Cellular Therapy (Ernst Schering Foundation Symposium Proceedings)

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Please log in to edit your catalogs. Discontinued Series. Although this series no longer publishes new content, the published titles listed below may be still available on-line e. About this series Titles in this series Subseries of this series. Your Shopping Cart. Subtotal: 0. To cart. Such predictions will be time-dependent as new informa- tion and data are obtained during the drug-development process Rolan Biomarkers used as part of internal company decision making in early development require validation to a level consistent with their intended application.

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Different levels of validation exist at different develop- ment phases. It should be made a mandatory deliverable of the lead optimization stage. During the late clinical phases, the principles of good laboratory practice GLP requirements are useful standards for validation of biomarkers Colburn The standards for linking a biomarker to a clinical out- come are higher for ordinary approvals than for accelerated approvals.

Approval may be subject to the requirement that the sponsor conduct appropriate postap- proval studies to validate the surrogate endpoint. Changes in biomarkers typically exhibit a time course that is different from changes in clinical endpoints and often are more directly related to the time course of plasma drug concentrations, possibly with a measurable delay.

In some cases, these relationships can also indicate how soon titration should oc- cur and can provide insight into potential adverse effects. Biomarkers can also be useful during the drug discovery and development stage, where they can help link preclinical and early clinical exposure—response rela- tionships and better establish dose ranges for clinical testing Guidance for Industry Examples for using biomarkers in drug discovery and preclinical development are summarized in Table 5.

The quantity of evidence needed to support effectiveness, other than two adequate and well-controlled clinical trials, is discussed in Section II of the FDA Guidance for In- dustry Food and Drug Administration. Center for Drug Evaluation and Research The Applications of Biomarkers Biomarker in drug discovery Aim To identify a suitable target Example Association of elevated serum cholesterol levels with an increased incidence of coronary heart disease provides an underlying rational search for developing new compounds that lower cholesterol B.

Biomarker in preclinical development pharmacology Aim To identify pharmacological activity Example Association of blood pressure-lowering effect in suitable animal models with likelihood of having the intended therapeutic activity in patients C. Biomarker in preclinical development toxicology Aim To identify potential risks Example Drugs found to prolong the QT-interval in animals may warn of potential cardiovascular risk in subsequent clinical studies.

Biomarkers are perhaps most useful in early phase of clinical de- velopment, when measurement of clinical endpoints may be too time- consuming or cumbersome to provide timely proof of concept POC or dose-ranging information. The use of changes in biochemical or clinical biomarkers in early clinical drug development to establish POC is only as good as the theoretical foundation for the biochemical or clinical biomarker. Gor- don et al. The extent of inhibition correlated very well with the individual plasma concentrations.

Therefore, the effects of BAY on the vasoactive hormones were determined in parallel in order to allow POM and enable an early decision point for further de- velopment. In this crossover, double-blinded placebo-controlled study, BAY was administered to healthy volunteers in a dose range of 10— mg p. Only the highest dosage group of mg showed a slight decrease in blood pressure, which was accompanied by a compensatory increase in heart rate Wensing et al. Cysteinyl-leukotrienes appear to be of major importance in the pathophysiology of asthma.

Inhalation of cysteinyl-leukotrienes leads to bronchoconstriction and can induce bronchial hyperreactivity both in healthy volunteers and the asthmatic Smith et al. Using a double-blind, placebo-controlled, crossover design, volunteers received , , and mg of BAY x as tablet or 2 and 4 mg of BAY x aerosol, respectively Bronchoprovocation with nebulized LTD4 was performed at different time points after drug administration. Eight hours p. For both doses, only three out of six volunteers showed a protective effect against LTD4 -induced bronchoconstriction 8 h after drug administration Wensing et al.

For the different doses tested, a clear dose—response relationship was observed. When added to whole blood, BAY inhibited the oxygen radi- cal formation with an IC50 value of 0. I studies of BAY The oxygen radical formation in neutrophils after ex vivo stimulation with f-MLP decreased in a dose-dependent manner with single oral dosages of BAY to healthy volunteers. After multiple oral dosing with 7. When developing truly innovative therapies for such conditions, a model, even though imperfectly validated, can be used to support the decision to commit to a major clinical trial program and to assist with dose selection.

