Kabir Soeny (1), Barbara Bogacka (1), Byron Jones (2), and Thomas Bouillon (2)
(1) Queen Mary, University of London ; (2) Novartis Pharma AG, Basel, Switzerland(2)
Objectives: Nowadays, regulatory authorities actively challenge the dose regimens suggested by the industry, usually by stating that the doses are unnecessarily high and leave the burden of proof with the company applying for the approval [1]. The dose regimen which minimizes the under- and over-exposure around the target concentration maximizes efficacy and safety, resulting in increased chances of a successful approval. For some indications (HIV, Malaria, Tuberculosis), combination therapies are mandatory to prevent the spread and/or development of resistance to the single components of the regimen and should be enforced. Therefore, it is crucial that the optimal dose ratio has been identified during the development process and has been taken forward for approval. In this paper we present a novel algorithm for optimization of loading and maintenance doses of single drugs and its extension to include the optimization of the ratio of drugs for a fixed dose combination.
We developed a general theory for dose regimens which minimize the under-and over-exposure around the target concentration. We developed the ‘Efficient Dosing algorithm’ (programmed in MatLab) for computation of such dose regimens. It is an iterative algorithm such that in each iteration, the dose regimen at the current iteration moves towards the optimum dose regimen. The algorithm converges when no further minimization is possible. We extend the algorithm for the case of combination therapies such that we determine not only the optimum dose regimen to be followed, but also the optimum ratio in which the drugs should be mixed in a dosing unit.
We applied our algorithm on the anti-malarial drug Coartem. Coartem is made up of Artemether and Lumefantrine in the ratio of 1:6. We applied our algorithm to optimize the dose regimen and the combination ratio. We found a dose regimen and a combination ratio which could be 40% more efficient than the ones currently used. We took the pharmacokinetic parameters of the drug from [2] and [3] and assumed the targets to be 50% and 75% of the maximum concentration achieved by Artemether and Lumefantrine respectively.
References:
[1] Novartis Pharma AG. Prexige receives “not approvable” letter in the US despite being one of the most studied cox-2 inhibitors. Technical report, Media Release, http://hugin.info/134323/R/1156327/223186.pdf, 2007.
[2] Nicholas J. White, Michele Vugt, and Farka D. Ezzet. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clinical Pharmacokinetics, 37(2):105–125, 1999.
[3] F. Ezzet, M. van Vugt, F. Nosten, S. Looareesuwan, and N. J. White. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 44(3):697–704, 2000.
Reference: PAGE 23 () Abstr 3022 [www.page-meeting.org/?abstract=3022]
Poster: Methodology - Other topics