Dose Optimization Based on Pharmacokinetic-Pharmacodynamic Modeling
Hartmut Derendorf, Günther Hochhaus in Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Whereas pharmacokinetics is an established routine discipline with widely accepted principles, pharmacodynamics is still an emerging field with many open questions. One reason for the delay in this development was the lack of techniques that allowed reproducible measurement of drug effects over time. A drug effect can be defined as any drug-induced change in a physiological parameter when compared to the respective predose or baseline value. The baseline value is the value of the same physiological parameter in the absence of drug dosing. Baseline values do not necessarily have to be constant but can change, e.g., as a function of time of day or food intake. Furthermore, the term effect has to be clearly separated from the term efficacy. Efficacy is the sum of all therapeutically beneficial drug effects and is the most relevant target parameter in PK-PD modeling. However, in many PK-PD studies there is little evidence if the pharmacodynamic effect parameter used has any correlation to the desired efficacy and is a validated surrogate marker.
Pharmacological Approaches To Behavioral Symptoms In Alzheimer’s Disease
Zaven S. Khachaturian, Teresa S. Radebaugh in Alzheimer’s Disease, 2019
Interactions between medications may potentiate efficacy, toxicity, or side effects by a variety of mechanisms, including changes in absorption, transport and metabolism, and drug interactions at the level of receptors. Elderly patients often take a large number of medications, which increases the risk of interactions. Special care should be taken when prescribing two or more psychotropic drugs, particularly agents with sedative, hypotensive, or anticholinergic properties. A basic tenet is to use the lowest effective dose of medication for behavioral symptoms. This usually means initiating treatment with a very low dose and increasing the medication gradually. The effective dose in elderly demented patients is often lower than that standardly recommended for younger adults.
Adrenoceptors: Classification and Distribution
Kenneth J. Broadley in Autonomic Pharmacology, 2017
The agonist dose-response curve is the starting point which provides a measure of the agonist potency as the EC50. However, more detail on the drug-receptor interaction may be obtained from the affinity and intrinsic efficacy of agonists. In spite of the development of equations relating dose and response, calculation of the affinity and intrinsic efficacy of an agonist is hampered by the unknown quantitative nature of the relationship that exists between stimulus and response. Since the stimulus (S) is linearly related to receptor occupancy (RA/Rt), receptor number (Rt) and intrinsic efficacy (ε) (equation 3.9), the nonlinear hyperbolic relationship between response and occupancy (Figure 3.6) must lie in the stimulus–response function (f). To eliminate the unknown tissue factors which control this relationship, assessment of drug-receptor interactions is made by means of null methods. That is, comparisons are made at equal responses either between agonists or for the same agonist in the absence and presence of an antagonist.
Controlled release of liposome-encapsulated temozolomide for brain tumour treatment by convection-enhanced delivery
Published in Journal of Drug Targeting, 2018
Chung-Yin Lin, Rui-Jin Li, Chiung-Yin Huang, Kuo-Chen Wei, Pin-Yuan Chen
Tumour-bearing mice treated with CED-LipoTMZ had significantly reduced tumour growth and improved survival times compared to the control groups. Since TMZ is an alkylating agent that targets proliferative cells, and tumour cells do not undergo cell division in a concerted manner, repeated administration of TMZ may kill the tumour cells that have delayed proliferation and further inhibit tumour growth. CED of nanodrugs into tumour tissue is dependent on the concentration difference between the infusion site and the tumour tissues, as well as the bulk flow between tumours and normal tissues [30,31]. The concentration of drugs in the vicinity of drug receptors can help determine their therapeutic efficacy and toxicity. At high concentrations, effects plateau so that further increases in drug concentration do not produce greater effects [32,33]. In this study, the plateauing phenomenon might have been due to a high load of 8.7 mg TMZ per mL of LipoTMZ suspension. The cumulative rate of the external pressure gradient elevation to augment the therapy through an additional 5 μL-dose of infusion could enhance drug concentrations in tumours when compared to a single injection.
A hybrid model to evaluate the impact of active uptake transport on hepatic distribution of atorvastatin in rats
Published in Xenobiotica, 2020
Priyanka Kulkarni, Ken Korzekwa, Swati Nagar
Drug transporters can complicate drug disposition as well as the safety and efficacy profiles of drugs (Giacomini et al., 2010; Shitara et al., 2006). Drug clearance and distribution can be impacted by active uptake of drugs into eliminating organs, as well as efflux out of the body, for example with biliary and renal excretion (Watanabe et al., 2009b). Uptake transporters can increase intracellular drug concentrations, thereby increasing the overall tissue distribution of the drug. Altered drug disposition in turn can affect the efficacy and toxicity profiles of drugs, and lead to drug-drug interactions (Hirano et al., 2006; Izumi et al., 2015). The organic anion transporting polypeptide (OATP) family of transporters has emerged as a determinant of drug disposition (Maeda et al., 2006; Shitara et al., 2013). These transporters catalyze the uptake of organic anions into the intestine and the liver, among other tissues. In the liver, predicted intracellular concentrations can be markedly higher than unbound plasma concentrations due to OATP activity (Hirano et al., 2004; Kulkarni et al., 2016; Menochet et al., 2012a,b). This may be especially important for drugs cleared primarily by the liver. In addition to increased clearance, higher intracellular concentrations can increase the likelihood of drug interactions due to enzyme induction or inhibition. For these reasons, it is important to understand and be able to predict the impact of transporters on intracellular and plasma drug disposition.
Polymer-based thermoresponsive hydrogels for controlled drug delivery
Published in Expert Opinion on Drug Delivery, 2022
Most of the principal side effects of therapeutic drugs are related to the route of administration, which influences the half-life of drug and its efficacy. New strategies involve the use of thermoresponsive hydrogels to overcome the limitation of commercial drugs. The main advantages of the use of thermoresponsive hydrogels are related to the possibility of being injected in the damaged tissue and release drug locally for a prolonged period. The development of thermoresponsive hydrogels can be performed by using different type of polymers that are intrinsically and not intrinsically thermosensitive. In the second case, particular compound or nanoparticles are used to achieve the same results. Moreover, the addition of nanoparticles inside the hydrogel can allow a local increment of temperature by using different types of sources, which guarantee a non-invasive way of drug administration.
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