Pupil reaction can be determined by light-evoked pupillography LEP to quantify pharmaco- dynamic effects on the autonomic and central nervous system. Therefore, pupillography should be a standard biomarker for effects of 5-HT1A compounds. There is an acute need for effective biomarkers in every phase of research and development, from discovery to preclini- cal studies up to clinical trials in the early and late stages of development. Success factors of biomarker development are: — Team work involving individuals with diverse backgrounds — Requisite core competencies — Activities and processes aligned with existing discovery, preclinical, and early clinical development milestones — Appropriate infrastructure, e.

Pharm Res — Food and Drug Administration Center for Drug Evaluation and Research, Cen- ter for Biologics Evaluation and Research Guidance for industry: providing clinical evidence of effectiveness for human drug and biological products. Exposure-response relationships — study design, data analysis, and regulatory applications. Circulation —15 van den Haak MA et al Industry success rates — including a focus on decision outcomes.

Kuhlmann J Alternative strategies in drug development: clinical pharma- cological aspects. J Clin Pharmacol — Rader DJ High-density lipoproteins as an emerging therapeutic target for atherosclerosis. JAMA — Rolan P The contribution of clinical pharmacology surrogates and models to drug development — a critical appraisal. Clin Pharmacol Ther — Schuehly U et al Randomized, double-blind, placebo-controlled, parallel group study on the safety, tolerability, pharmacodynamics and pharmacoki- netics of BAY after oral administration of increasing single doses to healthy male subjects.

Internal report no. Wensing G, Heinig R, Kuhlmann J Pharmacodynamics and pharmacoki- netics of BAY x aerosol, a new and selective receptor antagonist of cysteinyl-leukotrienes, in normal volunteers. Ex- ample of an angiotensin-II antagonist abstract. This approach supports quantitative integration of informa- tion across different species and throughout the clinical phases I—III.

If it is also involved in causal pathways in the pathophysiology of the disease POD , it may become a surrogate marker SM. SMs allow prediction of clinical outcomes for different dosing regimens of drug candidates and patient individualization of treatment in clinical practice.

Appropriate evaluation of BMs by mechanistic, epidemiological, and clinical pharmacology studies as part of the drug development process allow scientists to establish clinically relevant ER. Pharmacokinetics PK relates the dosing regimen with systemic exposure, typically measured as plasma concentration of active moieties. Finally, therapeutics encompasses the pharmacological chain of events with the pathophysiology of disease POD to result in desirable and undesirable COs. The overall clinical pharmacological paradigm in Fig. At each stage of this paradigm, i.

The clinical pharmacology paradigm relating dosing regimens to clinical outcomes via drug exposure and response biomarkers. These sources of variability may be unexplained or explained. For example, intrinsic factors such as phar- macogenetics, gender, age, etc.

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On the other hand, formulation performance and medication adherence may contribute to the unexplained, residual variability in drug response. These relationships also illustrate that an optimal exposure e. Therefore, knowledge of the underlying ER allows rational selection of an optimal exposure. Two different strategies may be appropriate: 2a. The dosing algorithm relates the optimal dose to the value of the respective clinical covariate; the most common adjustment is dosing by body weight, i. A posteriori dose titration The patient is started on a dose e.

This kind of therapeutic drug monitoring TDM can be based on drug exposure usually plasma concentrations , if PK is the major source of variability, or on BM or SM, if PD is the major source of variability. Example drugs would include cyclosporin and warfarin Venitz Prior to properly labeling and marketing a drug, the drug development process has to provide pertinent and comprehensive information to jus- tify the optimal dosing algorithm used in the clinical or outpatient set- ting.

Phase I includes exploratory dose ranging studies to assess safety, PK and PD, special population, drug—drug interaction and formulation development studies, typically in healthy subjects. In some cases, appropriate BMs can be measured throughout the pre- clinical and clinical development program and assist in identifying and separating PK and PD variability sources and help justify appropriate clinical dosing regimens.

