Questions related to Clinical Pharmacokinetics
In the article titled "FDOPA-(18F): a PET radiopharmaceutical recently registered for diagnostic use in countries of the European Union", two half-lives are reported for FDOPA.
"6-fluoro-(18F)-L-dopa is removed according to a bi-exponential kinetic process with biological half-lives of 12 hours (67-94 %) and 1.7 - 3.9 hours (6-33 %). Both these half-lives appear to be age-dependent. The 18F-activity is excreted through the kidneys, 50 % with a half-life of 0.7 hours and 50 % with a half-life of 12 hours.
On basis of these data, a biokinetic model for 6-fluoro-(18F)-L-dopa was developed. This model assumes that 100 % of the 18F activity is homogeneously distributed in the body and eliminated through the kidneys with biological half-lives of 1 hour (50 %) and 12 hours (50 %). This model was considered to be independent of age."
What does this mean?
Someone was taking Daflon 500 mg (450 mg Diosmin, 50 mg Hesperidin) twice daily for her varicose veins. Now, the manufacturer makes Daflon 1000 mg (900 mg Diosmin, 100 mg Hesperidin).
Now, the Q is, if she takes the new dosage form 1000 mg once daily, will this dose be equivalent to 500 mg once daily or the pharmacokinetics and the therapeutic effects will be different?
I have 2 concentration time curves of a subcut drug implant. the first group has a peak around the 50 day mark where as the second group does not. Both groups received the same implant by the same surgical procedure. If the AUC for group 1 (1018 ng.days.ml-1) is larger than group 2 (800.9 ng.day.ml-1) over the same amount of time, can you assume that the implant in group 2 has more drug left in it compared to group 1?
I have in vitro dissolution data for generic drug and I want to predict in vivo pharmacokinetics parameters, please suggest me free software tools or high quality R packages that can achieve this. Also please share suitable keywords I can use to search on this topic other than In- Vitro In Vivo Correlation (IVIVC)!
When I viewed the PK parameters of both warfarin and candesartan, I found that both medications have 99% plasma protein binding. I then went to check and confirm there will be PK interaction through resources and I was surprised when I found no interaction! So can it be? Any explanation?
Is there any reference/Book/Software that shows only the pharmacokinetic parameters of all medications available? For example, if I want to know the absorption, metabolism of acetaminophen, I should open the monograph in this reference and see all the information I need, the same goes for omeprazole, cetirizine, any medication. Is there such a resource/reference?
I appreciate your comments on the topic above.
Attached is an abstract which suggests the existence of an arteriovenous concentration difference, and that 'peak venous plasma concentrations generally occurred at 1 to 5 minutes after injection'. The abstract also states that 'the plasma concentration-time profile after an intravenous blous injection actually resembles that predicted for a short term intervenous infusion'. Is that your experience?
If someone has been taking Candesartan 4 mg one tablet daily for a year and want to take Diclofenac 25 mg for occassional pain, How can I eliminate the interaction between both (Aside from monitoring blood pressure and renal function)? Is there a way where I can separate the interaction. I read that half life of diclofenac is 2 hours so can he take Candesartan after 2 hours from ingesting Diclofenac or it (Candesartan) already in the blood as he has been taking it for a year, so the interaction will inevitably occur?
Is it after reaching the steady state concentration (3-5days) or it may take more days to reach the maximum effect for atrial fibrillation control?
Aren't we suppose to see the peak effect after 4-5 half lives of the drug? After reaching the Css? I did view the drug monograph, and it states that the peak effect is seen after 6 hrs not after 4-5 days with once daily dosing?
Following the FDA guidance (attached file), safety of metabolites should be tested depending of its exposure at the steady state in human.
"Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug-related exposure at steady state".
My concern is about the calculation of metabolic and total drug exposure. Should I use AUC0-24h ? AUClast ? AUCinf ? Should I consider the half-life of the analytes to choose the best AUC ?
Results can differ a lot depending on what kind of AUC I use.
