A limited sampling strategy for estimation of the cladribine plasma area under the concentration versus time curve after intermittent i.v. infusion, s.c. injection, and oral administration.

Abstract

Cladribine is a newly developed antimetabolite with promising activity in lymphoproliferative disorders. Recent pharmacokinetics investigations have suggested that there is a relationship between its plasma area under the concentration versus time curve (AUC) and the degree of neutropenia posttreatment as well as the therapeutic outcome in hairy-cell leukemia. To enable a simple estimation of the plasma AUC, a limited sampling strategy was developed. Stepwise linear regression was used to determine which were the most important data points for estimation of the plasma AUC after 2-h i.v. infusion, s.c. injection (5 mg/m2), and oral administration (10 mg/m2) in 27 patients. The most important data points after i.v. infusion in 12 patients were 1, 4, and 24 h, in order of importance. The AUC could be estimated as 2.9081 x C1h + 5.1851 x C4h + 20.3265 x C24h. The accuracy and precision (mean value +/- SD for the determined/estimated AUC was 0.99 +/- 0.053) of the model could not be increased by the addition of more data points. A somewhat lower accuracy and precision (0.96 +/- 0.089) was seen with the 2-, 4-, and 24-h data points. These were used to test the regression technique prospectively for the estimation of the AUC after i.v. administration in another set of 10 patients. The accuracy and precision of the estimation of the AUC was similar in this group (1.01 +/- 0.109). In all, 11 patients were treated orally (10 mg/m2) and 10 patients were treated by s.c. injection (5 mg/m2). The most important data points for estimation of the AUC were 2.5, 24, and 0.5 h after oral administration (AUC = 0.8630 x C0.5h + 4.2337 x C2.5h + 45.4364 x C24h) and 9, 1, and 16 h after s.c. injection (AUC = 1.8821 x C1h + 16.4256 x C9h + 25.4518 x C16h). The accuracy and precision were 1.01 +/- 0.064 after oral dosing and 0.99 +/- 0.11 after s.c. injection. The derived mathematical models are reliable for estimation of the plasma AUC of cladribine after 2-h i.v. infusion, oral administration, and s.c. injection.