Optimizing dose regimens and fixed dose combination ratios in clinical trials

ABSTRACT

Successful treatment of many diseases depends on the level of drug concentration in blood and its maintenance over a period of time around a value considered as therapeutic. The dose regimen that minimizes the underexposure and overexposure around the target concentration maximizes efficacy and safety, resulting in increased chances of a successful patient recovery. We present a method of computer-assisted dose finding by explicit optimization of a target criterion. We develop a general theory for such dose regimens and propose criteria for their computation. This approach is likely to supersede “brute force” techniques exclusively based on simulation. In case of a combination of two drugs in a single dosing unit, it is crucial that the optimal combination ratio is identified during the developmental process and is taken forward to further trials or approval. The algorithm computes the optimal ratio along with the optimal dose regimen. If the interest is in restricting the concentration profile of the drug to a therapeutic range, we adapt the algorithm to determine the optimal dose regimen. In future, this work is intended to aid the development of fixed dose combinations, especially antimalarials and other anti-infectives. The methodology also has potential applications in randomized concentration-controlled trials where adherence to the target concentration is a fundamental requirement.

KEYWORDS:

• Efficient dose regimens
• overexposure to a drug
• randomized concentration-controlled trials
• target concentration
• underexposure to a drug