Thank you for your help
Isn't Css the same as the plasma therapeutic level ? Because if so, in the case of Acetaminophen, just one dose of 500 mg would reach the Css, and there would be no need for 4-5 half life ?
if we want to reach the Css from one dose(Loading dose), we will use this equation Dose (Oral)=Vd*Css divided by the Bioavailability. Here are the info. The volume of distribution is about 70 L for someone who weigh 70 K.g and the oral bioavailability is about 70%, and the therapeutic level is 10 to 20 mcg/mL so a simple calculation would yield 500 mg to be the dose which is common in practice. So, how is this possible ? Aren't we suppose to reach the Css after 4-5 half life, not just from one dose ? Am I getting this right ? Or there is a difference between the therapeutic level and the Css ?
Will they have the same magnitude of therapeutic effect ? Or do I have to check for bioequivalence studies before choosing the brand name ?
Do all drugs need to achieve the steady state concentration after 4-5 half life in order to see the therapeutic effect ? Doesn't ibuprofen produce its effect from a single dose without 4-5 half life ?
Take this example (Bisoprolol is the mentioned example ) : assuming that 5 mg is the minimum effective dose
dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. So 5 mg dose will give a range of concentrations that are therapeutically active ranging from 16 ng/ml to 8 ng/ml , etc.. So how they are equating both terms minimum effective and minimum effective concentration although 5 mg will give a range of concentrations that will be active not like mec which is below which no activity ?
Lets say drug X and drug Y possess the same active ingredient and dose...So my Q is, can all the brand names in the market be used as alternatives to each other with no worries of bioavailability ? or Brand names didn't undergo bioequivalence studies ?
According to the attached image, no therapeutic window is there with regard to diclofenac potassium, because the maximum tolerated dose ( 150 mg/day PO ) is the same as the minimum effective dose ( 50 mg PO 3 to 4 times daily. ) for pain management?
Or there is something I miss, and the minimum effective dose isn't 150 mg (50 three times per day)?
And I have another Q, if there is hepatic impairment, it is said to initiate therapy at the lowest dose, so isn't 50 mg (3 times per day) the lowest dose possible with regard to pain management?
When modelling parent and metabolite pharmacokinetics it's assumed that the volume of distribution of the metabolite is same as that of the parent drug. Why this assumption?
I am testing a new compound on colorectal cancer cell lines and I want to compare it's efficacy with the standard drug utilized in the treatment, which is the 5-FU. What concentrations should I use? I am using plasmatic concentrations found in blood samples collected from patients in treatment 2-3 hours after the infusion, are those concentrations considered clinically relevant?
Thanks in advance.
I tried to measure my drug sunitinib 0.1mg/kg (0.07mM)samples in mice plasma and used an internal stranded verapamil 50nM and made a calibration standreds from 1nM to 3000nM but the problem is in some samples I GOT NO peaks and also the intercept was negative so please can you help me in addressing the problem
From Pharmaceutical point of view: Could it be possible to have liposomal form of certain protein to be delivered to the brain or not? What is the practical issues related to developing this?
Can we guarantee a 100% of drug protein delivery through BBB?
We have started our research on TPMT phenotyping in Azerbaijani population. Alongside with Red blood cell TPMT activity we also perform quantitative determination of TPMT concentrations in serum. There is very short information on quantitaive testing of TPMT concentrations in the litearture. We would be grateful if anybody could provide information about prior experience or report with the aforementioned method.
I'm working with a compound and wanted to determine how much of that parent compound is excreted (unchanged) trough urine and feces after the oral administration. I found some articles have done this work but haven't mentioned the methodology.
If you have any experience and suggestions, please share.
I am purifying my mushroom using Anion exchange Column DEAE Sephadex A50. The problem is that when I elute it with 1 M NaCl, the column is compressed. I am not sure if this is normal or should I do something about it.
Although I am in start of developing protocol but i feel that I might be getting some resin in my product (not sure why my product weigh more as if its actually resin or I haven't completely dried it). I am using Dithenolamine as a buffer (PH=8.4)
If I am getting resin at this stage and I run a LH-20 Size exlusion column of the semi-purified product, Can I get rid of my resin as my resin will weigh far less than my targeted polysaccharide and/or protein complexes.
