Pharmacokinetics in Everyday Clinical Practice
The addition of zinc at low concentrations allows the protamine to form crystals with insulin at neutral pH. In , insulin glargine became the first basal insulin analogue available. Insulin glargine differs from human insulin at position A21 of the A chain substitution of asparagine with glycine and position B31 and B32 of the B chain addition of two arginines.
These changes shift the isoelectric point from pH 5. Insulin glargine is injected as a clear acidic solution pH 4 , which forms microprecipitates that must dissolve before absorption can take place. Nonetheless, the time—action profile of insulin glargine is flatter and of longer duration compared with NPH insulin The analogue is supplied as a clear neutral solution and remains in solution in the subcutaneous depot, in the circulation and in the target tissues until interaction with the insulin receptor. Insulin detemir has a much flatter and longer time—action profile compared with NPH insulin 13 , as well as reduced variability compared with insulin glargine The information of most clinical relevance for basal insulins involves the critical issues of flatness, duration of action and variability.
For insulin glargine, all available studies, with one exception 15 , showed a very gentle rise and fall over time, indicating a relatively flat activity profile with some evidence of a very broad, albeit small, peak. Each subject received four single subcutaneous doses of each basal insulin on four different clamp days; all insulins were administered at the same dose 0.
A basal insulin analogue, when compared with NPH insulin, should result in: comparable metabolic control with less hypoglycaemic episodes; improved metabolic control with comparable hypoglycaemic events; or, in the best case scenario, improvement in both. Does this actually hold true in phase 3 trials?
One study 27 showed a lower rate of hypoglycaemic excursions and less variability of FPG in subjects taking insulin glargine compared with NPH insulin. Large randomised clinical trials comparing insulin detemir and NPH insulin have demonstrated that glycaemic control with insulin detemir was similar to, or better than, NPH insulin 29 , In addition, nocturnal plasma glucose profiles were more stable, with lower glucose fluctuations 32 , These studies showed a positive correlation between the incidence of hypoglycaemia and the coefficients of variation in FPG: a reduction of 2.
In both trials, insulin detemir and insulin glargine were equally effective in optimising HbA 1c. The two analogues were associated with comparable hypoglycaemia risks and variabilities, but insulin detemir therapy was associated with less weight gain. However, all next steps, from one to two or even more daily injections, are controversial and should be considered carefully with the respective patient. An important issue is the early intensification of insulin therapy to achieve and keep target HbA 1c values. Moreover, minor hypoglycaemic events were inconsistently reported as either higher than or equivalent to basal insulin, and there was greater weight gain with prandial compared with basal insulin 1.
Starting in the second year, sulfonylureas were replaced by an additional insulin basal insulin added to prandial insulin, prandial insulin three times daily added to basal insulin and prandial insulin at lunch added to biphasic insulin if HbA 1c levels were above 6. An important feature of this study was its long duration and the standardisation of insulin regimens. In addition, there were striking differences in outcomes between the first and third years. The basal insulin regimen, which was equivalent to the other regimens after the first year in patients with HbA 1c values of 8.
This conclusion is consistent with the concept that fasting hyperglycaemia contributes more than postprandial hyperglycemias to HbA 1c levels. Thus, it makes sense to focus on FPG during insulin initiation. Decisions on insulin dose adjustments should be knowledge based. Training should be provided to deal with the specific situations of illness, fever and demobilisation and unplanned exercise or extra meals.
General practitioners who face time constraints or lack familiarity with tailored insulin treatment should obtain continuing education and should have a hot line to specialists for rapid consultation Measurements of serum insulin concentrations in patients with diabetes do not add value to clinical practice. Instead, the PD profile is far more informative than the PK profile in terms of determining dosing frequency and expectations of efficacy over a given period of time. Results of studies using this technique have demonstrated that insulin glargine and insulin detemir have flatter, but not completely peakless, time—action profiles compared with NPH insulin.
Finally, in addition to a sufficient knowledge about insulin PD, appropriate education, empowerment and training of both the patient and the healthcare worker are essential to overcome potential barriers to insulin therapy, deal with specific situations and successfully implement everyday insulin supplementation. These steps, if followed through appropriately, should facilitate patient care and improve quality of life for patients with type 2 diabetes.
The authors thank David Norris, PhD for editorial assistance provided during the preparation of this manuscript. Volume 64 , Issue If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account. If the address matches an existing account you will receive an email with instructions to retrieve your username.