It may substitute for COs in the drug devel- opment process dosing regimen and dosage form optimization and possibly drug approval and in clinical medicine TDM. Biomarker intermediate endpoint A biological pathophysiological or pharmacological indicator that can be measured as a result of a therapeutic intervention drug. These endpoints are usually chosen based on the MOA of the drug and known receptor- mediated physiological or biochemical responses. This kind of marker usually requires additional special clinical testing and is rarely used in clinical practice for dose adjustment.

A challenge response is a continuous variable e. It requires additional interventions, may not be repeated often within the same individual during a dos- ing interval, and contributes possibly unacceptable additional safety issues in early phase clinical drug development. Categorical response A yes-or-no response due to drug administration that can be related to drug exposure, e.

This type of response is usually a clinically relevant outcome based on the disease progression in question, regardless of the MOA. It can be measured as part of clinical practice, but does not necessarily allow treatment adjustment. However, it can only be measured once within a given patient. It is a nominal variable that is not very informative statistically and requires a large sample size. Time-to-event response Time-to-event that is related to drug exposure, e.

It can be measured as part of clinical practice, but usually does not allow treatment adjustment. Table 1 summarizes and compares the use of BMs throughout the drug development process: In the preclinical development program, high drug exposures over long periods of time are achieved in two animal species homogeneous, i. Phase I studies in a very homogenous, healthy human population i.

Finally, postmarketing studies in the heterogeneous, representative patient population at large with long-term and possible high exposures may allow correlation of possible SMs with COs based on POD, or empirically, for safety. In early clinical drug development, BMs can be useful in translating information into the subsequent phase as follows: 1. Quantitative methods e. SAMs are expected to increase p50 , i.

S pO2 In vivo measure of O2 saturation of circulating blood, measured by pulse oximetry as a real-time BM. SAMs are expected to decrease S pO2. The in vivo and in vitro PK of efaproxiral was characterized by saturable plasma protein binding PPB , saturable RBC binding RBCB , as well as saturable renal tubu- lar secretion and hepatic glucuronidation and biliary excretion Venitz et al ; Hermening and Venitz ; Nasser et al.

Since both BMs were found preclinically to be predictive of dose- limiting toxicity and indicative of pharmacological POC MOA , the phase I starting dose and dose escalation increment were based on p50 as BM. Furthermore, the phase I dose escalation study was BM-guided in its stopping rules, namely the achieved p50 was not to exceed 10 mmHg BM-based dose escalation algorithm.

Continuous safety monitoring by pulse oximetry S pO2 was done to assess for any exaggerated PD response as the main toxicity.

Both BMs show a transient change, peak at the end of the second infusion i. Overall, using BMs throughout drug development will help to integrate information across development phases, identify sources of variability in assist in better dose selection and streamline drug development; however, the additional efforts in developing and implementing the BM assays have to be considered as well in assessing the utility of the BM approach.

Clin Pharmacol Ther — Hermening A, Venitz J In-vitro glucuronidation of RSR correla- tion of in-vivo intrinsic hepatic clearance and metabolic interaction with probenecid. Pharm Res — Lesko LJ, Atkinson AJ Jr Use of biomarkers and surrogate endpoints in drug development and regulatory decision-making: criteria, validation, strategies. Clin Pharmacokinet — Venitz J Pharmacokinetic-pharmacodynamic modeling of reversible drug effects. With the increasing cost and complexity of drug development, bio- markers will play an increasing role in the early phases.

Sultana et al. Penile plethysmography RigiScan Plus in male erectile dysfunction and phenylephrine challenge urethral pressure in benign prostatic hyperplasia are used to reduce time and cost to reach major exploratory development decision points in these indications. The pharmaceutical industry is faced with increasing costs of drug development, higher regulatory hurdles prior to drug approval, and erosion of the period of exclusivity by generic drug manufacturers challenging a variety of patents Grabowski The emphasis on unprecedented mechanisms is expected to rise as drug developers cap- italise on the better understanding of disease and metabolic pathways as more genomic, proteomic and metabonomic data become available.

