Gene expression profiling as a novel approach for justifying fixed drug combination products

Introduction: Combinations of drugs are common in many indications. But despite their established positive effects with regard to compliance, the number of available fixed combination products is comparatively small.

Aim: The regulatory rules of FDA and EMA for the justification of fixed combination products are based up to now on the theses of Crout from 1974 [1].

Methods: Therefore an overview of the present state of scientific approaches in this field is given.

Results: The equivalence or superiority of combinations, in comparison to the combination partners, is shown in studies with several arms, as the Vishnu- or the Diener study [2, 3]. In contrast, gene expression profiling allows a description of the pharmacological profile of the combination in comparison to the combination partners. According to this, the profile of the combination is different to that of the partners and the risk profile can be more favourable compared to that of the partners [4].

Discussion: A combination is, according to the equation 1 + 1 ≠ 2, a completely new active substance with an own pharmacological profile [4]. Instead of the combination partners [1], therefore the standard therapy in the indication should be used in comparison studies, as in other new active substances.

Dedication: This contribution is dedicated to Prof. Dr. Dr. h.c. mult. Hildebert Wagner, who has described in a multitude of scientific contributions the multi-target effect of multi-drug-combinations.

Keywords: Synergism, fixed combination, clinical efficacy, pharmacology, Gene expression profiling, herbal medicineal product, EMA, FDA

References:

[1] Crout J: Fixed combination prescription drugs: FDA policy. J Clin Pharmacol 1974; 14:249.

[2] Eckles R and Voelker M: Analgesic and decongestant efficacy of the combination of aspirin with pseudoephedrine in patients with symptoms of upper respiratory tract infection (Vishnu Study). Clin Pharm Drug Dev 2014; 3:118 – 125. doi: 10.1002/cpdd.39

[3] Diener HC, Pfaffenrath V, Pageler L, Peil H, Aicher B: The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. Cephalgia 2005; 25:776 – 787.

[4] Ulrich-Merzenich, G., Koptina, A., Kelber, O., Freischmidt, A., Heilmann, J., Müller, J., Sadeghlar, F., Zeitler, H., Wagner, H: Prediction of adverse events by in vivo gene expression profiling exemplified for phytopharmaceuticals containing salicylates and the antidepressant imipramine. Phytomedicine 2012; 19:322 – 329.