Antihypertensive Agents

Exposure-response information plays an important role in the development of drugs for the treatment of many cardiovascular illnesses, including hypertension. The surrogate markers measured as response for antihypertensive drugs include changes in blood pressure. Exposure-response data are usually collected in Phase II trials that are double-blind, randomized, placebo-controlled, and parallel-group in design. In the development of antihypertensive drugs such as the angiotensin-converting enzyme...

Study Participants and Control Group

Study participants may include mother-infant pairs or lactating women alone. Optimally, the study participants would be representative of the typical patient population for the drug to be studied. Maternal factors with significant potential to affect lactation (e.g., weight, gravity, parity, stage of lactation, postpartum status, episodes and duration of previous breastfeeding) or the PK of a drug to be studied (e.g., diet, smoking, alcohol intake, concomitant medications, ethnicity, other...

S

Note OATP organic anion-transporting polypeptide OAT organic anion transporter OCT organic cation transporter. Human OATs play important roles especially in the elimination of a variety of endogenous substances, drugs, and their metabolites from the liver and kidney. So far, five OAT members have been identified 39-43 . Structurally, OATs are membrane proteins with 12 putative membrane-spanning domains and function as sodium-independent exchangers or facilitators 44 . OATs are multispecific...

References

Medicinal products for human use Guidelines 3CC3A Pharmacokinetic studies in man. Available 2. FDA. Guidance for industry Population pharmacokinetics. 1999. 3. Rowland, M. Tozer, T.N. Clinical Pharmacokinetics. Concepts and Applications, 3rd Ed. Philadelphia Williams & Wilkins, 1995. 4. Power, B.M. Forbes, A.M. Heerden P.V. Ilett, K.F. Pharmacokinetics of Drugs Used in Critically 111 Adults. Clin. Pharmacokinet. 1998, 34, 25-56. 5. Cheymol, G. Effects of Obesity on Pharmacokinetics...

Biotransformationbased Pharmacokinetic Interactions

A number of prominent drug products have been withdrawn in recent years because of severe drug-drug interactions and despite preclinical safety assessment. Mibefradil, a novel calcium antagonist, for example, was approved in Switzerland in 1996 and was also launched in the U.S. in 1997 as well as in several other European countries. Shortly following its launch as an antihypertensive and antianginal agent, reports about serious pharmacokinetic and pharmacodynamic interactions with other drugs...

Effects of Impaired Liver Function on Pharmacokinetic Parameters

Presently, hepatic extraction and clearance are usually assumed to proceed according to the well-stirred model 3 . In this model, the liver is assumed to work as a well-stirred compartment where the drug and enzymes are evenly distributed. When predicting how the pharmacokinetics is affected by altered physiological conditions, it should be remembered that a simplified model of the liver is used. The hepatic blood-flow may be decreased in cirrhosis but predictions of the effect on...

Extrapolations from Cirrhosis to Other Liver Diseases

Although liver disease is a heterogeneous group of diseases, the pharmacokinetics of a new drug is often limited to studies in cirrhotic patients. As this is the most common liver disease, this is of benefit for the FIGURE 1 AUC of an antiinflammatory drug in patients with different degrees of liver function. FIGURE 1 AUC of an antiinflammatory drug in patients with different degrees of liver function. majority of patients. However, extrapolating to patients with other liver diseases may be...

Stroke and Cerebrovascular Diseases

Stroke and associated cerebrovascular disorders are a major public health concern and a leading cause of death in the United States and other countries 22 . Stroke is indicated by an abrupt manifestation of neurologic deficits secondary to an ischemic or hemorrhagic insult to a region of the brain. There are various candidate drugs for acute stroke, such as antithrombotic agents, anticoagulants, thrombolytic agents, and neuroprotectants. Thrombolytic agents, such as tissue plasminogen activator...

Gastric Acid Related Disorders

Gastric acid-related disorders include heartburn, gastric and duodenal ulcers, symptomatic gastroesophageal reflux disease (GERD), erosive esophagitis, and pathological hypersecretory conditions such as ZollingerEllison syndrome. The conventional treatment for these acid-related disorders is the suppression of gastric acid secretion by H2 blockers and proton pump inhibitors (PPIs). PPIs are currently the drugs of choice in the management of acid-related disorders. The use of antisecretory...

Pharmacokinetics in Patients with Impaired Renal Function Study Design Data Analysis and Impact on Dosing and Labeling

This guidance is intended for sponsors who, during the investigational phase of drug development, plan to conduct studies to assess the influence of renal impairment on the PK of an investigational drug. Topics covered in this guidance are deciding whether to conduct a study in patients with impaired renal function (when studies may be important, when studies may not be important) study design (basic full study design, reduced staged study design, population PK studies, effect of dialysis on...

Complex Drug Substances

There are many drug substances that may fit into the category of Complex Drug Substances. These include many proteins, peptides, botanicals, synthetic hormones, biotechnology products, and complex mixtures. For most of these drugs, the most difficult problem is to demonstrate FIGURE 5 Unlike endogenous substances such as hormones which are synthesized by the body, endogenous potassium arises solely from dietary sources. The body transports potassium from place to place and excretes excess...