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Clinical importance of pharmacokinetic parameters
Please review our Terms and Conditions of Use and check box below to share full-text version of article. Summary This pedagogical review illustrates the differences between pharmacokinetic PK and pharmacodynamic PD measures, using insulin therapy as the primary example. Review Criteria Information was gathered from the literature published on PubMed until 31 October on the topics of type 2 diabetes and insulin therapy, including basal insulin analogues, glucose clamps, pharmacokinetics and pharmacodynamics.
Message for the Clinic For insulin therapy, pharmacodynamic PD assessments have more clinical relevance than pharmacokinetic assessments. Question 1: What is the pharmacology of endogenous insulin? Question 2: What are the limitations of PK parameters relative to PD parameters for understanding therapeutic insulins? Figure 1 Open in figure viewer PowerPoint. Relationship between pharmacokinetics PK and pharmacodynamics PD. Figure 2 Open in figure viewer PowerPoint.
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Question 3: What is the best method to investigate insulin PD? Figure 3 Open in figure viewer PowerPoint. Figure 4 Open in figure viewer PowerPoint. Figure 5 Open in figure viewer PowerPoint. Insulin glargine In , insulin glargine became the first basal insulin analogue available. Insulin glargine vs. Insulin detemir vs. NPH insulin Large randomised clinical trials comparing insulin detemir and NPH insulin have demonstrated that glycaemic control with insulin detemir was similar to, or better than, NPH insulin 29 , Question 7: Treatment strategies with basal insulin analogues in type 2 diabetes: what is the evidence from clinical trials?
Conclusions Measurements of serum insulin concentrations in patients with diabetes do not add value to clinical practice. Acknowledgements The authors thank David Norris, PhD for editorial assistance provided during the preparation of this manuscript. Application of knowledge about the core pharmacokinetic parameters of bioavailability, distribution volume, protein binding, half-life and elimination helps to optimise drug therapy.
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Pharmaceuticals number among the most important therapeutic measures for restoring and maintaining health. In order to ensure an effective therapy devoid of side-effects, precise knowledge about the active substances and the form in which the drug is administered is vital. The plethora of substances that are currently available often complicates a meaningful appraisal of the contribution that individual active components make to a therapy. The pharmacokinetic properties of a substance and the relationship of these pharmacokinetics to the desired effect or side-effect is often not considered adequately.
However, an optimally effective and safe therapy can only be realised if one is aware of the duration and quantity of direct drug exposure that is required to bring about a therapeutic effect. Knowledge of the pharmacokinetics of a drug serves above all to allow individualisation of therapy, since drugs should ideally be administered in a manner tailored to the individual patient.
These days, however, most drugs are administered in combination to polymorbid and usually older patients. Because of functional disruptions of various body organs, and potential interactions between the drugs, complex situations can arise whose consequences cannot be adequately predicted without knowledge of the drugs' pharmacokinetics. There are of course exceptions to these scenarios, as is the case with all rules. A measure for this is the bioavailability BA of an active substance. In its strictest sense, the term bioavailability refers to the proportion of administered drug that reaches the systemic circulation and which is then available to exert the pharmacodynamic effect.
The BA is as such usually expressed as a percentage of the dose. Other definitions consider the rate of absorption and the concentration at the site of action.
In optimal cases substances with a high BA indicate a high absorption rate and a low pre-systemic breakdown by membranous enzymes and systemic breakdown by hepatic enzymes first-pass effect. A high bioavailability is also an indicator of the pharmaceutical quality and reliability of a medicinal form. This is of practical importance, particularly where generic preparations are being considered for prescription.
A number of mechanisms may underlie a low bioavailability:. For substances with a low BA, an oral dose must be considerably higher than a parenteral dose. For everyday clinical practice it must be remembered that drugs with a low BA suffer large interindividual variations in bioavailability, giving rise to unexpectedly high or low drug levels. A high first-pass effect can also be associated with pharmacokinetic interactions dependent on metabolism see Table 2.
The bioavailability is also of practical relevance when deciding on the bioequivalence of generic preparations. Two drugs are pharmaceutically equivalent if their bioavailabilities after provision of the same molar dose resemble one another in such a way that the drugs are essentially equivalent with regard to efficacy and harmlessness.
An affirmed bioequivalence is therefore an essential precondition for allowing a safe switching between and to generic preparations. Volume of distribution The volume of distribution V of a medication is an abstract parameter and is defined as the amount of drug in an organism divided by its plasma concentration.
After distribution of the drug within the organism, the volume of distribution is computed as follows:.
