Author reply to Fujimi et al

Abstract

We appreciate the interest of Fujimi et al. in our pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Philadelphia chromosomepositive chronic myeloid leukemia (CML) [1]. In their letter to the editor, Fujimi et al. [2] described a patient with CML who, after failure of two prior tyrosine kinase inhibitors (TKIs), imatinib and dasatinib, achieved complete cytogenetic response within 15 months on nilotinib. The authors’ observation about a potential role of bile acid on the absorption of nilotinib is consistent with our knowledge that nilotinib has a low aqueous solubility and that its in vivo dissolution and absorption may be enhanced by the presence of bile salts. While we agree with the authors’ conclusion that therapeutic drug monitoring of nilotinib may be useful in particular situations, such as the case presented, such a conclusion cannot be automatically applied to the general practice of CML therapy with nilotinib for the following reasons. Our analysis was based on pharmacokinetic data from 542 patients with newly diagnosed CML, whereas the case report by Fujimi et al. concerned a CML patient who experienced failure of two prior TKI therapies. Although the pharmacokinetic profile of nilotinib is unlikely to be altered by disease status, the pharmacokinetic–pharmacodynamic relationship may differ in these patient groups. While the analysis described in our manuscript showed a lack of significant correlation between nilotinib exposure and molecular response in newly diagnosed patients with CML, we have observed that lower nilotinib trough concentration (Cmin) significantly correlated to longer time to complete cytogenetic response and major molecular response, and shorter time to progression in patients with imatinib-resistant or -intolerant CML [3]. There was also a trend toward lower response rates in patients with lower versus higher nilotinib Cmin. These results suggest that conclusions from one study population (e.g., newly diagnosed CML) can not be automatically extrapolated to another (e.g., imatinib-resistant or -intolerant CML). The interand intra-patient variability in the pharmacokinetics of a drug is attributed to several factors. Despite the lower bioavailability of nilotinib compared with imatinib and dasatinib, inter-patient pharmacokinetic variability was comparable for these three TKIs in clinical trials [32–64 % in nilotinib area under the curve (AUC), 49 % in imatinib AUC, 56 % in dasatinib peak concentration (Cmax)] [4]. In situations where physiological changes or surgical procedures are involved, or significant drug–drug interactions or patient nonadherence are suspected, wider interand/or intra-patient variability would be expected. As already discussed in our manuscript, our analysis was based on the data obtained under a well-controlled clinical trial setting. The role of blood level testing in the special circumstances that may arise in the clinic, such as those mentioned above, needs to be further defined with additional studies. The case report by Fujimi et al. illustrated one of these special circumstances. R. A. Larson University of Chicago, Chicago, IL, USA