An important factor in deciding the dose adjustment is the knowledge of exposure-response relationship . Delineation of no-effect boundaries, based on dose- and/or concentration-response studies would be beneficial. Once the influence of intrinsic and extrinsic factors on drug exposure has been characterized and exposure-response has been established, appropriate dose adjustments can be recommended. Guidance on special populations (hepatic, renal) and extrinsic factors (food effect, drug interactions) recommend that in the absence of exposure-response data, the employment of a standard 90% confidence interval of 80-125% for AUC and Cmax can be used. If differences for populations of interest are within these boundaries then dose adjustments are not needed. These guidances also acknowledge that "FDA recognizes that documentation that a PK parameter remains within an 80-125% no effect boundary would be very difficult given the small numbers of subjects usually entered into these studies. If a wider boundary can be supported clinically, however, it may be possible to conclude that there is no need for dose adjustment."
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