Pharmacokinetic Considerations in Dose Regimen Selection

The emergence of pharmacokinetics as a discipline was driven by an increasing awareness of concentration – response relationships. At molecular level, pharmacokinetics is controlled in part by the drug metabolizing enzymes whose activities typically show large inter-individual differences in pharmacokinetic parameters. This results in the variability of pharmacodynamics of the drug.

Introduction
Before the concept of pharmacokinetics, drugs were administered simply on an experimental basis. The dose, the interval between doses, and the route of administration were selected by the clinical investigator. The therapeutic effect and toxicity were monitored on the patients. In case of any undesirable effect, the dosage regimen was adjusted empirically until an optimum effect was obtained i.e. a maximal therapeutic effect and minimal toxicity. Finally, after substantial experimentations on a large number of patients, dosage regimens were established. But, this approach did not answer many questions. For example, why some drugs have to be given once while others twice or thrice in a day? Why one route is more effective than other route for a drug?
To answer some of these questions, it is essential to know what happens to the drug once it is administered. In vitro and in vivo experiments demonstrate that the response is a function of the drug at the site of action. Most of the time, it is not feasible to measure drug concentration at the site of action and hence the drug concentration is determined in blood / plasma. This is based on the premise that the concentration of the drug in the systemic circulation is at equilibrium with the concentration of drug at the site of action. In a report on the workshop on the Qualitative and Quantitative Comparability of Humans and Animal Developmental Neuro-toxicity, Francis, Kimmel, and Rees (1990)1 stated that ?Comparisons of administered doses (resulting in similar effect levels) revealed a wide range of differences across species. On the other hand, comparisons across species using internal measurements of dose (e.g., blood or brain levels) showed a remarkable correlation (generally, a 1 to 2 fold difference).? There is plenty of human and animal data suggesting that pharmacological activity, in vivo, generally correlates better with the concentration of a drug in blood or in some other biophase than with the absolute dose administered. The drug's therapeutic response and toxicity have been found to have better correlation with the plasma concentration than with dose or any other parameter. From these observations it could be suggested that the optimum therapeutic effect can be achieved by maintaining an adequate concentration of drug at the site of action. However, it is known that very rarely any drug is placed at the site of action. Rather most of the drugs are given orally and they act on desired organ of the body. When a drug is administered, initially the rate at which it enters the body is more than the rate at which it is eliminated from the body and hence the concentration of drug increases in the blood and tissues and gives the desired therapeutic effect and some times even adverse effects. In due course of time, the rate at which it is eliminated from the body is more than the rate at which it enters the body and as a result, concentrations decreases and effects also diminish. Hence to have optimal effects of drug, it is essential to know about the absorption, distribution, metabolism and excretion of the drug as well as the rates of these processes in individuals.

{mospagebreak title=Significance of pharmacokinetics }

• 50% of hypertensive patients fail to respond to each of the six key groups of drugs
• African – Caribbean respond better to diuretics and ca2+ channel blockers and less well to ACE inhibitors
• ACE variation due to genotype
• There are many variations in structure of Ca2+ channel and hence genotypic variations
• 20% of patients develop resistance to corticosteroid treatment in Asthma, due to genetically determined down regulation of beta-2 receptors
• 25% of patients show poor response to anti-leukotriene treatment, due to mutation in promoter sequence
• Link between apolipoprotein E-4 (APOE4) and Alzheimer?s disease: Three alleles of APOE4 determine onset. APOE4 people get Alzheimer?s disease earlier and do not respond to cholinesterase inhibitors
Serious side effect of Seldane (anti-allergic, Terfenadine) with erythromycin only with particular isoenzyme of CYP
• Prozac with poor metabolizer patients shows increased plasma concentration of the drug
• Isoniazied do not get absorbed by ultra metabolizers.

These differences in drug responses have been explained by genetic differences which determine the disposition of a given drug in an individual. Drug disposition as mentioned earlier is determined by rate kinetics of drug absorption, distribution, metabolism and elimination. Therefore, genetic differences determining various physiological processes affect the plasma levels of drugs eventually determining the differences in drug response by an individual.

