dingemanse

Pharmaceutics 2010, 2(4), 364-388; https://doi.org/10.3390/pharmaceutics2040364 - 29 Nov 2010

Cited by 71 | Viewed by 15049

Abstract

Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in [...] Read more.

Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in particular, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework. This review summarizes the regulatory requirements and strategies for pediatric drug development from an industry perspective. It covers pediatric study planning and conduct, considerations for first dose in children, appropriate sampling strategies, and different methods for data generation and analysis to generate knowledge about the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug in children. The role of Modeling and Simulation (M&S) in pediatrics is highlighted—including the regulatory basis—and examples of the use of M&S are illustrated to support pediatric drug development. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics in Children: Establishing Differences from Adults)

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Open AccessReview

Tacrolimus Pharmacokinetic and Pharmacogenomic Differences between Adults and Pediatric Solid Organ Transplant Recipients

by Kwaku Marfo, Jerry Altshuler and

Amy Lu

Pharmaceutics 2010, 2(3), 291-299; https://doi.org/10.3390/pharmaceutics2030291 - 09 Sep 2010

Cited by 25 | Viewed by 8524

Abstract

Tacrolimus is a calcineurin inhibitor immunosuppressant that has seen considerable use in both adult and pediatric solid organ transplant recipients. Though there is much pharmacokinetic data available for tacrolimus in the adult population, the literature available for children is limited. Furthermore, very little [...] Read more.

Tacrolimus is a calcineurin inhibitor immunosuppressant that has seen considerable use in both adult and pediatric solid organ transplant recipients. Though there is much pharmacokinetic data available for tacrolimus in the adult population, the literature available for children is limited. Furthermore, very little is known about the pharmacogenomic differences in the two patient groups. Based on what information is currently available, clinically significant differences may exist between the two populations in terms of absorption, distribution, metabolism and elimination. In addition, inherent physiological differences exist in the young child including: less effective plasma binding proteins, altered expression of intestinal P-glycoprotein, and increased expression of phase 1 metabolizing enzymes, therefore one would expect to see clinically significant differences when administering tacrolimus to a child. This paper examines available literature in an attempt to summarize the potential pharmacokinetic and pharmacogenomic variability that exists between the two populations. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics in Children: Establishing Differences from Adults)

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