Pharmacokinetic Modelling Services for Drug Development
Cost and time reduction are the core questions for all businesses to maximize their profits, regardless of their sizes, annual revenue, or business area. Especially, the high cost and long duration of the clinical phase of new drug development make it an obvious targeted area for time-budget management for most pharmaceutical companies. Moreover, reducing the time and cost of drug development is also beneficial to public health, as the patients can approach more treatment choices at a decent price.
A 2020 review estimated that the median capitalized research and development cost per product was $985 million (including the unsuccessful clinical trials) which ranged from $314 million to $2.8 billion. A typical innovative drug required about 9.1 years for the clinical development stage (Brown et al., 2021). This is due to the complexity of the clinical trials and the low success rate of clinical drug development, which can be up to 90% cases of failure.
To improve the success rate, Pharmacokinetic modelling and simulations have become more and more widely accepted by authorities and pharmaceutical entities to streamline drug development. This allows the sponsor to give better evidence-based “Go/No-Go” decisions. They also play as a surrogate for a human clinical trial to predict the PK/PD effect as an alternative cost-effective option.
At BioPharma Service, using Certara Phoenix (WinNonlin) Pharmacokinetic/Pharmacodynamic (PK/PD) software, our Pharmacometric team provides several Pharmacokinetic (PK) modelling and simulation options and customizing them to support your drug development plan.
Non-Compartmental and Compartmental Pharmacokinetic Analysis
Non-compartmental and compartmental Pharmacokinetics are the two common approaches to explaining a drug’s pharmacokinetics – estimated PK parameters.
The non-compartmental analysis (NCA) is a simple, fast, cost-efficient, and model-independent method. The estimated pharmacokinetic parameters from NCA exclusively depend on the algebraic equations, and the analysis results are most likely consistent from one pharmacokineticist/analyst to another.
Thus, the NCA is commonly used to describe the initial Pharmacokinetic Profiles (e.g., nonclinical PK and toxicology studies) and for simple in vivo studies with Pharmacokinetic endpoints. NCA is recommended by authorities for pharmacokinetic analysis of many comparative studies such as bioequivalence, food effect, drug-drug interaction, or dose-proportionality studies.
The compartmental analysis relies more on the model specifically used for each analysis. The method considers the human body as a combination of multiple compartments which are mixed, connected, and together impact the pharmacokinetic of the drug.
The complexity of the compartments and their interaction required certain assumptions and the model choice is somewhat subjective, which eventually increases the variability of the analysis results from one analyst to another.
However, the complexity of the compartment analysis has its advantages, such as exploring the pharmacokinetic variability due to intrinsic factors and extrinsic factors. Moreover, the outcome from this analysis can be carried out or provides more information for more complicated models establishment (e.g., simulation multiple ascending dose study, PK/PD, or PBPK models)
The minimum data to be required for NCA or compartmental pharmacokinetic analysis at BioPharma Services, including:
- Study information (e.g., study protocol, SAP, randomization scheme)
- Dataset conclusion or data for dataset determination (e.g., AEs, concomitant medication, drop-out subject, major protocol deviation)
- Raw concentration-time data (e.g., including baseline, actual collection time if required)
- Interfering factor(s) (for compartment PK, if required).
In Vitro In Vivo Correlation (IVIVC) Model
IVIVC model is a predictive model to describe the relationship between the in vitro dissolution and the in vivo absorption of an oral dosage form.
Two applications of IVIVC that were agreed upon by both FDA and EMA are
- Setting dissolution specifications for in vitro test; and
- Surrogate for clinical bioequivalence studies.
Please refer to our previous blog on this topic for more details on this interesting model. The minimum data required for a Level A IVIVC model at BioPharma Services:
- In vitro dissolution data from dissolution studies performed by sponsor/external party. At least 12 testing unit for each test formulation is required. The dissolution-time value should be presented as an individual and mean value. The CV for mean dissolution profiles of a single batch should be less than 10%.
- In vivo absorption data from clinical studies performed by BioPharma Services or sponsor. It is recommended to include test products with three different release rates: slow, medium–target, fast, and the IR reference product (as an IV solution, aqueous oral solution, or IR product)
Simulation PK data to facilitate new strength or repeated-dose dosing selection
It is recommended to use the model for planning or justifying the early phase/first-in-human dose selection based on the predicted pharmacokinetic data of the new single/repeated dose(s) on a specific dose upon the observed pharmacokinetic data from animal or lower dose(s) in human.
At BioPharma Services, we can provide the PK prediction using the Phoenix Model unit simulation function. The repeated dose can be facilitated by both ADDL or Extend SS per request. The minimum data required for this simulation:
- Investigator’s brochure or other alternative documents that provide details about the product chemistry characteristic and available pre-clinical and clinical data.
- Raw time-concentration of the dose will be used for the prediction. The study protocol and other study information that impacts the analysis.
- Target doses and dosing regimen that the sponsor wants to estimate OR stopping threshold/criteria for the simulation (e.g., the highest dose that provides Cmax less than a specific value).
Adjusted Indirect Comparison (AIC)
Different from the above pharmacokinetic models which were performed using the Certara Phoenix WinNonlin application, the AIC is a statistical analysis service that we provide for a sponsor who is looking for an indirect statistical comparison of two products using data from other clinical trials when they were compared to a different product.
“If A = B and B = C, will A = C”
This statistical analysis was widely used to indirectly compare the bioavailability among different generic products using the data from their bioequivalence (BE) studies when each generic product was compared to the reference listing product. However, this analysis can also be useful for the sponsor who wants to assess the drafting bioavailability of a new/generic product including fixed-dose combination which is considered as difficult product to be developed.
There are many reasons that a direct clinical trial to compare the new fixed-dose combination and the reference listing mono active ingredients is not feasible (e.g., the reference products are not available anymore). The AIC can be used as a surrogate to justify the absence of bioavailability drift.
Please find more information about this method from our poster will be presented at the 2022 AAPS PharmSci 360 conference: “Cost-effective strategy – An innovative approach assessing the drifting bioavailability of fixed-dose combination formulations” which will also be shared on this website after the conference presentation.
Why Choose BioPharma Services for your next Clinical Trial Protocol Development?
Above are some common and basic pharmacokinetic modelling that we can quickly perform upon clients’ request. If you are interested in other pharmacokinetic modelling or pharmacodynamic modelling and would like to discuss further to customize a model for the objective, please visit our Contact page and an expert Pharmacometric team member will be happy to discuss our capabilities with you.
BioPharma Services, Inc., a Think Research Corporation and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.