Ideally this should be achieved in early development through the use of biomarkers to determine proof of concept POC. Experiences with Dose Finding The rising cost of developing new drugs and shortening period of exclu- sivity requires smarter clinical programs that allow quick, cost-effective and well-informed decision making. This can be achieved through the sensible use of biomarkers to achieve POC and to explore the effective dose range prior to large-scale outpatient studies.

A biomarker is a biological measure that can detect physiological changes due to a disease process or therapeutic intervention. A surrogate endpoint is a biomarker accepted by regulatory agencies as a substitute for a clinical endpoint e. It is important to note that for the purpose of decision making in early drug development, there is no need to develop and validate each biomarker to the level of regulatory acceptance as a surrogate endpoint. A target biomarker is one that measures a direct phar- macological effect as a result of an interaction with the target receptor, enzyme or transport protein e.

A mechanism biomarker is one where the downstream pharmacological effect measured is directly related to the expected mode of action of the drug e. Hence, it may not be appropriate for other mechanisms that treat the same condition. Hence high linkage denotes a biomarker where changes are shown to correlate reproducibly with disease state or treat- ment effect. The ultimate goal would be to use a biomarker-based study design to replace the larger study.

This may be achieved by using an outcome biomarker that has high linkage to outpatient effect. A mechanism or target biomarker with lower linkage to outcome can still be used in early studies to describe the pharmacological concentration response relationship and narrow the range of doses that need to be assessed in the phase 2b study, reducing the size of this study and hence saving time and money.

Mod- elling for emerging NCE data is based on reference animal model and biomarker data generated on marketed drugs whose outpatient dose re- sponse is well understood. It therefore enhances the use of biomarker data to replace or reduce the size of phase 2b studies.

In this technique, sensor loops are placed around the tip and the base of the penis. The loops are connected to a recording device that monitors the circumference tumescence and radial tension rigidity at tip and base of the penis Fig. CMPD-A is an agent effective in preclinical models of erectile func- tion intended for the p. Blood samples for drug concentration were taken at the end of the penile plethysmography period.

Simulations based on the predicted outcome dose response that was informed by the penile plethysmography study were used to inform the choice of doses and number of subjects of a subsequent outpatient study. The RigiScan Plus technique was also used to determine time to onset. Penile plethysmography study in MED patients. Scaling relative to predicted outpatient conventional endpoint EDD score improve- ment. These data will help inform dosing instructions and design of Phase 3 studies. Alpha-blockers have a number of dose-limiting side effects, particularly postural hypotension.

The urethral pressure challenge methodology was designed to assess drugs that target urethral prostate tone, i. The technique makes use of custom-designed 9-Fr urethral catheters Gaeltec Ltd, Dunvegan, UK that contain microtip pressure transducers. These catheters have been used to record urethral pressure continuously for up to 6 h at a time in healthy male volunteers aged 40—65 years. Simultaneous blood pressure recording allows a direct comparison of the effects of drugs on urethral vs blood pressure.

Early studies showed that changes in baseline urethral pres- sure over a 4- to 6-h period were less reliable than intermittent escalating infusions of phenylephrine, an alpha-adrenoceptor agonist that elevates urethral and blood pressures. By using the phenylephrine challenge, these early studies showed that the methodology was able to deter- mine an alpha-blocker effect on urethral and blood pressures, estimating selectivity for the urethral effect, and therefore the therapeutic index relative to hypotensive changes Sultana et al.

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Diagrammatic representation of urethral pressure catheter in place. Coro- nal section through male bladder base and prostate with self-retaining catheter in situ. The catheter has one bladder pressure sensor and three prostatic urethra sensors. Urethral pressure reading is taken from middle prostatic urethral sensor. The effect of this compound tenfold dose range on urethral and blood pressures was assessed in two studies involving a total of 22 healthy male volunteers aged 40—65 years.