{mospagebreak title=Drug metabolizing enzymes }

There is no doubt that advances in molecular biology, molecular genetics, genomics and in the associated technologies have had a huge impact on our knowledge of drug action. The interface between these rapidly developing areas and the discovery, development and use of new medicines are being recognized as new discipline termed pharmacogenetics. Pharmacogenetics describes the interactions between the characteristics of drugs and individuals, which might be related to inborn traits to some extent. Pharmacogenetics was introduced into the medical literature by Motulsky and Vogel and was defined as the study in animal species of genetically determined variations that are revealed by the effects of drugs. Much progress was made in 1950s and in 1960s it was established that one of the most common primary biotransformations which happen to drugs (and other foreign compounds) in the mammalian body is the addition of oxygen i.e. hydroxylation. This process was found to vary greatly between individuals and twin studies indicated that it was under genetic control. In 1970s the genetic polymorphisms of the hydroxylation of sparteine and debrisoquine were described and later were found to be due to the same genes.
Now it is well known that CYPs are principal catalysts involved in the disposition of drugs and other xenobiotics. Out of many physiological processes mentioned earlier, genetic differences in drug metabolism have been studied in detail. Cytochrome P-450, comprising the major enzyme system is involved with metabolism of all xenobiotics. This enzyme complex located in liver has a wide range of activities acting upon all foreign molecules found in the body and the metabolic capacity of this enzyme system is not equal in all members of a population. Not surprisingly it has been observed that there is a wide inter-individual variation in the rates of metabolism of several drug groups within human population. As a result, the metabolic conversion and excretion rate of drugs vary between individuals, from extremely slow to ultra fast. The 10,000-fold differences in metabolizing capacity have been observed in the literature5. We have also observed that drugs like pantoprazole and omeprazole exhibited 5 to 7 - fold differences in pharmacokinetic parameter area under the curve (AUC) and 2 to 3 fold differences in pharmacokinetic parameter maximum concentration (Cmax)7, and drugs like paroxetine exhibited 60 -fold differences in AUC and 20 -fold differences in Cmax6. Literature indicates that about 3% of Caucasians are classified as poor metabolizers (PMs), however, a higher proportion (about 15%) has been reported as PMs in people of Asian origin7. In another study, the percentage of PMs was shown to be 12% in North Indians. However, in our pantaprazole pharmacokinetic study, 31% of the subjects showed comparatively high concentrations of pantaprazole, an indication of PM population. Literature indicates that proton pump inhibitors (pantaprazole and omeprazole) have a broadly similar mechanism of action and are extensively metabolized in the liver via cytochromes CYP2C19 and CYP3A48. Similarly antidepressants (paroxetine and fluoxetine) are extensively metabolized via cytochromes CYP2D6 and glimeperide via cytochrome CYP2C9. In human, the most important CYPs from the point of view of drug metabolism are CYP1A29,10, CYP3A411,12, CYP2B6, CYP2C913-17, CYP2C1918, CYP2D65,19-27 and CYP2E128. CYPs typically show large inter-individual differences in activity that lead to differences in drug response. Further complications will arise because of induction, inhibition and activation of CYP isoenzymes due to other drugs and physiological conditions.

{mospagebreak title= Tool to approach the problem of inter-iIndividual variability}

Collectively several hundred genes and their alleles and protein products determine the over all drug disposition in an individual. In recently evolved field of pharmacogenomics, attempts are made to determine and quantify these genetic variations and use them in predicting drug disposition by an individual. Genotyping techniques for Cytochrome P450 enzymes can be used to predict one’s disposition to a given class of drug without doing any evaluation of pharmacokinetic parameters, which can subsequently be used for deciding choice of drug and its dose. By the use of genotyping methods individual can be classified as poor metabolizer (PMs), intermediate metabolizer (IMs), extensive metabolizer (EMs) and ultra rapid metabolizer (UMs) for a given group of drugs. The PM subjects will develop higher serum drug concentrations in comparison with EMs, resulting in increased risk of suffering from concentration dependent side effects when subjected to standard recommended doses. UM subjects, on the other hand, will not reach therapeutic serum concentration upon treatment with standard doses. They may fail to respond to treatment. Moreover when the parent compound is a prodrug, which requires bioactivation by the enzyme to the active drug, the effects of polymorphism can be quite complex in PMs and UMs. Thus these individual differences in drug disposition could be compensated for in part by dose adjustment according to the metabolic capacity, determination of drug metabolism genotypes prior to drug therapy. PM and UM subjects can thus be identified and dosage could be tailored to the individual patient in order to reach therapeutic levels of drug in plasma from the beginning. This can help to avoid adverse reaction or therapeutic failure. It can be recommended as predictive-cum-complementary to plasma concentration determination when aberrant metabolic capacity (poor or ultra rapid) of CYPs substrates is suspected.

{mospagebreak title= Current issues and future challenge}

If we agree that blood level of drug / metabolite is a reliable index of efficacy and if we also agree that inter-individual variability can be as high as 100 fold as reported in our clinical studies, then the question is should we consider achieving similar drug levels in blood in all patients as our therapeutic objective.

{mospagebreak title= Conclusion}

{mospagebreak title= References}

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{mospagebreak title= About the author}

Dr. Shubha Rani received her postgraduate and Ph.D. degree in Statistics from Indian Institute of Technology, Kanpur. She is associated with the PERD Centre for last 10 years. Before joining The PERD Centre, she worked as a lecturer at P.P.N. College, Kanpur and L.D. Arts College, Ahmedabad for 2.5 years. Presently, she is working as a senior research scientist in the Pharmacokinetics & Biostatistics division of B.V. Patel PERD Centre, Ahmedabad.
At PERD Centre, her work focuses on pharmacokinetics, biostatistics and biopharmaceutics, such as (i) Pharmacokinetic modeling to study the behavior of pharmaceutical formulations; (ii) Statistical methods used in Bioequivalence of formulations; (iii) Study the performance of several metrics of rate and extent of absorption using computer simulation; (iv) Statistical approaches for sparse and limited sampling in toxicokinetics and in experiments with destructive measurements tecqniques; (v) Utilizing pharmacokinetic principles in the design of controlled or sustained release formulations using simulation; (vi) Designing the experiment and statistical analysis of data (for example clinical trials, comparison of different diagnostics, etc.).
She has published many research papers in national and international journals. Two of her publications have been awarded with best publications in the field of Pharmacology, Drug Metabolism and Pharmacokinetics from IDMA and IPA.
She is a faculty of Educational Programmes of PERD Centre, both Ph.D. and continuing education. She has also given invited lectures in various institutes addressing academicians as well as persons from industries. She provides consultancy services to pharmaceutical companies. She is Life member of (i) Indian statistical Association; (ii) Gujarat Statistical Association; (iii) Indian Society for Medical Statistics; and (iv) Indian Pharmaceutical Association. She is also a member of expert committee for drafting the Indian guidelines for conducting Bioavailability / Bioequivalence Studies on pharmaceutical products.

Contact information:

Tel: 079-27439375, Fax: 022-27450449, Email : perd@perdcentre.com, Shubha_rani@yahoo.com