The Role of Pharmacokinetics and Pharmacodynamics in Phosphodiesterase-5 Inhibitor Therapy
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International Journal of Impotence Research (2007) 19, 253–264 & 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00 www.nature.com/ijir REVIEW The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy N Mehrotra1, M Gupta2, A Kovar3 and B Meibohm1 1Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA; 2Clinical Pharmacology and Therapeutics Division, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA and 3Clinical Pharmacology and Pharmacokinetics, Merck KGaA, Darmstadt, Germany Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) relationships and their relevance to dose selection and applied pharmacotherapy. It is followed by a detailed comparative discussion on the pharmacokinetics and exposure–response relationship of the currently available PDE5 inhibitors, including known drug–drug interactions and dosage adjustments in special populations. The review is aimed at providing a critical assessment of the pharmacokinetics of PDE5 inhibitors, which may assist clinicians in tailoring drug and/or treatment regimens to the unique needs of each individual patient with erectile dysfunction. International Journal of Impotence Research (2007) 19, 253–264. doi:10.1038/sj.ijir.3901522; published online 21 September 2006 Keywords: phosphodiesterase-5; erectile dysfunction; pharmacotherapy; pharmacokinetics; phar- macodynamics Introduction therapeutic recommendations, but have also the opportunity to individualize therapy with PDE5 Pharmacotherapy with the three Food and Drug inhibitors to meet the medical and lifestyle needs Administration (FDA)-approved phosphodiesterase of the individual patient. Knowledge of the PK (PDE)5 inhibitors, sildenafil, vardenafil, and tadala- and PD properties of these compounds is im- fil, is currently the mainstay of treatment for erectile perative for understanding their clinical pharma- dysfunction (ED). These three PDE5 inhibitors share cology and provides the basis for a rationale, the same mechanism of action, but there are noted scientifically based pharmacotherapy. Thus, the pharmacodynamic (PD) differences between the present article reviews basic principles in clinical compounds regarding their selectivity and specifi- pharmacology with focus on pharmacokinetics city for PDE inhibition with consequences pre- and exposure–response relationships and sub- dominantly for their safety profile, as well as sequently discusses the relevance of these concepts biopharmaceutic and pharmacokinetic (PK) dispa- for the pharmacotherapy with currently available rities that largely affect their efficacy profiles. As PDE5 inhibitors. more PDE5 inhibitors become available, clinicians are increasingly being asked to differentiate among these alternative treatment options in their The role of clinical pharmacology in pharmacotherapy The rational use of drugs and the design of effective Correspondence: Dr B Meibohm, Department of Pharma- dosage regimens are facilitated by the appreciation ceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 874 Union Avenue, of the central paradigm of clinical pharmacology Suite 5p Memphis, TN 38163, USA. that there is a defined relationship between the E-mail: [email protected] administered dose of a drug, the resulting drug Received 15 June 2006; revised 29 July 2006; accepted 22 concentrations in various body fluids and tissues, August 2006; published online 21 September 2006 and the intensity of pharmacologic effects caused Pharmacokinetics and pharmacodynamics in PD-5 inhibitor therapy B Meibohm et al 254 by these concentrations. In clinical practice, this across the gastrointestinal mucosa are their physico- relationship between the concentration (exposure) chemical properties, including lipophilicity, solubi- and its beneficial and/or toxic effects (response), lity, polarity and ionization status. Physiological however, is not always simple, but may be obscured characteristics such as gastric emptying time and by intermediate processes that may lead to a pH conditions throughout the gastrointestinal tract temporal dissociation between the time courses of (GIT) also affect oral absorption. The presence of concentration and effects, or by imprecise outcome food, other drugs and certain digestive disorders may measures that are unable to delineate subtle differ- further alter the rate and extent of absorption. For ence in response within a relatively high level of example, high-fiber food may bind drug substance measurement noise.1 and prevent it from being absorbed. On the contrary, These dose–exposure–response relationships and bioavailability of poorly soluble, lipophilic drugs thus the dose of a drug required to achieve a certain may be enhanced when taken with fatty meals.3 effect are determined by the drug’s PK and PD Drug that is absorbed in the GIT is first transported properties. Pharmacokinetics describes the time via the portal vein to the capillary bed of the liver course of the concentration of a drug in a body before it reaches the systemic circulation. Thus, the fluid, preferably plasma or blood that results from liver is the first major elimination organ which the administration of a certain dosage regimen. In any drug encounters following oral administration. simple words, pharmacokinetics is ‘what the body This phenomenon is referred to as first-pass meta- does to the drug’. Pharmacodynamics describes the bolism. The hepatic extraction ratio is the fraction intensity of a drug effect in relation to its concentra- of a dose that is removed during the first passage tion in a body fluid, usually at the site of drug of the liver and does not reach the systemic cir- action. It can be simplified to ‘what the drug does culation. Apart from liver, orally administered drug to the body’.2 may also be metabolized by enzymes expressed The plasma concentration–time profile resulting in the gut wall or may be degraded in the lumen from drug administration is determined by PK of the GIT before it ever reaches the systemic parameters and the administered dosage regimen. circulation. Whereas the PK parameters are characteristic for the disposition or handling of a drug in a specific patient and can thus usually not be modulated during pharmacotherapy, the dosage regimen is the Distribution clinician’s tool to affect drug concentrations for Once drug has entered the vascular system, it maximum therapeutic benefit.3 becomes distributed throughout the various tissues Generally, a drug is introduced (administration) and body fluids. However, most drugs do not into the body at a location remote from the intended distribute uniformly throughout the body. This effect site. Following uptake into the systemic heterogeneous distribution is based on tissue- circulation (absorption), it is transported to and specific differences in rate and extent of drug taken up into various organs and tissues including uptake, including blood flow, that is, the delivery its target sites (distribution). Some drugs are chemi- of drug to the tissues, the ability for the drug to cross cally altered (metabolism) by the body before they biomembranes, partitioning into the tissue, and drug perform their action (e.g. activation of so-called pro- binding to tissue elements including binding to drugs); others are metabolized afterwards; and still proteins and other macromolecules. For example, others are not metabolized at all. Finally, the drug hydrophilic drugs tend to stay within the blood and and its metabolites are removed from the body the interstitial fluid, whereas lipophilic drugs tend (excretion). to concentrate in tissues with high fat content. Many drugs interact with plasma or tissue proteins or with other endogenous macromolecules to form drug–macromolecule complexes generally General PK principles referred to as protein binding of a drug. Protein binding is a major determinant for drug disposition Absorption and efficacy. Drug bound to protein is not pharma- As the overwhelming majority of drugs are intended cologically active, is for most drugs not accessible to be administered orally, the ability of a compound for drug-metabolizing enzymes and excretion pro- to achieve activity after the administration via the cesses, and is not able to pass biomembranes. In oral route, that is a good bioavailability, is impera- contrast, free drug is relevant for the pharmacologi- tive. Absorption in vivo is a complex phenomenon, cal effects as it can interact with its target structure, involving several possible mechanisms, although for example, a receptor or ion channel, can be passive diffusion has been identified as the pre- metabolized and excreted, and may pass biomem- dominant mechanism of gastrointestinal absorption branes by passive diffusion. Thus, only free drug for most commercial drugs.4 The most relevant concentrations are ultimately relevant to pharma- factors that regulate the passive diffusion of drugs cotherapy.5 International Journal of Impotence Research Pharmacokinetics and pharmacodynamics in PD-5 inhibitor therapy B Meibohm et al 255 Metabolism Excretion Elimination of drugs occurs by metabolism and Excretion of drug or drug metabolites from