Phenylephrine dose-escalating infusions were administered at the estimated times of peak plasma concentrations for CMPD-B and for tamsulosin. Figure 7 shows that CMPD-B has greater urethral selec- tivity relative to hypotensive effect compared to tamsulosin. The relative urethral effect measured was used to scale outcome data available for tamsulosin to make predictions for CMPD-B. Phenylephrine ED50 is used to calculate pressor effect at each dose level of the agents. This technique therefore allows a comparison of the effect of novel agents relative to the current market leader tam- sulosin in a POC study conducted in healthy volunteers.

There is therefore an increased pressure to use smart clinical trial designs in exploratory development. Biomarkers should be developed and used where appropriate to replace larger, conventional endpoint studies.

At the very least, these biomarkers should better inform the design of outpatient studies to reduce the risk of failure and allow smaller studies that assess fewer doses. Clinical biomarker studies are becoming an essential aspect of early drug development, with key decisions based on their outcome. Predictions of the likely outpatient dose response can then be made on the basis of the emerging biomarker data for novel compounds.

Together, these approaches provide a powerful tool in guiding dose selection and optimal outpatient trial design for novel compounds. The examples cited in this paper should convince the reader of the important role biomarker methodologies could play in early drug de- velopment. We now routinely use the RigiScan Plus technique in male erectile dysfunction and have found the phenylephrine challenge urethral pressure technique equally useful in benign prostatic hypertrophy. Be- sides their use in determining POC, these techniques can also be used to characterise the dose response, as well as additional pharmacodynamic properties such as time to onset and offset of activity.

By allowing di- rect comparison with competitor agents, these techniques enable the differentiation of novel compounds to be determined. We would like to acknowledge Dr. Jaap Mandema Phar- sight Corp now Quantitative Solutions for the modelling and simulation work he did for the examples presented. Br J Urol — Diamond LE, Earle DC, Rosen RC et al Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction.

Med Aspects Hum Sex —16 Grabowski H Are the economics of pharmaceutical research and de- velopment changing? Productivity, Patents and political pressures. Roots et al.

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A standard dose will bring about more adverse effects than usual if enzymatic activity is lacking or feeble. This concept does not present the physi- cian with new chemical entities but helps streamline the therapeutic regimen. It is also safer because some side-effects are avoided Fig. Nevertheless, some pharmacogenetic phenomena had already been described years ago, e. There are many examples of genetic variations in drug receptors and drug targets with important clinical consequences. However, drug-. Their functional consequences range from a moderate reduction to a complete lack of enzymatic activity, but even a consider-.

Table 1. Hereditary polymorphisms in important enzymes metabolizing drugs and xenobiotics and their therapeutic consequences Roots et al. Table 2. Differences in activity might be less pronounced in heterozygous individuals than in homozygotes. However, genetic variations in drug transporters can also cause variable drug disposition. These individuals metabolize substrates of CYP2D6 considerably more slowly, with respective plasma levels be- ing higher. The normal dose creates a supranormal response and those individuals experience more side effects caused by overdosage.

This is a very special case: these individuals have three active alleles that cause enzyme activity to be considerably higher than in wild-type car- riers. Clinical studies indicate that a genotype-adapted dosage regimen could help avoid therapeutic failure and side effects. CYP2D6 genotype-based dose recommendations for antidepressive agents.

Figure 2 shows CYP2D6-based dose recommendations for antidepres- sive agents. Genetic differences in enzymatic activity are without practical conse- quence if the metabolite and the mother substance are equally potent. But this is a rare case indeed, as most metabolites are without therapeutic effects.

Figure 3 illustrates the substantial differences in systemic clearance and the area under the concentration-time curve of the antidepressant doxepin Kirchheiner et al.

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With pro-drugs it is different. These pharmacologically inactive sub- stances are transformed into active drugs in the body. The antimalarial proguanil is another example. CYP2C19 metabolizes proguanil to cycloguanil, the active antimalar-. CYP2D6 polymorphism and doxepin elimination. Right panel Oral clearance of the E-enantiomer of doxepin. Kirch- heiner et al. Polymorphisms in drug metabolizing enzymes do not exert the same effects on every drug: the pharmacokinetics of some of them are only slightly affected.

