Highly variable drugs ratio

If safety data suggest a narrow therapeutic ratio, highly variable pharmacokinetics may be unacceptable and could ultimately result in a decision to discontinue the drug from development. 

A retrospective study in a 73-patient cohort showed that the addition of amiodarone, an antiarrhythmic medication, resulted in highly variable changes in warfarin dose requirements. Metabolites of amiodarone in human plasma were quantified by a liquid chromatography-electrospray ionization-tandem mass spectrometry assay, and inhibition constants (Kj) were determined for the inhibition of (S)-warfarin 7-hydroxlylation in human liver micro-somes. By calculating the ratios of unboxmd plasma concentrations to the microsomal Kj for the unbound drug, a minor metabolite of amiodarone, N,N-didesethylamiodarone, was identified as a major contributor to the interaction between amiodarone and warfarin [11 ]. 

Figure 4.52. Coefficients of variation that reflect both tablet to tablet and analytical variability. For formulation B, particularly strengths 2 and 3, the drop in CV with higher cumulative release (a - b) is marked, cf. Fig, 4.50. When the dissolution rate is high, individual differences dominate, while towards the end analytical uncertainty is all that remains. The very low CVs obtained with strength 3 of formulation A ( 0.7-0.8%, data offset by +10% for clarity) are indicative of the analytical uncertainty. Because content uniformity is harder to achieve the lower the drug-to-excipient ratio, this pattern is not unexpected.

---