10 research outputs found
Translational Medicine Guide transforms drug development processes: the recent Merck experience.
Merck is implementing a question-based Translational Medicine Guide (TxM Guide) beginning as early as lead optimization into its stage-gate drug development process. Initial experiences with the TxM Guide, which is embedded into an integrated development plan tailored to each development program, demonstrated opportunities to improve target understanding, dose setting (i.e., therapeutic index), and patient subpopulation selection with more robust and relevant early human-based evidence, and increased use of biomarkers and simulations. The TxM Guide is also helping improve organizational learning, costs, and governance. It has also shown the need for stronger external resources for validating biomarkers, demonstrating clinical utility, tracking natural disease history, and biobanking
Translational strategies in drug development for knee osteoarthritis.
Osteoarthritis (OA) is a common disease worldwide with large unmet medical needs. To bring innovative treatments to OA patients, we at Merck have implemented a comprehensive strategy for drug candidate evaluation. We have a clear framework for decision-making in our preclinical pipeline, to design our clinical proof-of-concept trials for OA patients. We have qualified our strategy to define and refine dose and dosing regimen, for treatments administered either systemically or intra-articularly (IA). We do this through preclinical in vitro and in vivo studies, and by back-translating results from clinical studies in OA patients
Utility of in vitro systems and preclinical data for the prediction of human intestinal first-pass metabolism during drug discovery and preclinical development
A growing awareness of the risks associated with extensive intestinal metabolism has triggered an interest in developing robust methods for its quantitative assessment. This study explored the utility of intestinal S9 fractions, human liver microsomes, and recombinant cytochromes P450 to quantify CYP3A-mediated intestinal extraction in humans for a selection of marketed drugs that are predominantly metabolized by CYP3A4. A simple competing rates model is used to estimate the fraction of drug escaping gut wall metabolism (f g ) from in vitro intrinsic clearance in humans. The f g values extrapolated from the three in vitro systems used in this study, together with literature-derived f g from human intestinal microsomes, were validated against f g extracted from human in vivo pharmacokinetic (PK) profiles using a generic whole-body physiologically-based pharmacokinetic (PBPK) model. The utility of the rat as a model for human CYP3A-mediated intestinal meta bolism was also evaluated. Human f g from PBPK compares well with that from the grapefruit juice method, justifying its use for the evaluation of human in vitro systems. Predictive performance of all human in vitro systems was comparable [root mean square error (RMSE) = 0.22-0.27; n = 10]. Rat f g derived from in vivo PK profiles using PBPK has the lowest RMSE (0.19; n = 11) for the prediction of human f g for the selected compounds, most of which have a fraction absorbed close to 1. On the basis of these evaluations, the combined use of f g from human in vitro systems and rats is recommended for the estimation of CYP3A4-mediated intestinal metabolism in lead optimization and preclinical development phases
In Vitro Approach to Assess the Potential for Risk of Idiosyncratic Adverse Reactions Caused by Candidate Drugs
Idiosyncratic adverse drug reactions (IADRs) in humans
can result
in a broad range of clinically significant toxicities leading to attrition
during drug development as well as postlicensing withdrawal or labeling.
IADRs arise from both drug and patient related mechanisms and risk
factors. Drug related risk factors, resulting from parent compound
or metabolites, may involve multiple contributory mechanisms including
organelle toxicity, effects related to compound disposition, and/or
immune activation. In the current study, we evaluate an <i>in
vitro</i> approach, which explored both cellular effects and
covalent binding (CVB) to assess IADR risks for drug candidates using
36 drugs which caused different patterns and severities of IADRs in
humans. The cellular effects were tested in an <i>in vitro</i> Panel of five assays which quantified (1) toxicity to THLE cells
(SV40 T-antigen-immortalized human liver epithelial cells), which
do not express P450s, (2) toxicity to a THLE cell line which selectively
expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and
galactose media, which is indicative of mitochondrial injury, (4)
inhibition of the human bile salt export pump, BSEP, and (5) inhibition
of the rat multidrug resistance associated protein 2, Mrp2. In addition,
the CVB Burden was estimated by determining the CVB of radiolabeled
compound to human hepatocytes and factoring in both the maximum prescribed
daily dose and the fraction of metabolism leading to CVB. Combining
the aggregated results from the <i>in vitro</i> Panel assays
with the CVB Burden data discriminated, with high specificity (78%)
and sensitivity (100%), between 27 drugs, which had severe or marked
IADR concern, and 9 drugs, which had low IADR concern, we propose
that this integrated approach has the potential to enable selection
of drug candidates with reduced propensity to cause IADRs in humans