Genotype-based dosing only makes sense if a clinically important polymorphism dominates the metabolism of a substance with small therapeutic range; these conditions are met by a rather small portion of our therapeutic equipment. Carriers of the gene for CYP2D6 duplication were shown to be nonresponders to tropisetron and ondansetron Fig.

These individ- uals are ultrafast metabolizers; obviously, they do not have drug plasma concentrations within the therapeutic range and should get considerably higher doses of tropisetron or ondansetron. Tremblay et al. Kaiser et al. However, this genotype occurs only in about 1. Omeprazole is a good example to illustrate pharmacogenetics-based optimization of therapy.

Obviously, omeprazole is quite innocuous even if plasma concen- trations are high. Therapeutic results seem to depend on the CYP2C Upper panel Plasma concentration time courses of 40 mg omepra- zole p. Bottom panel Helicobacter py- lori cure rates in 62 peptic ulcer patients having received an eradication ther- apy.

The cure rates of heterozygous individuals with an active and an inactive gene ranged between these two groups. Cyclophosphamide is con- sidered a pro-drug. This primary metabolite furnishes the precursor material for the formation of alkylating agents, such as phosphoramide mustard. We studied the plasma-elimination constant ke of cyclophosphamide in a group of 49 cancer patients who received below 1, mg per m2 of body surface, most of them together with other cytostatics.

Figure 6 shows a clear gene—dose effect for the elimination constant when re- sults were graded according to the CYP2C19 genotype. Cyclophosphamide elimination rate ke dependent on CYP2C19 geno- types. Results are given as box plots Timm et al. They should also in- clude a pharmacogenetic evaluation of all the other enzymes involved in cyclophosphamide activation and disposition. The latter two are highly polymorphic enzymes that trans- form clinically important drugs, with some widely used antidiabetics among them Table 1. The greatest ef- fect is seen with glyburide glibenclamide.

In African and Far Eastern populations, these alleles are very rare. Impact of CYP2C9 genetic variance on oral clearance of several antidi- abetic drugs. In this experiment, genotype—phenotype correlation was established for CYP1A1 variants that were expressed — together with P reductase — in Spodoptera frugiperda Sf9 insect cells. In comparison to the wild-type protein, metabolite formation of the CYP1A1. Genotype and Phenotype Relationship in Drug Metabolism Not long ago, drug tissue distribution was thought to be mainly a pro- cess of passive diffusion.

Transmembrane transporters are integral membrane proteins and occur in several organs with absorptive and excretory functions e. Furthermore, they play an important role in forming blood—tissue barriers, such as the blood—brain barrier, the blood—placenta barrier, and the blood—testis bar- rier, thereby protecting these sensitive tissues against toxic xenobiotics. Organic anion transporting polypeptides OATPs constitute a large family ubiquitously expressed in human tissues, such as liver, kidney, brain, and intestine.

Liver OATPs serve in the extraction of xenobi- otics and drugs from portal venous blood. Most of these variants are rare, with frequencies between 0. Plasma concentration-time curves after a mg oral dose of pravastatin in relation to tested OATP-C haplotypes in healthy volunteers. In general, Pgp diminishes drug absorption and enhances drug excretion.

Polymorphic expression of Pgp was assumed to be an important modulator of individual response to pharmacotherapy. The discrepancies in study results might partly be attributed to experimental conditions, for example steady-state vs single-dose kinetics, involvement of other transmembrane transporters, and the genetic surrounding of the MDR1 locus. Thus, future investigations have to take into account the haplotype aspect. In accordance with the rules of evidence-based medicine, a pharmacogenetic dosage regimen should prove its superiority over standard methods in clinical studies.