The old version of Winnonlin is not working on my computer. I need it urgently to analyze my data to complete within a due date. If anyone has an idea of downloading the Winonlin software (trial version or free download), please help me.
I realize that Bitartrate is considerably larger that HCl but would this affect the efficacy of a topical gel? I've tried to find case studies comparing the two salt forms but without any luck. Initial thoughts are the large salt may take longer to absorb through the skin or it could somehow be interfering with the interaction between Epinephrine and adrenergic receptors. Any thoughts, references, or insights would be greatly appreciated.
Hi all, i'll try and keep this short as i can. i have been undertaking an honours project for the past 5 weeks about determining cyp3a4 degradration via mRNA suppression. I have derived a half life value but i want to know how this value and those mentioned previously in literature regarding cyp3a4 can be important for patients as a predictor of drug-drug interactions and clinically. Many thanks for helping.
I want to compare Bioequivalence of test IR and test MR formulation with IR reference formulation. Is it possible to compare both test formulation with reference formulation in single study. ???
I have repeated my assay to assess for synergy multiple times, and after plotting the median effect plot, I have calculated the m values and Dm values for both single agents and combination. From this I have calculated the CI values and have plotted the combination index plot. However, each repeat gets slightly different m and Dm values which affects the combination index plots. How can I take my repeats into consideration? I would like to get the mean result from my repeats. I have thought about taking the mean m and Dm values and generating a combination index plot from the mean values, will this be ok?
There are several books talking about Phase I clinical trials establish that this type of clinical trial must be brought in healthy volunteers. Nevertheless, the are clinical trials reports that were carried out with patients... Are there both alternatives correct?
Thanks in advance.
Most people involved in clinical pharmacokinetics are familiar with the 80-125% criterion. This criterion is used to compare two treatments with the purpose of evaluating if the treatments are bioequivalent. But, where did this come from? Why 80-125%? Why not 90-110%? or why not 80-120%?
I like to follow the microscopic mass balance approach for predicting intestinal absorption. Three dimensionless numbers viz., dose number, absorption number, and dissolution number can be calculated with the appropriate parameters. Then these dimensionless numbers can be substituted in the differential equations and it can be solved together.
I found an article published in Springer, AAPS PharmSciTech (attached).
I followed the same values and try to solve with R program, I can't able to solve (Authors used Matlab to solve the differential equations). Please give an idea to solve these differential equations.
if the same drug is given by subcutaneous and intramuscular route, which one would be absorbed faster?
reach faster Tmax?
Hello There, I have been doing some researches through my post- graduate students looking at the effect of some medicinal herb with (and without) the exciting medicines using for Acute Lymphocytic Leukemia (ALL) treatment such as Vincristine on some ALL cell lines. My question is how can we convert or calculate the treatment dose of medicine (for instance Vincristine, which is taken as mg/m2 in adults or mg/kg in pediatrics) to nano molar of Vincristine/mm3 for cell culture? Indeed, how much of this medicine, Vincrictine per body weight or surface equals with the amount of Vincristine per one mm3 of cell culture? Because we have been looking for the optimum dose of Vincristine in cell culture after adding the medicine in ALL-cell lines, which should not be more than therapeutic dosage in clinic.
Could somebody with expertise in methods of drug administration point me in the right direction? I'm working with a new polymer which can be customized to degrade in different pH environments along the GI tract, and I was wondering about the challenges faced/applications of current technologies. I can't find much information on pH-sensitive hard shell capsule materials other than hypromellose. Is this a beneficial property? Can it be used for site-specific drug targeting etc?
Any feedback is much appreciated!
I consulted three elderly patients who used eye drop with dexamethasone after cataract surgery. On the 3rd-4th day there was a significant increase of blood pressure compared with the pre-operative period. Is it possible to reduce the dose for this category of patients?
