Pharmacokinetics (PK) Services

In Vivo Pharmacokinetics Services

Apredica offers three levels of service for the pre-GLP pharmacokinetic (PK) studies needed subsequent to the early ADMET phase of drug development:

• In-Life Phase: Full or fast pharmacokinetics services. While standard industry-accepted protocols are available, Apredica can support fully customized PK study designs. Plasma, blood, or other tissues can be collected and prepared to your specifications. All PK studies are conducted under strict IACUC guidelines in an AAALAC-approved lab and require IACUC approval.
• Bioanalytical Method Development: Bioanalytical methods can be developed for your test agent in any biological matrix. The limits of quantitation and detection as well as recovery from many matrices can be determined using our state-of-the-art LC/MS/MS analytical equipment. More about our bioanalytical methodology.
• Bioanalysis: The amount of test agent in the collected plasma or tissue is analyzed and quantified using LC/MS/MS.

Apredica provides fast turnaround and close management of pharmacokinetics projects. Contact us to learn more.

Customized In Vivo PK Studies

Contact us to discuss any special pharmacokinetics issues associated with your program. For example:

• Administration routes: PO, IV, IP, SC, TD.
• Pre-formulation needs.
• Issues with the lower limits of detection.

In Vitro Pharmacokinetics Services

Apredica supports in vivo PK studies with a range of in vitro PK assays which help prioritize compounds for in vivo pharmacokinetics studies, as well as help interpret PK results, including:

• Hemolysis
• In vitro metabolism assays
• Plasma Protein Binding
• In vitro permeability: Caco-2, MDCK, PAMPA
• Red Blood Cell Partitioning

Contact us to discuss what in vitro pharmacokinetics assays are appropriate for your program.

Principles of Pharmacokinetics

Pharmacokinetics (PK) describes what the body does to a drug. PK is dependent on the dose administered, site of administration, and physiological state of the organism. A typical PK study involves administering a fixed amount of the drug (the dose) to the subject (human or animal) and at various times post dose, samples of an easily accessible tissue (usually blood/plasma) are drawn and collected for analysis of the drug and its metabolite concentrations. These concentration values are plotted against the sampled times then the data are mathematically analyzed to yield parameters that are associated with the disposition of the drug.

Pharmacokinetics - Purpose and Place

Pharmacokinetics studies in rodents set the stage for understanding drug action in large animals, primates, and, ultimately, humans. Species comparisons done using in vitro ADME Tox assays help plan and interpret animal PK studies. Significant species differences in metabolism exist, particularly in the liver, and need to be considered before starting in vivo PK studies. In vitro metabolism studies (e.g., liver microsomes and plasma stability) are the standard required step towards in vivo PK studies. Once metabolism differences between species are understood and optimized to the desired properties for program requirements, such as therapeutic area, patient population, method of delivery (PO, IV, TD, etc.), the choice of species needs to be considered. Normally understanding PK in the efficacy model is the logical choice. Repeating PK in the toxicity species may be recommended, too.

Apredica's ADDME^sm (Avoid Drug DevelomentDevelopment Mistakes Early) approach emphasizes the use of in vitro ADME Tox early in the discovery process to make attrition decisions before any in vivo pharmacokinetics is performed. Once your hit-to-lead and lead optimization studies narrow the series to a few compounds with desired metabolism and permeability properties, Apredica can move your program into the in vivo pharmacokinetic studies required by the various regulatory bodies such as the FDA and EMEA.

Toxicokinetics

Toxicokinetics (TK) is pharmacokinetics applied at high doses used in toxicity testing of drug candidates. Sometimes such high doses result in a saturation of kinetic (mass transfer) pathways, which can affect the PK profile.

Pharmacokinetics in Clinical Trials

As you finish your drug discovery phase and begin planning human clinical trials, it is useful to think about clinical implications to put your in vitro and in vivo PK results in perspective. Clinical and population pharmacokinetics will need to be considered.

• Clinical pharmacokinetics is pharmacokinetics applied to clinical situations and the therapeutic management of patients.
• Population pharmacokinetics is the study of the sources and correlates variability in drug concentrations among individual patients (inter- and intra- individual variability) such that, if necessary, dose adjustments can be made to offset the variability and maximize therapeutic benefit.

One can begin addressing these issues in the early preclinical phase. Understanding the need to look at differences in individuals guides in vitro metabolism studies as you start looking at individual differences in CYP-450 enzymes activity, for example. Selecting a candidate with minimal interactions with the CYP-450 enzymes that have large genetic variability will make for fewer surprises in the clinic and in the market.

Need a CRO to help guide your pharmacokinetics studies towards IND? Contact us.