Pharmacodynamics efficacy and

Several investigations are reported in the literature describing the utility of the SMEDDS in oral delivery. The major advantages of SMEDDS include improvement in oral bioavailability, quick onset of action [87] and reduction in intra- and inter-individual variability and food effects [88]. Most of the investigations described so far have focused on the pharmacokinetics of the drug to assess oral bioavailability but not on the pharmacodynamic efficacy and the candidates explored so far belong to discrete therapeutic classes. Table 9.5 enlists examples of various SMEDDS reported so far and their in vivo advantage. 

Scheen AJ (2015) Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75 33-59 Scheen AJ (2015) SGLT2 inhibition efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf 14 1879-1904... 

It is one of the peculiarities of herbal drugs that their indications have for the most part been determijied empirically. The reason is easily understood most herbal drugs have been used for a very long time to alleviate or cure illnesses and more especially disorders. Their introduction in therapeutics happened at a time when pharmacodynamics and pharmacokinetics were unknown concepts, when there was no Medicines Act to require proof of the quality, efficacy, and innocuity of herbal medicines. Today, when introducing a new medicine, extensive investigations are required in the interest of safety. To many the requirement of the proof of activity of such a drug as chamomile appears to be superfluous, but nevertheless, as a representative of a scientifically oriented pharma-... 

The consequence of moving consciously toward this model will be the provision of a robust and scalable IT infrastructure and systems able to cope with exponentially growing data mountains that will need to be integrated and shared, accessed and mined in the most effective way. It will also require formidable computing power and sophisticated algorithms to be able to simulate both organs and whole body systems to reduce expensive failures in the clinic and predict much earlier the pharmacokinetic and pharmacodynamic properties and toxicological and efficacy profiles of molecules in pharmaceu-... 

Integration of both pharmacokinetic and pharmacodynamic properties of an agent is important when choosing antimicrobial therapy to ensure efficacy and prevent resistance. Antibiotics may demonstrate concentration-dependent (aminoglycosides and fluoroquinolones) or time-depen-dent (/l-1 acta ms) bactericidal effects. 

It has become increasingly accepted that the pharmacokinetic behavior of new drugs represents an important attribute, along with efficacy and safety. The frequency with which a drug must be taken is a function of several factors the half-life, the span between minimally efficacious concentrations and concentrations that cause side-effects, and the pharmacokinetic-pharmacodynamic relationship. Typically medicinal chemists optimize the predicted pharmacokinetics of... 

As it is often very difficult to quantify therapeutic performance with pharmacodynamic and clinical studies, pharmacokinetic studies are usually the most suitable tool to describe the performance of the drug product in vivo. Once a relationship between the plasma concentration of the drug or active moiety and the therapeutic effect has been established, BA may be considered to be the perfect surrogate parameter for efficacy and/or safety of a drug product. 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

There was a direct relationship between the effect and the plasma concentration in the rat pharmacodynamic data and it was well described by a simple Emax model. Based on preclinical models for efficacy, a 90% effect was considered as the target for therapeutic effect. Finally the human C90 (human concentration corresponding to 90% effect, C90 man) was estimated by accounting for the different affinities and unbound fractions of each compound for the rat and human receptors as follows ... 

This section deals with the question of whether there are quantitatively detectable and interpretable correlations between the dose of an administered drug, or the concentration of a drug and its metabolites measured in the blood or plasma (blood or plasma level), and the therapeutic action or side effects observed. Investigations relating to questions of this type are called PK PD (pharmacokinetic pharmacodynamic) studies. The PK PD analysis is a bidirectional approach pharmacokinetics represent what the body does with a drug, and pharmacodynamics describes what a drug does to the body. The PK PD analyses are key elements of early drug development, and PK PD trials are able to answer specific disease-related efficacy and safety questions. 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

Adkins JC, Faulds D. Micronised fenofibrate a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs 1997 54(4) 615-33. 

Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS. Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984 28(1) 38-61. 

Schentag, J. J. (1999). Antimicrobial action and pharmacokinetics/pharmacodynamics The use of AUIC to improve efficacy and avoid resistance. J. Chemother. 11 426-439. 

Bhavnani SM, Andes DR. Gemifloxacin for the treatment of respiratory tract infections in vitro susceptibility, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2005 25 717-740. 

Drugs can therefore resemble a double-edged sword in that they can both help and harm the patient. By fully appreciating the nature of pharmacokinetics, pharmacodynamic principles, and drug-drug interactions, practitioners can drastically reduce unwanted side effects and at the same time enhance the therapeutic efficacy and usefulness of drugs. 

R. N. Brogden, R. C. Heel, T. M. Speight, and G. S. Avery, Beclomethasone dipropionate. A reappraisal of its pharmacodynamic properties and therapeutic efficacy after a decade of use in asthma and rhinitis, Drugs 28 99 (1984). 

C. Raffanel, R. Sabo, S.K. Gupta, M. Salfi, and S. Jacobs. 2000. Pegylated interferon-a2b pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin. Pharmacol. Then 68 ... 

For BA studies, measurement of individual enantiomers may be important. For BE studies, this guidance recommends measurement of the racemate using an achiral assay. Measurement of individual enantiomers in BE studies is recommended only when all of the following conditions are met (1) The enantiomers exhibit different pharmacodynamic characteristics. (2) The enantiomers exhibit different pharmacokinetic characteristics. (3) Primary efficacy and safety activity resides with the minor enantiomer. (4) Nonlinear absorption is present (as expressed by a change in the enantiomer concentration ratio with change in the input rate of the drug) for at least one of the enantiomers. In such cases, BE criteria should be applied to the enantiomers separately. 

Houk BE et al (2010) Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer results of a pharmacokinetic/pharmacodynamic meta-anal-ysis. Cancer Chemother Pharmacol 66 357-371... 

---