Prelimi- nary results have already been presented for neuroleptics, antidepressive agents, azathioprine, and others. Naturally, the demand for proofs by expensive clinical studies should not be pushed to an extreme. Although haloperidol kinetics clearly depends on CYP2D6, an alterna- tive, pharmacologically active metabolite is formed via carbonyl reduc- tion. We consider pharmacogenetics as a part of future molecular medicine. We can expect that therapy will become safer. With fewer adverse side effects and the avoidance of ineffective therapy, even health care costs should decrease.

Response to antiretroviral treatment in HIVinfected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. The increasing size of the elderly population means that both the relative and absolute numbers of prescriptions for elderly patients are increasing. Prescribing for elderly patients as opposed to younger patients is thus ever more important.

In addition, the development of drugs to be used in older patients requires an awareness of a number of physiological, pathophysiological and sociological considerations. Age, however, is only one of many factors affecting pharmacokinetics. A number of age-related changes in physiology give rise to changes in pharmacokinetics associated with ageing Table 2. There is no convincing evidence that age affects the rate or extent of absorption Gainsborough et al. Pharmacokinetics Liberation Absorption Distribution Metabolism Elimination Pharmacokinetic interactions Drug A alters the pharmacokinetics of drug B Pharmacodynamics Pharmacodynamic interactions Drug A alters the pharmacodynamics of drug B independently of pharmacokinetic changes.

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Thus, the elimination half-life of drugs cleared wholly by renal excretion may double. Where the toxic level is close to the therapeutic level a narrow therapeutic window , such a change can lead to toxic effects. Digoxin is probably the most widely used drug in this category. While younger individuals typically require 0. Serum creatinine is also determined by muscle mass. Thus serum creatinine is not a good marker of renal function.

The most useful surrogate marker of clearance for renally cleared drugs is creatinine clearance. This is most easily derived using the well-known Cockroft—Gault equation Cockroft and Gault For most drugs cleared in this way, the hepatic extraction ratio the proportion of molecules removed from the blood during passage through the liver is low and mainly determined by liver volume. Therefore, as a result of normal ageing, there is a reduction in hepatic clearance of such drugs due to a reduction in liver volume Wynne et al.

The variability in the decline of hepatic clearance with age is much greater than that of renal clearance. The most important pharmacokinetic consequence of this is the increase in volume of distribution of lipid-soluble drugs such as benzodiazepines. There will, in addition, be an effect of reduced liver volume on clearance.

These patients have reduced hepatic enzyme activity, which further reduces the clearance of hepatically metabolised drugs. In addition, the reduced serum albumin results in reduced protein bind- ing of acidic drugs. For heavily protein-bound drugs such as ibuprofen Stem Cell Technologies: Basics and Applications. Satish Totey.

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Michael B. The Rise of Fetal and Neonatal Physiology. Lawrence D. A History of Modern Immunology. Zoltan A. Peter Beaconsfield. Issues and Reviews in Teratology. Strategies of Immune Regulation. Eli Sercarz. The Climacteric: An Update. Philip Furmanski. Reproduction and Development. Current Topics in Experimental Endocrinology. L Martini. Reproductive Genetics. Sean Kehoe. Genetic Origins of Tumor Cells. Breast Cancer: Scientific and Clinical Progress.

Diana M. Biological Application of Anti-Idiotypes. Constantin A. Teratology in the Twentieth Century Plus Ten. David M. Bacterial Lipopolysaccharides.

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Cellular Therapy (Ernst Schering Foundation Symposium Proceedings) Cellular Therapy (Ernst Schering Foundation Symposium Proceedings)
Cellular Therapy (Ernst Schering Foundation Symposium Proceedings) Cellular Therapy (Ernst Schering Foundation Symposium Proceedings)
Cellular Therapy (Ernst Schering Foundation Symposium Proceedings) Cellular Therapy (Ernst Schering Foundation Symposium Proceedings)
Cellular Therapy (Ernst Schering Foundation Symposium Proceedings) Cellular Therapy (Ernst Schering Foundation Symposium Proceedings)
Cellular Therapy (Ernst Schering Foundation Symposium Proceedings) Cellular Therapy (Ernst Schering Foundation Symposium Proceedings)
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