Bioanalysis of tucatinib and metabolite, and a five-way cross-validation to support clinical pharmacokinetic analysis.

Tucatinib, a tyrosine kinase inhibitor of HER2, is approved in multiple regions for metastatic breast cancer and is being evaluated in metastatic colorectal and gastric cancers. During clinical development, quantification of tucatinib plasma concentrations for pharmacokinetic analysis was performed using MS/MS analysis by three laboratories using five different methods. Cross-validation was required to confirm data across laboratories were comparable. A five-way cross-validation procedure was developed where bioanalysis performed by one laboratory and method was used as a 'base' against which the other methods were validated. This cross-validation method provides an alternative to multiple head-to-head comparisons between two methods, and enabled combination of data from multiple tucatinib clinical trials for a single population pharmacokinetic analysis.

A five-way cross-validation approach was successfully used to compare pharmacokinetic samples, tested using five different methods over twelve clinical trials, allowing combination of data and avoiding the need for multiple head-to-head method comparisons.

In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo.

The purpose of the current investigation was to optimize an intranasal (IN) galantamine (an acetylcholinesterase inhibitor used for treatment of Alzheimer's disease) formulation using an in vitro tissue model, to correlate those results to in vivo bioavailability, and to compare emetic response to oral dosing. A design-of-experiments (DOE) based formulation screening employing an in vitro tissue model of human nasal epithelium was used to assess drug permeability, tight junction modulation, and cellular toxicity. In vivo studies in rats compared pharmacokinetic (PK) profiles of different formulations dosed intranasally. Finally, studies in ferrets evaluated PK and gastrointestinal (GI) related side effects of oral compared to nasal dosage forms. Galantamine permeation was enhanced without increasing cytotoxicity. Pharmacokinetic testing in rats confirmed the improved drug bioavailability and demonstrated an in vitro-in vivo correlation. Compared to oral dosing, IN galantamine resulted in a dramatically lowered incidence of GI-related side effects, e.g., retching and emesis. These findings illustrate that IN delivery represents an attractive alternative to oral dosing for this important Alzheimer's disease therapeutic. To our knowledge, the data herein represent the first direct confirmation of reducing GI-related side effects for IN galantamine compared to oral dosing.

Development of a novel high-concentration galantamine formulation suitable for intranasal delivery.

The goal of the current study was to develop an intranasal (IN) formulation of the acetylcholinesterase inhibitor galantamine, an important therapeutic for treating Alzheimer's disease. To allow for delivering a therapeutically relevant dose, it was necessary to greatly enhance drug solubility. Various approaches were examined to this end, including adding co-solvents, cyclodextrins, and counterion exchange. Of these, the latter, for example, replacement of bromide ion with lactate or gluconate, resulted in a dramatic drug solubility increase, more than 12-fold. NMR confirmed the molecular structure of new drug salt forms. An in vitro epithelial tissue model was used to assess drug permeability and cellular toxicity. In vitro, galantamine lactate formulations performed as well as or better than their hydrobromide (HBr) counterparts with respect to drug permeation across the epithelial membrane with minimal toxicity. In vivo studies in rats compared pharmacokinetic (PK) profiles of different formulations. The in vivo studies confirmed that IN galantamine achieves systemic blood levels comparable to those of conventional oral administration. Both the in vitro and in vivo data support the feasibility of IN administration of this important drug.