The preclinical pharmacokinetics (PK) experiment is to understand the characteristics of the dynamic changes what the body does to the drugs and to provide references for clinical rational drug use. PK profiles of the drug are affected by physicochemical properties of the drug, product/formulation, administration route, and the patient's intrinsic and extrinsic factors (e.g., organ dysfunction, diseases, concomitant medications, and food). Current research mainly uses kinetic principles and mathematical models to study the dynamics of drug absorption, distribution, metabolism, and excretion over time, and to calculate PK parameters. Creative Bioarray provides comprehensive experimental technology to solve all problems from experimental design to data analysis. Our extensive expertise and experience in preclinical PK research enable our scientists to help you in every step of the drug development.

Experimental Model Screening

Rats, guinea pigs, dogs are commonly used for model screening. The preferred animals and gender should be used in pharmacodynamics or toxicology studies. Animals should be kept in the laboratory for 3-5 days before the experiment.

Pre-Testing

To evaluate the effects of the drug, it is necessary to conduct pre-tests. The contents of the pre-tests include the following parts:

  1. Determine the dose/dosing regimen to achieve the target drug exposures.
  2. Determine the concentration range of the standard curve.
  3. Determine the intravenous dose based on absolute bioavailability.
  4. Determine the dosage at three levels: mild, moderate, and severe. The selection of the dose should take into account the interaction and simulate the clinical setting to the greatest extent, with due consideration for the safety of the study population.
  5. Note: Pay attention to characteristics of the drug and determine whether it is dose-dependent and linear PK.

Absorption

One needs to collect the concentration-time data of all tested animals in the experiment separately, and calculate the PK parameters. The parameters of intravenous administration include T1/2 (half-life), Vd (volume of distribution), CL (clearance), AUC (area under the plasma concentration-time curve), and other parameters. In addition, the parameters of extravascular administration also include Tmax, Cmax, and other data that determine the law of drug absorption. Tmax represents the most appropriate time to perform safety assessments. Cmax and AUC are very important for dosage selection.

Distribution

Drugs should reach the target site(s) of action immediately in an effective/non-toxic concentration, and will not accumulate in non-target organs. The extent of drugs distribution and the amount in the body necessarily affect the compound concentration in blood and tissues, which is assessed by its volume of distribution (Vd). The following parts should be recorded:

  1. Blood sampling points: One needs to take sample blood/plasma over seven or more time points for characterize the blood/plasma concentration versus time profile of drugs.
  2. Tissue: After administration, observe the changes of the drug in the heart, liver, spleen, lung, kidney, gastrointestinal tract, gonads, brain, body fat, osseous muscles, and other tissues.
  3. Note: Pay attention to drugs are not significantly (>80 to >95%) bound to plasma proteins, and the extent of protein that binding are not concentration and time-dependent.

Drug-Protein Binding Rate

The plasma proteins that bind a compound (and its metabolites) include albumin. There are several methods for measuring the unbound fraction in plasma.

Measuring the unbound fraction in plasma: The ability of drug binding to plasma proteins is affected by many factors, such as plasma PH, plasma concentration, drug concentration. The plasma pH should be fixed at 7.4 to measure. Equilibrium dialysis and ultrafiltration are the two commonly used methods.

According to each project, single dose (if linear & time-independent PK), parallel groups, males & females with varying degrees of hepatic impairment (≥6 per group) are required in the experiment.

Excretion

As mentioned earlier, drug metabolism usually involves a chemical or enzymatic conversion of the parent compound into one or more metabolites, which are readily excreted, and the excretion is mainly facilitated by renal or biliary clearance. The body's ability to eliminate compounds is reflected by clearance (CLs). The following excrement should be recorded:

1. Bile: The sample collection needs to be taken up to 24 hours. Generally, the rats are collected by the bile duct drainage route under ether anesthesia.
2. Urine and feces: Collect the mount of urine and feces and record the time. Clearance can be estimated from the rate of excretion.
3. The main metabolic route: Calculate the excretion speed and total excretion of drug feces, urine, bile, and determine the main excretion route in the end.

Conclusion

The preclinical PK comprehensively discusses the characteristics of drugs in animals through comprehensive experimental observation. our scientists will study the design and implementation of each link in the process. For drug development, our advantage lies in: we have a strong technical team and scientific research strength, will provide satisfactory services for your project.

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