In fact, elderly patients are at increased risk of adverse events due to atypical antipsychotic drugs because of age-related changes in pharmacokinetics and pharmacodynamics and current medical conditions, polypharmacy, and potential drug interactions. US Food and Drug Administration black box warnings have clearly shown the potential risks of their use (eg, cerebrovascular accidents, risk of sudden death). Furthermore, metabolic adverse events are extremely dangerous. They are probably linked to an increase in adiposity associated with a variety of adverse physiological effects, including a decrease in insulin sensitivity and changes in plasma glucose and lipid levels.
So, whom could share great experience on this issue?
Many physiological factors affect and alter drug absorption from the g.i. tract. Ionization, the conc. of free and bound drug, solubility, formulation etc. But isn't it true that more there is free unionized unbound portion of a drug available, more of it is rapidly metabolized and exerts its toxicity? Plasma protein binding reduces the free concentration of drug. If more of the active ingredient (herein drug) is present unbound to plasma protein (in free state), does it mean that a much greater amount of it will be rapidly absorbed from the gastrointestinal tract? But why this is reverse in the case with unionized drugs?
We want to improve bioavailability of plant based lipophilic compound. Please let me know various pharmacological mechanism to improve kinetics.
Whats the difference between erythromycin base, erythromycin ethyl succinate and erythromycin estolate ? Why does estolate form cause hepatotoxicity in pregnancy while the other two forms are considered safe ?
Paracetamol suppositories made with PEG 4000 and PEG 6000 as suppository bases undergo dissolution test. After 45 minutes, both batches have mean % of drug release that is higher than 100%.
PEG 4000- 150% and PEG 6000- 120%
Why does the cumulative drug release exceed 100%? Is there error during measuring of absorbance or is it some form of degradation or hydrolysis of the medicine during manufacture/storage?
We have designed and synthesized a number of prodrugs for commonly used drugs and looking for a place to conduct toxicity tests for these novel compounds.
Can anybody suggest online free tools or downloadable software for the prediction of ADMET parameters of drugs?
I've seeking any peer-reviewed research re: the bio-availability of crystalline methylamphetamine when vaporised and inhaled. There is a lot of grey literature that claims more than 60% or more than 90% of the dose is absorbed into the bloodstream when it is smoked (by someone who knows how to do it properly), and I am not questioning the veracity of this information, however a quick scholar search hasn't yielded any research that actually quantifies bio-availability via this route of administration. If you’re aware of any relevant published research I would be very grateful…
I am performing pre-clinical studies in order to develop a novel cancer vaccine. However, I need to get a cell line approved for use as as cell substrate to manufacture my vaccine. Approvals should meet Health Canada specifications. Any resources or details would be greatly appreciated.
Are there any studies which have used the mother as the mode of drug delivery via breast milk?
How would one go about to determine the amount of drug to administer to the mother to reach the litter?
Krishna et al. 2013 provide a review where they present a formula to calculate human inflant exposure to drug:
The maternal plasma concentration of drug (Cmaternal), area under the concentration-time curves (AUC) of the drug in maternal milk and plasma (M/P AUC) ratio and the volume of milk ingested by the infant (Vinfant):
Dose of infant (mg/kg/day) = Cmaternal (mg/L) x M/PAUC x Vinfant (L/kg/day)
Is this model valid to use in a murine system?
Moreover, is there a model or formula to calculate how much drug would the mother need to ingest (systemic administration through first pass metabolism) to achieve the target dose for an infant?
Reviews, original research papers as references or any interjections/insights are much appreciated.
In order to attain our goal we have main stage:
Development of therapeutic local action drug forms for skin and nail mycoses and vaginal candidoses and in vitro bio-pharmaceutical study of them; micro-biological studies within the system “ointment-fungous strain” and “suppository-fungous strain”.
I want to do a pharmacokinetic study for oral administration of a compound. I calculated conc. vs time. I'm using R program with PK package for non compartmental analysis. With the batch design, I could get the pharmacokinetic parameters like,
- AUC to tlast (μg h ml-1)
- AUC to infinity
- AUMC to infinity
- Mean residence time
- non-compartmental half-life
- Volume of distribution at steady state
I have not performed intravenous route for calculation bioavailability F. In the above the parameters what can be used for oral administration. Somewhere I read clearance and volume of distribution can't be considered for oral administration. Further could some one help me to get the Cmax, Tmax with R program. I'm using Linux OS, R program only suits for me. I can't purchase Gastroplus, Kinetica, and other user friendly softwares.
