Case Studies
Problem:
A client was developing a potent drug candidate, which showed low maximum plasma concentration and marginal bioavailability after oral dosing despite a very long half-life. The project team had explored a number of formulation strategies, none of which led to a better pharmacokinetic profile.
Solution:
TSRL conducted comprehensive mechanistic absorption studies in rats, which revealed the involvement of a saturable, carrier-mediated absorption process that posed a limit to the overall absorption rate even with increasing doses. The compound underwent significant entero-hepatic recycling, which resulted in the long terminal half-life and flip-flop pharmacokinetics. The client chose to discontinue the lead candidate and TSRL screened a number of back-up compounds for their absorption characteristics, one of which was taken forward and is moving towards NDA filing.
Problem:
Another client approached TSRL with a soon-to-be-marketed amino acid prodrug of an antiviral agent with a concern that the compound may utilize a carrier-mediated absorption pathway, that could result in drug-drug interactions at the absorption level.
Solution:
TSRL conclusively demonstrated linear absorption pharmacokinetics over a 1000-fold concentration range in the relevant dosing window. Furthermore, we showed that there was no interaction at the absorption level with any of the common concomitant medications commonly administered to the targeted patient population.
Problem:
A generic company was struggling with achieving clinical bioequivalence (BE) between an innovator and their generic controlled-release drug product despite matching in vitro dissolution profiles. They initially approached TSRL to request consultative input on additional formulation strategies they should consider.
Solution:
A careful review of the existing data on the therapeutic revealed that it underwent significant metabolism via a pathway that exhibits genetic polymorphism. This resulted in an in vivo pharmacokinetic profile of such great variability that theoretically BE would be only possible to demonstrate with very large numbers of patients per treatment group. Prior to investing in such a study, the company wanted to have greater assurance that a given formulation would show BE in vivo. Therefore a pilot study was recommended with six patients per cohort in prescreened slow-metabolizers of the drug candidate, resulting in bioequivalence between the innovator and generic product.
Problem:
Bioequivalance (BE) studies with an active ingredient that is highly metabolized and/or prescribed for cancer treatment for ANDA submissions can be cost prohibitive. Phase I BE trials for cancer compounds require testing in patients as opposed to healthy subjects, and enrollment for this patient population can be extremely time consuming.
Solution:
TSRL successfully contributed to a number to BCS biowaivers for cancer therapeutics, some of which, in addition to extensive metabolism also exhibited some level of instability in the gastro-intestinal environment. Careful assessment of the pH-stability profile under permeability study conditions provided the scientific rational for a high permeability classification of the active ingredient and ultimately led to a successful BCS biowaiver application.
BCS Strategy: TSRL successfully submitted a full BCS biowaiver application for an oral combination product which had to be reformulated due to long term shelf-life issues. Testing of the reformulated combination product in bioequivalence trials would have likely been cost prohibitive for the client. However, the successful application of a BCS biowaiver strategy allowed our client to file their NDA with minimal delays.
Problem:
Oral delivery continues to be a challenging field for many promising biologic drugs.
Solution:
TSRL offers a series of sophisticated preclinical absorption models to clients which allow for mechanistic assessment of the rate-limiting steps during oral drug absorption. Intestinal perfusion studies with simultaneous mesenteric blood collection represent an elegant way to assess absorption rate constants, draw conclusions about gut wall first-pass metabolism, and investigate the influence of formulation excipients. We have successfully applied this technique to the optimization of an oral parathyroid hormone (PTH) formulation, where we screened a number of stability and absorption enhancing excipients to maximize appearance of the hormone in the mesenteric blood circulation.