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The formula can be easily understood if one considers that concentration c represents the quotient of the mass m and the volume V. Only for a few medications, however, does the distribution volume correspond to a real physiological space, such as:. This is due on the one hand to the accumulation of many medications in various tissues, such as the adipose tissue or the bones producing an increase in the numerator , and on the other to the avid binding with plasma proteins that prolongs the persistence of the agent within the vascular system producing an increase in the denominator.
Both are properties resulting from the solubility and the plasma-protein binding of a medication and which are constant only for one particular patient. Interindividual differences depending on the amount of body fat or body water must also be taken into consideration. In the case of intravenous injection or rapid absorption, the medication distributes itself first of all in a central compartment and only then throughout the whole distribution volume, that is, into the peripheral compartment.
The consequence of this is redistribution within the entire organism. For such medications two half-lives are often provided, namely the distribution half-life first phase and the elimination half-life second phase. With large distribution volumes there is a tendency towards a long terminal half-life, ie the larger the distribution volume, the longer the terminal half-life. Because of this disproportionately high tissue affinity, high levels are reached in target tissues such as the lung, tonsils and the prostate.
The terminal half-life in the tissues is 2—4 days. As such, one can only administer doses once daily and for a duration of just three days in all. As such they can access a large number of pathogens pneumococci, enterobacteria that also occur extracellularly see Figure 2. Chlamydia , legionella and mycobacteria, on the other hand, also persist intracellularly, and macrolides and quinolones, which can penetrate the cell membrane, are effective against these pathogens see Figure 2. The larger the volume of distribution of a drug is, the less effective are detoxification measures such as haemodialysis and haemoperfusion.
On the other hand, a large distribution volume contributes to a lower elimination of such substances when haemodialysis is carried out so that these agents need not be topped up see Table 3. It must be considered when administering drugs that with advancing age the muscle mass decreases and the body fat increases. As such, lipophilic substances can show a larger distribution volume. The half-life lengthens and there is a risk of accumulation. In the case of diazepam the agent has a half-life of approximately 20 hours in a year-old patient, whereas in a year-old patient the half-life is approximately 70 hours.
For lipophilic substances the much larger distribution volume with advancing age correlates directly with the half-life. Because of the smaller volume of tissue water, hydrophilic medications have a smaller distribution volume, which can result in higher concentrations at the site of action and as such an increase in adverse drug reactions. Together with drug concentration in the steady state, the distribution volume is of decisive importance for determining the initial dose loading dose.
An initial "saturation dose" is useful when the medication has a long half-life, since four or five half-lives may elapse before a steady-state concentration is achieved. Protein binding Substances which dissolve poorly in water can only be transported in the blood if they are bound to plasma proteins.
Weak acids mainly bind to albumin and weak bases bind mainly to alphaacid glycoprotein. The clinical relevance is comparatively small, however, since the concentration increase is only transient. Usually a balancing with the free concentration in the tissue occurs and with increases in the free concentration the clearance also increases. However, only the free, and not the bound fraction, is pharmacodynamically effective. If this free fraction increases, these considerations can be important, for example when comparing the plasma concentrations of antibiotics with the minimal inhibitory concentrations MICs.
Due to the delayed renal clearance resulting from this only the free portion is filtered by the glomerulus , a single dose is sufficient over 24 hours to exceed the MIC values. The plasma protein binding of ceftriaxone is concentration-dependent. With an increase in concentration the extent of protein binding decreases and the free, effective fraction increases disproportionately. Only the free fraction of a medication can be removed by glomerular filtration in the kidneys or dialysed. A medication with low protein binding is therefore more susceptible to glomerular filtration and effective elimination by haemodialysis.
With age the plasma albumin concentration decreases and with that also the degree of protein binding. A higher free substance fraction resulting from that is counteracted in the case of phenytoin by the raised whole body clearance so that this phenomenon is not usually therapeutically relevant. Plasma half-life As far as the elimination of active substance is concerned, the time that elapses until the amount of medication is reduced to a half is what we refer to as the half-life.
Measurements are usually taken from plasma samples so that we usually talk about the plasma half-life. Awareness of the half-life of an active substance allows an estimate to be made of the duration of an effect from a single dose. The half-life is thus the most important parameter for deciding on a dosing regime. Figure 3 shows that half-life is in fact a derived pharmacokinetic parameter. The half-life lengthens with a large distribution volume and shortens with a large total clearance.
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For clinical purposes the aspects set out below are important see Figure 3.