If a patient has a penytoin level of 15mg/L and has a Albumin level of 15g/L. He is showing signs of toxicities.
If the average albumin level is 35-50g/L.
What would be the corrected phenytoin level?
My collegue thinks its 37mg/L but surely thats way above the therapeutic range? Thats why im confused, can I have an explanation?
Does anybody have the pharmacokinetic data that reflects the drug absorption time in mice after oral administration ? Such as 2 hr or 3 hr. In my case the drug that is impermeable to the BBB was orally pre-treated 1 hr before MCAo surgery but the drug still showed the neuroprotective effect. So at this case how can I discuss the result? If the drug absorption time is about 2 hr then we can say BBB rupture and drug is penetrating the brain, or does the drug has indirect neroprotective effect?
A new class of cholesterol drugs - the PCSK9 inhibitors - might reduce the risk of heart attacks and strokes, and some trials were recently presented demonstrating these evidences, but we do not have large populacional studies really showing it? What do you think? Is longer the time for regulatory agencies release this group of medications for regular use of the population?
I had read many articles which worked on pharmakinetic of a drug. In many of them, they stated that they use computer program 3P97 to calculate the half life and ...
I really appreciated if you help me.
I need some information about computer program 3P97 Pharmaceutical Kinetics Software.
What are these parameters?
C = Ae^−αt+ Be^−βt.
Do you know where I can obtain it?
Is it free?
When we review the literature we find many different values used, and none disclose where and how they got the A and E values they employ, or why the value they use is different from others. References appreciated.
Almitrine-Raubasine combination effectively increases both arterial oxygen partial pressure and it is known as effective O2 supplier. However, what is the actual mechanism of these two components separately or in combination.
I will highly appreciate your suggestion on this regard. (Pathophysiology, pharmacology, pharmacokinetics ......etc....)
I successfully implemented a two-compartment (gut-blood) mathematical model for a single oral dose (20 mg/kg) to simulate the SWCNT distribution in the blood using intestinal absorption constant (Ka = 0.033 min^-1/1.98 hrs^-1), volume of distribution ((Vd = D/C0), experimentally determined), and volume of the gut compartment (V1 = 82.5 ml/kg). The methodology might be further applied to build the two-compartment (peritoneum-blood) PBPK model for a single i.p. drug injection if the peritoneum-blood permeation constant is established.
I try to analyze a PK study that we've conducted in mice. Since I don't expect the concentrations in the plasma to be very high, I have to increase sensitivity of my detection system. I am using a Micromass quattro micro MS with ESI interface.
The problem is, that I "see" peaks down to 100ng/mL in SIR as well as MRM mode. But below this concentration it's getting hard. My idea was to do a derivatization of the keto function. But somehow nothing seems to work.
Does anyone have an idea what I could try?
Should a drug in liquid form (Geraniol) be first dissolved in solvent (DMSO/Ethanol) then diluted in media or directly added to media to make different concentrations for an MTT assay? Geraniol directly used in media is showing no effect .
What is the most used technique to calculate chemotherapy dosage? What are emerging techniques, including their pros and cons? Can anybody give me a pointer to reference documents?
Pre-clinical drug-drug interaction (DDI) assessment using in-vivo animal models along with in-vitro human systems based assays, aids in early prediction of clinical interactions possibilities and may help to prevent late phase failure of drug in clinic.
But DMEs and transporters of animals vary remarkably from humans, thus limiting their use for clinical predictions. Owing to these limitations "humanized" animal models are developed, which serves as a better model for prediction of metabolism and potential DDI in humans.
Apart from these humanized animal models what are other pre-clinical novel methodologies which are used for investigating/ predicting clinical DDI?
I am looking for the release parameters of Microtrol beads for Adderall XR so that I may include absorption rate or rate constants in a pharmacokinetic model of Adderall XR. Can you describe the kinetics or provide references?